A Prospective, Randomized, Double-blind, Sham-controlled Multi-center Clinical Study Assessing the Safety and Efficacy of Nerivio for the Preventive Treatment of Migraine
Phase: NA
Conditions: Migraine
Sponsor: Theranica

 
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Approval 
 
Name 
Position 
Date 
Signature 
Revised by 
 
Maya Vizel 
Clinical Research Director 
 
 
Reviewed by 
 
Dagan Harris 
VP clinical and regulatory 
affairs 
 
 
Approved by 
 
Alon Ironi 
CEO 
 
 
Effective date of the document is from the date of approval. 
 
 
Change History 
Rev 
Rev. Date 
Revised by 
Change description and reason for change 
Training is 
required? Y/N 
1.0 
01-Feb-2021 
Maya Vizel 
Initial version 
N 
2.0 
01-Sep-2021 
Maya Vizel 
Minor changes in study efficacy endpoints and 
dataset definition, revised definition of 
migraine day, definition of a visit permitted 
timeframe, addition of study TCH004 
synopsis. Correction of grammar and typo 
errors 
 N 
3.0 
10-Mar-2022 
Maya Vizel 
Sample size increase. Adjusted definition of 
mITT set, adding exploratory endpoints 
N 
 
 
 
 
 
 

 
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CLINICAL INVESTIGATION PLAN  
STUDY TITLE:  
A prospective, Randomized, double-blind, sham-controlled multi-center 
clinical study assessing the safety and efficacy of Nerivio for the preventive 
treatment of migraine. 
 
PROTOCOL NUMBER: 
 
TCH008 
REVISION: 
 
 
3.0 
RELEASE DATE:  
 
10/March/2022 
DEVICE: 
Nerivio, a Neuromodulation device for the prevention of 
migraine 
INVESTIGATOR:    
_____________________ 
SPONSOR:  
 
 
Theranica Bio-Electronics Ltd 
4 Ha-Omanut st, Netanya, Israel 
CONTACT DETAILS: 
  
Dagan Harris, VP Clinical & Regulatory 
Tel: +972.72.390.9758 
Fax: + 972.72.390.9762 
Mobile: +972-0542220121 
EMAIL: daganh@theranica.com 
 
 
 
APPROVED BY: 
POSITION: 
DATE: (DDMMYY) 
SIGNATURE: 
 
___________ 
____________ 
  _ _ /_ _ /_ _ 
 
______________ 
___________  
____________ 
  _ _ /_ _ /_ _  
______________ 
 
 
 
 

 
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The sponsor of this study, Theranica Bioelectronics Ltd, manufacturer of the Nerivio 
device for the acute treatment of migraine, states the following: 
a) 
This study will be conducted in compliance with the protocol (after being 
approved by the local IRB/EC and, if required, by the relevant health care 
agencies), US 21 CFR Parts 50, 54, 56 and 812, 45 CFR Part 46, national laws and 
regulation concerning clinical trials, the Good Clinical Practices (GCP) set forth in 
ISO 14155 (2020) 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 for Investigator 
The signing of this Clinical Investigation Plan (CIP) by the Principal Investigator signifies that 
the contents have been laid down in full agreement and that the study will be conducted per 
this CIP, its amendments, the clinical trial agreement and the applicable regulatory 
requirements.  
 
The Principal Investigator confirms that written Institutional Review Board (IRB) Ethics 
Committee approval for the amended CIP will be obtained prior to commencing with data 
collection. This approval must be in the Principal Investigator’s name and a copy sent to 
Theranica Bioelectronics. Additionally, the Principal Investigator must sign the declaration 
below: 
 
I will provide copies of this CIP and all pertinent information to the study personnel under 
my supervision. I will discuss this material with them and ensure they are fully informed 
regarding the conduct of the Study. 
 
 
 
 
 
Investigator’s Signature 
 
Date 
 
 
 
 
 
 
 
 
 
Investigator’s Printed Name 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Site Name 
 
Site # 
 
 
 

 
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Table of contents 
1. 
Synopsis ................................................................................................................................... 8 
2. 
BACKGROUND .......................................................................................................................14 
3. 
IDENTIFICATION AND DESCRIPTION OF THE DEVICE INFORMATION ............................15 
3.1. 
Intended use ............................................................................................................................15 
3.2. 
Contraindications .....................................................................................................................15 
3.3
 .
 
Device description ...................................................................................................................16 
3.4. 
The application ........................................................................................................................16 
3.5
 .
 
Operational context .................................................................................................................17 
3.6. 
Principle of operation ...............................................................................................................18 
3.7. 
Output parameters ...................................................................................................................19 
3.8. 
Instructions for use ..................................................................................................................20 
3.9. 
Identification of the medical device ..........................................................................................20 
3.10. 
Training ...................................................................................................................................20 
4. 
PRELIMINARY INVESTIGATIONS AND JUSTIFICATION FOR THE STUDY DESIGN .........21 
4.1. 
Previous pre-clinical experience ..............................................................................................21 
4.2. 
Previous clinical experience ....................................................................................................21 
4.2.1. 
Pilot Study TCH-001 (NCT02453399) .....................................................................................22 
4.2.2. 
TCH-003 Pivotal Study (NCT03361423) .................................................................................22 
4.2.3. 
Clinical study TCH-005 (NCT04161807) .................................................................................24 
4.2.4. 
Clinical study TCH-006 (NCT04194008) .................................................................................25 
4.2.5 
Clinical study TCH-004 (NCT04089761) ............................................................... 28 
4.3. 
Clinical investigation risks and benefits ...................................................................................29 
4.3.1. 
Anticipated benefits to participants ..........................................................................................29 
4.3.2. 
Risks and adverse effects .......................................................................................................29 
4.3.3. 
Risk-benefit balance ................................................................................................................30 
5. 
OBJECTIVES & HYPOTHESES .............................................................................................30 
5.1. 
Study objectives ......................................................................................................................30 
5.2. 
Study hypothesis .....................................................................................................................30 
6. 
STUDY DESIGN......................................................................................................................31 
6.1. 
Participants ..............................................................................................................................31 
6.1.1. 
Inclusion criteria.......................................................................................................................31 
6.1.2. 
Exclusion criteria .....................................................................................................................31 
6.1.3. 
Withdrawal / Discontinuation ...................................................................................................31 
6.2. 
Stimulation program ................................................................................................................32 
6.3. 
Procedures ..............................................................................................................................32 
6.3.1
 .
 
Study duration .........................................................................................................................36 

 
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6.4. 
Study endpoints .......................................................................................................................36 
6.4.1. 
Primary efficacy endpoint ........................................................................................................36 
6.4.2. 
Secondary efficacy endpoints ..................................................................................................36 
6.4.3. 
Exploratory efficacy endpoints .................................................................................................37 
6.4.4. 
Safety endpoints ......................................................................................................................38 
6.5
 .
 
Methods and timing of assessing and analysing variables ......................................................38 
6.7. 
Data management ...................................................................................................................39 
6.8. 
Monitoring plan ........................................................................................................................40 
7. 
STATISTICAL CONSIDERATIONS.........................................................................................41 
7.1. 
Study design and aim ..............................................................................................................41 
7.2. 
Endpoints ................................................................................................................................41 
7.2.1. 
Primary efficacy endpoint ........................................................................................................41 
7.2.2. 
Secondary efficacy endpoints ..................................................................................................41 
7.2.3. 
Exploratory efficacy endpoints .................................................................................................42 
7.2.4. 
Safety endpoints ......................................................................................................................43 
7.3. 
Statistical hypothesis ...............................................................................................................43 
7.4. 
Sample size .............................................................................................................................43 
7.5. 
Analysis sets ...........................................................................................................................43 
7.6. 
Statistical analysis ...................................................................................................................44 
7.6.1. 
General considerations ............................................................................................................44 
7.6.2. 
Demographic and other baseline variables .............................................................................44 
7.6.3. 
Efficacy analysis ......................................................................................................................44 
7.6.4. 
Safety analysis ........................................................................................................................44 
7.6.5. 
Treatment by sites interaction .................................................................................................45 
7.6.6. 
Handling of missing data .........................................................................................................45 
7.6.7. 
Interim analysis........................................................................................................................45 
7.6.7.1. Procedure ...............................................................................................................................45 
7.6.7.2. Blinding ..................................................................................................................................46 
7.7. 
Randomization.........................................................................................................................46 
7.8. 
Blinding ....................................................................................................................................46 
8. 
DATA MANAGEMENT ............................................................................................................47 
8.1. 
Data capture ............................................................................................................................47 
8.1.1. 
Direct data entry ......................................................................................................................47 
8.2. 
Data quality assurance ............................................................................................................47 
8.3. 
Electronic signatures ...............................................................................................................47 
8.4. 
Verification, validation and securing of electronic data capture system ...................................48 
8.5. 
Records and data retention .....................................................................................................48 

 
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8.6. 
Other aspects of clinical quality assurance ..............................................................................48 
9. 
AMENDMENTS AND DEVIATIONS FROM THE PROTOCOL ...............................................49 
9.1. 
Protocol amendments ..............................................................................................................49 
9.2. 
Protocol deviations ..................................................................................................................49 
9.3. 
Procedures for recording, reporting and analysing protocol deviations ...................................49 
9.4. 
Notification requirement and timelines .....................................................................................50 
10. 
DEVICE ACCOUNTABILITY ...................................................................................................50 
11. 
INFORMED CONSENT PROCESS ........................................................................................51 
12. 
ADVERSE EVENTS ................................................................................................................51 
12.1. 
Characteristics of AEs .............................................................................................................52 
12.2. 
Reporting of AEs and SAEs ....................................................................................................53 
12.3. 
Anticipated device-related AEs ................................................................................................53 
12.4. 
Device malfunction ..................................................................................................................53 
13. 
EARLY TERMINATION ...........................................................................................................54 
13.1 
Criteria and procedures ......................................................................................... 54 
13.2 
Requirements for patient follow-up in case of withdrawal ................................ 54 
14. 
PUBLICATION POLICY ..........................................................................................................54 
15. 
PATIENT CONFIDENTIALITY & DATA PROTECTION ..........................................................54 
16. 
GUIDELINES AND APPLICABLE DOCUMENTS ...................................................................55 
17. 
REFERENCE ..........................................................................................................................56 
 
 
 

 
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1. 
Synopsis 
Title 
A prospective, randomized, double-blind, sham-controlled multi-center clinical 
study assessing the safety and efficacy of Nerivio for the preventive treatment of 
migraine. 
Investigational 
Device 
Nerivio is an FDA-approved remote electrical neuromodulation (REN) device for 
the acute treatment of migraine with or without aura. Nerivio delivers 
transcutaneous electrical stimulation to the upper arm to induce conditioned pain 
modulation (CPM) that activates a descending endogenous analgesic 
mechanism. The treatment is self-administered and controlled by a smartphone 
application. The study will assess Nerivio for the preventive treatment of 
migraine using a 45-minute treatment given every other day.  
Objectives 
To evaluate the safety and efficacy of Nerivio for migraine preventive treatment. 
Participant 
Population 
Adults (18-75) meeting the International Headache Society criteria (ICHD-3) for 
migraine with or without aura, with 6-24 headache days per 28-day period and at 
least 4 days fulfilling ICHD-3 criteria for migraine without aura (code 1.1; C and 
D) or with aura (code 1.2; B and C), probable migraine, or requiring the use of 
triptans or ergot derivatives. 
Sample size 
Up to 375 participants  
Inclusion Criteria 
 
1. Age 18-75 years old 
2. Must have at least a 6-month history of headaches that meet the ICHD-3 
diagnostic criteria for migraine with or without aura, either chronic or non-
chronic migraine.   
3. History of 6 to 24 headache days per 28-day period for each of the 3 months 
preceding study enrolment (based on patient report). 
4. Subjects on prophylactic migraine treatment are permitted to remain on 1 
medication with possible migraine-prophylactic effects if the dose has been 
stable for at least 2 months prior to the screening visit, and the dose is not 
expected to change during the course of the study. 
5. Have personal access to a smartphone (24/7). 
6. Must be able and willing to comply with the protocol. 
7. Must be able and willing to provide informed consent. 
Exclusion Criteria 
1. An active implanted electrical and/or neurostimulator device (e.g. cardiac 
pacemaker, cochlear implant). 

 
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2. Uncontrolled epilepsy. 
3. History of use of opioids or barbiturates on more than 4 days a month in the 
last 6 months.  
4. Current participation in any other interventional clinical study  
5. Participants without basic cognitive and motor skills required for operating a 
smartphone. 
6. Pregnant or breastfeeding.  
7. Other significant pain, medical or psychological problems that in the opinion 
of the investigator may confound the study assessments. 
8. Prior experience with the Nerivio device. 
Study Design  
A prospective, randomized, double blind, sham controlled, multicenter trial, 
conducted in three phases. The trial will consist of a screening/enrollment visit, 
followed by a 4-week (28 days) baseline phase. Eligible participants will enter an 
8-week double-blind preventive treatment phase. Following the preventive 
treatment phase, patients will be offered to participate in a 4-week open label 
pre-emptive treatment phase or continue their prevention treatment with an 
active device, according to their eligibility. 
Patients will complete an electronic diary throughout the study; this includes a 
daily evening report (completed regardless of whether the patient had a 
headache) and a treatment feedback during the follow up pre-emptive phase 
Phase I – Baseline - 4 weeks (weeks 1 through 4):  
Eligible participants will install the Nerivio app on their smartphones and will be 
instructed to record daily their migraine/headaches symptoms and medication 
use on the Nerivio app.  
Transition to the treatment phase: 
Participants who meet the following criteria in the baseline phase will be eligible 
to continue to the treatment phase: 
• Complete the diary in at least 22 out of the 28 days during the baseline 
phase (80%) 
• Have between 6 to 24 headache days during the 28-day baseline period. 
• At least 4 of their headache days during the baseline phase fulfill 
the ICHD-3 criteria for migraine (migraine without aura [code 1.1; C and D] 
or with aura [code 1.2; B and C], or probable migraine, or headaches 

 
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requiring the use of migraine-specific medications including triptans, 
gepants or ergot derivatives) 
 
Phase II - treatment phase (prevention) – 8 weeks (weeks 5 through 12): 
Participants who meet the baseline phase requirements will be randomized in a 
1:1 ratio to active and sham groups. Participants will be instructed to complete a 
daily diary (in the Nerivio app) about their headaches, associated symptoms, 
and medication use. They will also be instructed to conduct a 45-minute 
treatment with Nerivio every other day.  
Transition to the follow-up phase (open label): 
At the end of the treatment phase, participants from both arms (active and 
sham) may continue to a follow-up phase in which they will receive an active 
device that can be used during this phase. The data of all participants will be 
used for safety analyses.  
The data of participants from the baseline and treatment phases will be used to 
assess their eligibility to participate in the pre-emptive follow-up phase. 
Participants eligible for the follow-up phase meet the following conditions: 
• 
Between 6-16 headache days during the baseline phase. 
• 
Participants experience prodrome symptoms within 24 hours prior to the 
onset of their migraine headache in at least half of their migraine attacks 
during the baseline phase. 
• 
Participants completed the daily questionnaires in at least 70% of the 
days during the treatment phase.  
• 
Treated every other day in at least 24 and less than 33 days during the 
56 days of the treatment phase.  
Phase III – Follow-up phase (open label) - 4 weeks (weeks 13 through 16): 
All participants will receive an active Nerivio device to use during the follow-up 
phase. Participants who do not meet the above requirements will be able to 
enter into the safety follow-up and continue to use Nerivio every other day for 
the preventive treatment of migraine. They will be instructed to compete a daily 
diary as was done in the treatment phase.  

 
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Participants who meet the above requirements will enter the pre-emptive follow-
up phase and be instructed to conduct a 45-minute device treatment within 60 
minutes of prodrome symptom onset. Participants will be instructed to complete 
questionnaires regarding their headache, prodrome symptoms, and medication 
use at baseline (start of treatment), 2 hours post-treatment, and 24 hours post-
treatment. In addition, participants will be instructed to continue to report the 
daily diary, as performed in the other phases of the study. 
Primary efficacy 
endpoint 
Mean change in number of migraine headache days per month comparing the 4-
week baseline phase (weeks 1 through 4) with the last 28 days of the treatment 
phase (weeks 9 through 12).  
A migraine headache day is defined as a calendar day with headache that is 
accompanied by at least one of the following symptoms: aura, photophobia, 
phonophobia, nausea and/or vomiting; or a calendar day with a headache that is 
treated with a migraine-specific acute medication. 
Secondary 
efficacy 
endpoints 
 
1. Mean change in number of moderate/severe headache days per month 
comparing the 4-week baseline phase (weeks 1 through 4) with the last 28 
days of the treatment phase (weeks 9 through 12) 
A moderate/severe headache day is defined as a calendar day with 
moderate or severe headache.  
2. Mean change in the number of headache days per month from the 4-week 
baseline phase (weeks 1 through 4) to the last 4 weeks of the treatment 
phase (weeks 9 through 12). 
A headache day is defined as a calendar day with headache (at any 
severity). 
3. Percentage of patients achieving at least 50% reduction from baseline in the 
mean number of headache days (all severities) per month in the last 4 
weeks of the treatment phase (weeks 9 through 12). 
4. Mean change in the HIT-6 total score from baseline to the last 4 weeks of 
the treatment phase (weeks 9 through 12). 
5. Mean change in the MSQ role function from baseline the last 4 weeks of the 
treatment phase (weeks 9 through 12). 
Exploratory 
efficacy 
endpoints 
1. Reduction in the mean number of acute headache/migraine medication days 
per month in the last 4 weeks of the treatment phase (weeks 9 through 12) 
compared to Baseline (weeks 1 through 4).  
An acute headache/migraine medication day is a calendar day on which the 

 
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patient consumes at least one dose of any medication (OTC or prescribed) 
for acute treatment of headache or migraine.  
 
[Endpoints 2-6 below relate to the pre-emptive follow-up phase]  
2. Percentage of patients who treat for the first treatment in the pre-emptive 
phase, during a prodrome, when they are pain free, and remain pain free 
during the following 2 hours after the treatment, without use of acute 
medication.  
3. Percentage of patients who treat for the first treatment in the pre-emptive 
phase, during the prodrome, when they are pain free, and remain pain free 
during the following 24 hours after the treatment, without use of acute 
medication.  
4. Percentage of patients who treat for the first treatment in the pre-emptive 
phase, during the prodrome, when they are pain free, and remain either pain 
free or with mild pain during the following 24 hours after the treatment without 
use of acute medication.  
5. Mean change in the percentage of prodromes which were followed by a 
headache within 24 hours from baseline to the end of the pre-emptive follow-
up phase.  
6. Mean change in the average number of moderate/severe headache days per 
month in the pre-emptive phase compared to the 4-week baseline phase. 
 
[Endpoint 7 relate to Health Economics analysis] 
7. Differences between active and sham groups in reduction of the following 
events from baseline (weeks 1-4) to the last 4 weeks of treatment phase 
(weeks 9-12): (a) Absenteeism, (b) Presenteesim, (c) Healthcare provider 
appointments, (d) ED/ER visits, (e) Brain MRI/CT scans 
[Endpoint 8 relate to migraine prediction analysis]8. Feasibility of a migraine 
prediction algorithm:  
Analysis of the daily information provided by the participants during the 
baseline period (weeks 1-4) for the purpose of predicting their migraine days 
 
Safety endpoints 
1. The incidence of adverse events in general and by seriousness, severity and 
association to the device. 
2. Treatment tolerability (by electronic patient report). 

 
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Datasets 
1. Intent to treat analysis set (ITT) 
The ITT analysis set includes all randomized participants  
2. Modified intent to treat analysis set (mITT) 
The mITT analysis set includes all ITT participants who had at least 22 days 
of efficacy assessments in the last 4 weeks of the treatment phase (weeks 9 
through 12) and at least 12 treatments performed throughout weeks 9-12.  
Data Analysis 
The ITT analysis set will be used for the safety assessments and the mITT 
analysis set will be used for the efficacy assessments. 
 
 
 

 
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2. 
BACKGROUND 
Migraine is one of the most prevalent and disabling neurologic disorders [1]. The 
International Headache Society defines migraine as a recurrent headache disorder 
manifesting in attacks lasting 4-72 hours. In addition to the disabling pain attacks, 
migraines can be either with or without aura, and accompanied by at least one of the 
symptoms: nausea, photophobia and phonophobia. Some patients also experience 
additional symptoms occurring hours or days before the headache, known as the 
prodromal phase, or after pain resolves, known as the postdromal phase. The prodrome 
symptoms include food cravings, repetitive yawning, fatigue and neck stiffness.[2].  
 
Patients experiencing a frequent number of migraine attacks and a myriad of related 
symptoms require a treatment regime to manage their pain levels and extensive 
accompanying symptoms. Current treatment strategies for migraine consists of both 
preventive treatment and acute treatment. Preventive treatments have been shown to be 
efficacious for patients in reducing the number and severity of headache days, making it 
the primary treatment plan for chronic migraine patients  [3].  
 
However, current preventive treatments demonstrate only up to 50% response rate [4-6] 
and only 30% adherence rate [7], requiring additional new preventive treatments for these 
non-responders. Moreover, even when highly effective, preventive treatments do not 
prevent all migraine attacks, thus requiring the use of acute treatment [8], and if used 
excessively, acute medications can often lead to medication overuse headache (MOH) 
[9]. Thus, there is a great unmet to have a preventive treatment that does not increase 
medication intake on one hand, and on the other hand reduces the number of headache 
days and pain severity.  
 
This unmet need can be met using remote electrical neuromodulation (REN) [10]. REN is 
a novel acute migraine treatment which stimulates upper arm peripheral nerves to induce 
conditioned pain modulation (CPM) - an endogenous analgesia mechanism in which 
conditioning stimulation inhibits pain in remote body regions [11]. The safety and efficacy 
of REN (Nerivio®, Theranica Bio-Electronics LTD., Israel) have already been established 
for acute treatment [12,13]. Nerivio was assessed for migraine in a randomized, double-
blind, sham-controlled multi-center study (NCT03361423). This study demonstrated that 
REN provides superior clinically meaningful relief of migraine pain and MBS compared to 
placebo, offering a safe and effective non-pharmacological alternative for acute migraine 
treatment. Specifically, the active stimulation was more effective than sham stimulation in 
achieving pain relief (66∙7% [66/99; CI95% 56∙48-75∙82] vs. 38∙8%, p<0∙001), pain-free 
(37∙4% vs. 18∙4%, p<0∙005) and MBS relief (46∙3% vs. 22∙2%, p<0∙001) at 2 hours post-
treatment, and that the pain relief and pain-free superiority of the active treatment was 
sustained 48 hours post-treatment. In addition, the incidence of device-related adverse 
events was low and similar between treatment groups (4∙8% vs. 2∙4%, p=0∙49). All device-
related adverse events were mild, did not required medical intervention and resolved 

 
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within 24 hours. The device was granted a 510k De novo approval (DEN180059) for the 
acute treatment of migraine in people who do not have chronic migraine. In addition, two 
open label studies of the Nerivio for acute treatment of migraine in chronic migraine 
patients demonstrated similar patterns of pain relief, pain free and consistency of pain 
relief across treatments. Based on these studies, the device was granted a 510k pre-
market notification (K201824) for the acute treatment of migraine in people 18 years and 
older.  
 
The aim of the present study is to evaluate the safety and efficacy of Nerivio for a 
preventive treatment of migraine, thus establishing Nerivio as a digital health tool offering 
a complete treatment management of migraine. Since already demonstrated to be 
effective for acute treatment, Nerivio can provide a complete management of migraine 
pain and symptoms that will greatly benefit the quality of life of migraine patients, improving 
adherence and lowering the side effects. 
 
 
3. 
IDENTIFICATION AND DESCRIPTION OF THE DEVICE INFORMATION 
3.1. 
Intended use 
Current indication for use of the device: 
The Nerivio is indicated for acute treatment of migraine with or without aura in patients 
18 years of age or older. It is a prescription use, self-administered device for use in the 
home environment at the onset of migraine headache or aura. 
 
This study aims to expand the current indication to include the preventive treatment of 
migraine in patients 18 years of age or older. 
 
3.2. 
Contraindications 
• The device should not be used by people with congestive heart failure (CHF), severe 
cardiac or cerebrovascular disease. 
• The device should not be used by people with uncontrolled epilepsy. 
• The device should not be used by people with active implantable medical device, such 
as a pacemaker, hearing aid implant, or any implanted electronic device. Such use 
could cause electric shock, electrical interference or serious injuries or medical 
conditions. 
 
Main warnings and precautions: 
• The device should not be used over skin conditions, such as open wounds or rashes, 
or over swollen, red, infected or inflamed areas or skin eruptions or fragile skin on the 
upper arm at the treatment location.  
• The device should not be shared with other people. The device is intended to be used 
by a single person to avoid skin disease or any transmissible disease. 

 
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• The device should not be used on the heart, chest, neck, head or any other body 
location other than the upper arm, because this could cause severe muscle spasms 
resulting in closure of your airway, difficulty in breathing, or adverse effects on heart 
rhythm or blood pressure.  
• The device has not been evaluated for use in pregnant women and people less than 
18 years of age    
  
 
3.3. 
Device description 
The device is a wireless wearable battery-operated stimulation unit controlled by a 
smartphone software application. Treatments with Nerivio are self-administered by the 
user at the onset of a migraine attack. 
 
The device includes several main components:  
• 
A pair of electrodes covered with hydrogel and a removeable protective film 
• 
An electronic circuitry and a battery contained in a plastic case 
• 
A software that includes firmware and a software application for mobile platforms 
•  An armband to improve the adhesiveness and enable a discreet treatment 
 
The external side of the Nerivio (Figure 1) includes an "ON" switch and a LED indicator 
that signals various modes of operation, located on the enclosure. The internal side 
includes the electrodes and a biocompatible adhesive material that holds the device in 
its location. The armband is applied over the device to further secure its location on the 
arm and conceal the device to enable a discreet treatment. 
 
The device produces a proprietary electrical signal comprising a modulated 
symmetrical bi-phasic square pulse with a modulated frequency of 100-120-Hz, pulse 
width of 400 μs, and up to 40 mA output current (adjusted by the participant). 
 
A 
B 
 
C 
 
Figure 1:  Nerivio device. (A) Internal side, (B) External side, and (C) The armband 
 
3.4. 
The application 
Activation, control over stimulation intensity and termination of stimulation are 
performed via a dedicated smartphone application and installed on the user’s 

 
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smartphone (Figure 2). The application has a graphical user interface (GUI) which 
includes graphical controls that the user can select using a touch screen. The app 
enables the user to start treatments and control them.  
 
 
 
 
Figure 2: The app screens 
 
In addition, the application sends the user a daily questionnaire of migraine related 
symptoms.   The application also provides notifications and indications on connection 
state and remaining number of treatments.  
The device communicates with the mobile application software through a Bluetooth® 
radio protocol (BTLE) which uses 2.4GHz carrier.  
 
The application can be installed from Google Play or the App store and supports 
Hebrew and English menu displays. 
  
3.5. 
Operational context 
Nerivio is a wearable, battery-powered medical device for the acute treatment of 
migraines with or without aura. Nerivio delivers transcutaneous electrical nerve 
stimulation (TENS) through the control of the Nerivio iOS or Android app. Nerivio is a 
home-use device that requires prescription but does not require training. The device is 
provided with a printed QuickStart guide and a user manual in the app. The first use of 
the device requires the user to install the app and pair the smartphone to the device. In 
each treatment, the intensity level should be individually set so it feels strong yet 
comfortable and painless. The battery of the device is non-rechargeable, the electrodes 
should be covered with protective liners and the device should be stored in its original 
package.  

 
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Nerivio should be placed on the user’s arm (Figure 3), currently – per the present 
indication - at the onset of a migraine episode, the device should then be turned on and 
a treatment can be activated via the mobile application. The treatment includes a weak 
electrical current delivered to the skin via the electrodes. The arm was chosen for 
several reasons. First, it is distal from the head, enabling to produce CPM response. 
Second, it may be easily accessed independently by the user without the help of others. 
Finally, it provides a discreet location that maintains the privacy of the user and enables 
to continue with ongoing activities during treatment.   
 
Figure 3:  Nerivio location of treatment 
 
3.6. 
Principle of operation 
Conditioned pain modulation (CPM) is a descending endogenous analgesic 
mechanism that originates in the brainstem (rostral ventromedial medulla), in which 
pain in one part of the body inhibits pain in multiple remote body regions [13]. According 
to this well-established mechanism, also known as “pain inhibits pain”, the intensity of 
a painful stimulus can be reduced by a second painful stimulus at a different location 
[14,15]. Notably, it has been shown that very strong but subjectively non‐painful 
stimulus is sufficient to trigger pain inhibitory effects [16].    
From a neuronal level, noxious sensory information is carried by two primary afferent 
fibers – the Aδ and C fibers (Table 1). Aδ fibers are small myelinated afferents that 
respond to mechanical and thermal stimuli, and carry rapid, sharp pain. These fibers 
are responsible for the initial withdrawal reflex responses. C fibers are unmyelinated 
and have a small diameter and low conduction velocity. These fibers respond to 
chemical, mechanical and thermal stimuli and produce slow, burning pain. The 
headache of migraine is believed to be mediated by activation of both types of fibers 
that innervate meningeal blood vessels [17]. CPM inhibits the responses of these fibers, 
with an inhibitory preference towards the C fiber mediated responses [18]. Another type 
of primary sensory afferent fibers is the Aβ fibers which are large and thickly myelinated, 
enabling rapid signal conduction (Table 1). These fibers have a low activation threshold 
and transmit tactile information.  
 
   

 
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Nerve fiber type 
A-delta 
C 
A-beta 
Diameter 
Medium (1-5 
microns) 
Small (< 2 
microns) 
Large (> 5 microns 
Myelination 
Thinly 
myelinated  
Unmyelinated 
thickly myelinated 
Signal 
propagation 
Medium (5-30 
mS-1) 
Slow (< 2mS-1) 
Fast (>35mS-1) 
Activation 
threshold 
High and Low 
High 
Low 
Sensation with 
stimulation 
Rapid, Sharp. 
Localized pain 
Slow, diffuse. 
Dull pain 
Tactile information 
Table 1:  Characteristics of nerve fibers 
 
In Nerivio, the stimulation (secondary stimulus) is engineered to produce a strong but 
non-painful stimulus that invokes the CPM as a pain relief mechanism for the migraine 
headache (initial stimulus). The patient is instructed to adjust the intensity to the 
strongest stimulation which is still below the perceived pain level. The area of the 
electrodes of Nerivio is relatively large, enabling to recruit a large number of fibers 
during treatment. The pulse frequency and duration are designed so that C fibers and 
Aδ fibers are stimulated below their thresholds, aiming to produce a local sensation 
below the pain threshold, as well as to avoid excitation of motor nerves. Furthermore, 
the local pain sensation in the arm may be inhibited by Aβ fibers through the “gate 
control” theory of pain [19], further preventing the perception of pain. In addition, the 
pulses frequency gradually changes during the stimulation to avoid pain habituation, 
and a low frequency modulating waveform is added to invoke the release of 
neurotransmitters to further enhance the analgesic impact. 
 
The expansion of this mechanism of action to prevention is based on the hypothesis 
that frequent triggering of the CPM mechanism (in this case, every other day) train this 
mechanism for rapid activation upon need.   
 
3.7. 
Output parameters 
The user controls the stimulation intensity within the specified limits. A dedicated 
mechanism controls speed of intensity adjustment in order to protect the user from 
unexpected strong stimulation intensity variations.  
 
The Nerivio output parameters is described in Table 2.  
 

 
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Parameter 
Nerivio Device 
Mode or program name 
REN 
Waveform 
Biphasic, 
symmetrical 
Shape 
Rectangular 
Maximum output voltage (V)  
  
500Ω 
20 
2KΩ 
60 
10KΩ 
60 
Maximum output current (mA)  
  
500Ω 
40 
2KΩ 
30 
10KΩ 
6 
Duration of primary (depolarizing) phase (µsec) 
200 
Frequency (Hz) 
100-120 
Maximum average power density (mW/cm²)500Ω 
1.14 
Maximum phase charge (µC) 
  
500Ω 
8 
Maximum current density (mA/cm², r.m.s) 
  
500Ω 
1.6 
Table 2:  Key output parameters of Nerivio 
 
 
3.8. 
Instructions for use 
Device instructions for use will be available in a separate document which will be 
provided to the participants with the device and its package. 
 
3.9. 
Identification of the medical device 
The device label includes the address of the legal manufacturer and all other essential 
information, enabling complete traceability of the medical device, consistent with the 
regulatory labeling requirements. Investigational sites outside the USA, where the 
device is not yet approved, will receive a device with an additional label for clinical 
investigation use only. 
 
3.10. Training 
Participants will receive general instruction and will undergo training on using the device. 
The intended study population does not require special training but is expected to be 

 
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familiar with smartphone use. The training will be administered by designated study 
personnel and will be recorded in a corresponding CRF. In addition, records of the 
training session will be documented in the study data base with a label “training”. The 
criteria for training effectiveness will be the ability of the participant to independently 
administer a training treatment session.  
 
The sponsor representative will be responsible to provide a formal training to the 
investigator and site personnel, which will include a demo and training activities. In order 
to provide additional support to the clinical personnel, a training video clip will be used 
at all training sessions for the study personnel and the participants.  
 
 
4. 
PRELIMINARY INVESTIGATIONS AND JUSTIFICATION FOR THE STUDY DESIGN 
4.1. 
Previous pre-clinical experience 
No animal studies were conducted with the Nerivio device. The necessity for an animal 
study has been deemed unnecessary since the device utilizes similar output parameters 
to those of FDA approved TENS devices, and in accordance with the application of risk 
management according to EN ISO14791. Furthermore, there is no valid animal model 
to test the effectiveness of this device.  
 
4.2. 
Previous clinical experience 
The device described in this submission is identical to the version in K201824, and 
accordingly, the nonclinical testing that supported this clearance remains fully applicable 
to the device for the proposed modified indications for use.  No additional bench testing 
will be conducted.  A brief summary of the existing clinical experience with the device is 
summarized in this section.  
 
Clinical data supporting the safety and performance of the Nerivio device for the 
treatment of migraine headaches has been collected across a series of studies: 
 
Study 
number 
Design 
Population 
Submission 
TCH-001 
prospective, double-blind, 
randomized, crossover, sham-
controlled pilot study 
Patients with migraines, 
aged 18-75 years old 
DEN180059 
TCH-003 
prospective, randomized, 
double-blind, sham-controlled 
pivotal study 
patients with migraines, 
aged 18-75 years old  
DEN180059 
TCH-005 
prospective, open-label, single 
arm, dual-center study 
patients with chronic 
migraine aged 18–75 
years 
K201824 

 
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Table 3 - Prospective clinical data supporting prior clearances  
 
4.2.1. Pilot Study TCH-001 (NCT02453399)   
As previously presented to the agency in DEN180059, the pilot study was a single-
center, prospective, double-blind, randomized, crossover, sham controlled pilot study to 
collect clinical data related to the safety and effectiveness of non-invasive remote 
electrical stimulation with Nerivio device for the acute treatment of migraine. Briefly, 86 
migraineurs with or without aura (in accordance with ICHD classification criteria) who 
had 2–8 attacks per month without preventive medications for at least 2 months were 
recruited.  The participants were requested to treat migraine episodes at home using 
the device, which randomly provided four different stimuli programs (P200, P150, P100 
and P50 with frequencies of 100-120Hz each and pulse width of 2x200msec, 
2x150msec, 2x100msec and 2x50msec, respectively). 
Stimulation period was set to 20min and the intensity was self-adjusted to a "well 
perceived, but non-painful" level. Stimuli were given at random sequence. Pain levels 
were self-reported using the numeric rating scale (NRS) of 0 – 10 via a smartphone 
application at onset and 10, 20, and 120 minutes after stimulation onset.  The primary 
endpoint was the proportion of participants reporting pain decrease of at least 50% at 2 
hours post-treatment in at least 50% of completed treatments.  
The other primary endpoint was the relative pain reduction by NPS at two hours post-
treatment as a percentage of pre-treatment pain. This was calculated per each type of 
stimulation.  
The analysis of the primary endpoint revealed a 64% rate of at least 50% pain reduction 
at 2 hours post-treatment, in at least 50% of completed active treatments. Pain reduction 
was defined as a reduction from severe or moderate pain to (i) mild or no pain; and (ii) 
to no pain This rate was significantly higher than the 26% rate found for the sham 
treatment (p=0.005). The data demonstrated that the P200 program presented the most 
potential effect of migraine headache reduction. Moreover, no device-related adverse 
events were reported. The next studies utilized devices with the P200 program only. 
 
4.2.2. TCH-003 Pivotal Study (NCT03361423)  
As previously discussed in DEN180059, this study was a prospective, randomized, 
double-blind, sham controlled multi-center pivotal study aiming to demonstrate the 
efficacy and safety of Nerivio. The study was performed in 7 sites in the USA and 5 sites 
in Israel.  
TCH-006 
prospective, open-label, single 
arm, multicenter study 
patients with chronic 
migraine aged 18–75 
years 
K201824 
TCH-004 
prospective, open-label, single 
arm, multicenter study 
patients with episodic 
and chronic migraine 
aged 12–17 years 
K203181 

 
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Eligible patients were 18–75 years old females and males who met the 
inclusion/exclusion criteria of the study. The study included two phases.  In the first (“roll-
in”) phase, participants were asked to keep a headache diary for one month in which all 
migraine episodes were documented.  The second phase was a double-blind treatment 
phase, in which eligible participants were randomly allocated in a 1:1 ratio to either active 
stimulation (treatment group) or sham stimulation (sham group), in a double-blind 
manner.  Participants were then asked to treat their migraine episodes for 6 weeks using 
the device and to treat each migraine episode within 60 minutes of symptom onset.  The 
participants used the application (installed on their personal phones) to record pain 
scores (scale: none, mild, moderate, or severe) at baseline, 2 hours post-treatment and 
48 hours post-treatment, and to record the presence/absence of associated migraine 
symptoms (nausea, photophobia, phonophobia).  The first reported treatment was 
considered a "run-in test" treatment, aimed to verify that the participants use the device 
properly, and was only included in the safety analysis.  The efficacy endpoints were 
evaluated on the first reported treatment following the "run-in test" treatment (hereby 
termed “Test treatment”). 
Results 
In the mITT analysis set, the proportion of participants achieving a pain-relief response 
2 hours after treatment was 66.7% (66/99) in the treatment group compared to 38.8% 
(40/103) in the sham group (therapeutic gain 27.9%; p<0.0001).  The active treatment 
was also superior to the sham for the reduction of pain for each one of the possible 
baseline pain levels (severe, moderate, and mild). Furthermore, the active stimulation 
treatment was significantly more effective than the sham treatment for the proportion of 
participants achieving 2 hours of MBS relief (46.3% vs. 22.2%; p=0.0.0008) and for the 
proportion of participants who achieved both headache relief and MBS relief at 2 hours 
post-treatment (40.0% vs. 15.2%; p=0.0004. There was no significant difference 
between active and sham treatment for MBS-free 2 hours post-treatment (40.7% vs. 
36.4%; p=0.0.55).  For pain-free 2 hours post-treatment, the active device was superior 
to the sham device, with statistical significance (37.4% vs. 18.4%; p=0.0036). 
The active treatment was significantly more effective than the sham treatment for all 
measures of sustained efficacy, including 48-hour sustained pain-free response with 
device single use (p=0.007), 48-hour sustained headache reduction with device single 
use (p=0.0015), 48-hour sustained pain-free response with device reuse (p=0.0148), 
and 48-hour sustained headache reduction with device reuse (p=0.0010).  In addition, 
the consistency of pain reduction over multiple treatments was also significantly higher 
in the treatment group (62.6%) compared to the sham group (45.6%, p=0.0154). 
With regard to safety, the incidence of device-related adverse events was low (3.6%), 
and similar between treatment groups (active group: 6/126 [4.8%]; sham group: 3/126 
[2.4%]; pFisher’s=0.4998). There were no unanticipated adverse device effects and all 
device-related adverse events reported were mild in severity, did not require treatment 
and were self-resolved.  No serious adverse events related to the device were reported. 

 
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No statistically significant differences were found between treatment groups in either the 
type or rate of adverse events during the double-blind treatment phase.  
In this randomized, double-blind, sham-controlled study, the Nerivio was effective and 
well-tolerated for the acute treatment of migraine. From a risk-benefit perspective, 
treatment with Nerivio achieved significant pain relief without serious side effects. 
Therefore, Nerivio demonstrated that it offers an alternative for current pharmacological 
and non-pharmacological treatments that combines efficient treatment with minimal side 
effects.  
 
4.2.3.  Clinical study TCH-005 (NCT04161807) 
A prospective, open-label, single arm, dual-center study pilot study of the Nerivio device 
in patients with chronic migraine was performed to assess the performance of Nerivio in 
people with chronic migraine across two clinical sites: one site in the USA and one site 
in Israel. Specifically, it assessed the capability of the Nerivio device to alleviate migraine 
headache and additional symptoms in patients with chronic migraine and support the 
submission of a 510(k) notice with an expanded indication for use of Nerivio in people 
with chronic migraine, compared to the original De Novo submission. This study has 
been previously presented to FDA in the 510k pre-market notification (K201824) and 
summarized below. 
The study included patients with chronic migraine aged 18–75 years old, who met the 
International Classification of Headache Disorders (ICHD-3) criteria for chronic migraine 
(at least 15 headache days a month, with at least eight days a month on which their 
headaches and associated symptoms meet diagnostic criteria for migraine).  
Study design and procedures 
Participants treated their migraine attacks at home for 4 weeks (treatment phase), with 
their optimal stimulation intensity, as soon as possible after migraine headache began 
and always within one hour of attack onset. Participants were instructed to avoid taking 
rescue medications within the first two hours post-treatment. Pain scores (none, mild, 
moderate, or severe), absence/presence of migraine associated symptoms including 
nausea/vomiting, photophobia and phonophobia, and functional disability were recorded 
at baseline, 2- and 24-hours post-treatment in electronic diary application included in the 
Nerivio mobile application that was installed on the participants’ smartphones. 
Results 
A total of 296 qualifying migraine headaches (defined as a migraine headache that is of 
moderate or severe intensity and preceded by 24 hours of no pain or mild intensity pain; 
or is of mild intensity and preceded by 24 hours of no pain) were treated with Nerivio 
(average of 7.8 treatments per participant per 4 weeks for 38 participants), of which 
baseline pain level was reported in 270 treatments.  
A total of 210 evaluable treatments (excluding the training treatment) of qualifying 
migraine headaches were conducted by the 38 participants included in the analyses, 
with an average of 5.5±2.6 evaluable treatments per patient per 4 weeks. Rescue 

 
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medication at 2 hours was used across 16 subjects in 22 of the 210 treatments (89.5% 
compliance rate). 22 (57.9%) of the patients did not use any medication during the trial 
(for all their treatments). Use of medication was considered a failure for the specific 
treatment. 
The primary, secondary and exploratory endpoints of a single attack were conducted on 
the test treatment of the final analysis set of 38 participants. Pain relief and pain-free at 
2 hours were achieved by 50.0% (19/38; CI95% 33.4-66.6%) and 26.3% (10/38; CI95% 
13.4-43.1%) participants, respectively. Pain relief was sustained for 24 hours in 83.3% 
(10/12; CI95% 51.6-97.9%) of the participants who achieved relief at 2 hours (7 
participants did not report pain level at 24 hours and were thus, excluded from the 
analysis). Nausea, photophobia, and phonophobia disappeared at 2 hours in 58.8% 
(10/17; CI95% 32.9-81.6%), 37.5% (9/24; CI95% 18.8-59.4%), and 50.0% (8/16; CI95% 
24.7-75.3%) participants, respectively. Furthermore, 46.7% (14/30; CI95% 28.3-65.7%) 
participants experienced improvement in functional ability at 2 hours and 72.7% (16/22; 
CI95% 49.8-89.3%) participants experienced improvement in functional ability at 24 
hours (8 participants with missing data at 24 hours were excluded from the analysis).  
Consistency analyses across all attacks (excluding the training treatment) demonstrated 
that 73.7% (28/38) of the participants experienced pain relief in at least 50% of their 
treated attacks. Mean pain relief rate across subjects was 58.8%, median pain relief rate 
across subjects was 60% and the inter quartiles rang (IQR) was 43.67 - 87.50%. 
According to the safety analyses, the percentage of participants experiencing at least 
one adverse event was 4.7% (2/42) with 95% confidence interval of (0.6 – 16.2%). A 
single device-related adverse event was reported (2.3% [1/4])). The device-related 
adverse event was moderate, resolved within 48 hours following drug therapy (triptan). 
There were no serious adverse device-related events and none of the participants 
withdrew from the study due to adverse events. 
The findings of the study demonstrated that Nerivio is effective for the acute treatment 
of migraine in people with chronic migraine. Acute treatment of migraine headaches 
resulted in clinically meaningful benefits. Pain relief and pain-free rates were generally 
similar to those found in people with non-chronic migraine as reported in the Nerivio 
clinical study presented in DEN180059. Overall, the data reveal consistent response 
rates from treatment to treatment, with no evidence of reduction in therapeutic benefits 
over time. Specifically, over 73% of the patients achieved pain relief at 2 hours in more 
than half of their attacks. The findings of this study also show that the device is safe and 
well-tolerated. No safety issues were associated with the more frequent use of the 
device in patients with chronic migraine. 
 
4.2.4. Clinical study TCH-006 (NCT04194008) 
A large multicenter study of the Nerivio device in patients with chronic migraine was 
performed to further assess the performance of Nerivio in the chronic migraine 
population. This study has also been previously presented to FDA in the 510k pre-
market notification (K201824) and summarized below for completeness. 

 
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The study included patients, aged 18-75 years, with chronic migraine who met the 
International Classification of Headache Disorders (ICHD-3) criteria for chronic migraine 
(at least 15 headache days a month, with at least eight days a month on which their 
headaches and associated symptoms meet diagnostic criteria for migraine).  
Study design and procedures 
This study was a prospective, open-label, single arm, multicenter study conducted 
across 9 clinical US sites. Participants entered a 4-week “Run-in” phase in which they 
had to report their migraine attacks and continue with their usual treatment care. 
Participants who reported at least 6 qualifying migraine headaches with pain data at 
baseline and 2 hours post-treatment were eligible to continue to the “Treatment” phase. 
During the “Treatment” phase, participants were asked to treat their migraine attacks at 
home for 4 weeks with their optimal stimulation intensity, as soon as possible after 
migraine headache began and always within one hour of attack onset. Participants were 
instructed to avoid taking rescue medications within the first two hours post-treatment. 
Pain scores (none, mild, moderate, or severe), absence/presence of migraine 
associated symptoms including nausea/vomiting, photophobia and phonophobia, and 
functional disability were recorded at baseline, 2- and 24-hours post-treatment in 
electronic diary application included in the Nerivio mobile application that was installed 
on the participants’ smartphones.  
Participants who finished the “Treatment” phase were offered to continue to an 8-week 
follow-up phase in which they could incorporate the device into their usual care. 
Following the 8 weeks of “Follow up” phase, participants fill out their end of study 
questionnaire and completed the study. 
Results 
Run-in phase 
A total of 997 qualifying migraine attacks were reported during the run-in phase by the 
126 enrolled patients, with an average of 7.9 attacks per participant. Of these, pain level 
at baseline was reported on 993 reported attacks. 
  
Treatment phase 
A total of 711 qualifying migraine headaches were treated with Nerivio (average of 7.3 
treatments per participant per 4 weeks for 97 participants [2 participants had no 
qualifying migraine attacks]), of which baseline pain level was reported in 635 
treatments. Pain severity of treated migraine headaches was mostly moderate (57.2% 
[363/635]). 157/635 (24.7%) of the treated migraine headaches were severe and 
115/635 (18.1%) of the treated migraine headaches were mild. Generally, the 
characteristics of treated migraine headaches were comparable to those reported in 
previous migraine studies and are consistent with the pain intensity characterization of 
the target patient population of the device. 
A total of 493 evaluable treatments (excluding the training treatment) of qualifying 
migraine headaches were conducted by the 91 participants included in the analyses, 

 
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with an average of 5.4±2.8 evaluable treatments per patient per 4 weeks. Medication at 
2 hours was used in 54 of the 493 treatments (89.0% compliance rate). Use of 
medication was considered a treatment failure.  
The primary, secondary and exploratory endpoints of a single attack were conducted on 
the test treatment of the final analysis set of 91 participants. Pain relief and pain-free at 
2 hours were achieved by 59.3% (54/91; CI95% 48.5-69.5%) and 20.9% (19/91; CI95% 
13.0-30.6%) of the participants, respectively. Pain relief was sustained for 24 hours in 
73.3% (33/45; CI95% 58.0-85.3%) of the participants (9 participants did not report pain 
level at 24 hours and were thus excluded from the analysis). Nausea, photophobia, and 
phonophobia disappeared at 2 hours in 48.8% (20/41; CI95% 32.8-64.8%), 40.5% 
(30/74; CI95% 29.2-52.5%), and 44.6% (29/65; CI95% 32.2-57.4%) participants, 
respectively. Furthermore, 59.4% (19/32; CI95% 40.6-76.3%) of the participants 
experienced improvement in functional ability at 2 hours (participants with missing data 
at baseline or at 2 hours were excluded from the analysis) and 50.0% (7/14; CI95% 
23.0-76.9%) of the participants experienced improvement in functional ability at 24 hours 
(participants with missing data at baseline or at 24 hours were excluded from the 
analysis). 
Consistency analyses across all attacks (excluding the training treatment) demonstrated 
that 57.1% (52/91; CI95% 46.3-67.4%) of the participants experienced pain relief in at 
least 50% of their treated attacks. Mean pain relief rate across subjects was 50.4%, and 
median pain relief rate across subjects was 50%. Pain relief in at least 2 of 3 consecutive 
treatments (first 3 treatments excluding the training treatment) was reported by 64.4% 
(47/73; CI95% 52.3-75.3%) of the participants. 
The percentage of participants experiencing at least one adverse event was 9.1% (9/99) 
with 95% confidence interval of (4.2 – 16.6%). One device-related adverse event was 
reported (1.0% [1/99]) in which pain in the arm was felt following the use of the device 
on that arm. The device-related adverse event was mild, resolved within 24 hours 
without medication. The other adverse events which were deemed unrelated to the 
device.  
The findings of the study show that Nerivio is effective for the acute treatment of migraine 
in people with chronic migraine. Acute treatment of migraine headaches resulted in 
clinically meaningful benefits. Pain relief and pain-free rates were generally similar to 
those found in people with non-chronic migraine, indicating that Nerivio provides an 
alternative acute migraine treatment independent of the frequency and severity of 
migraine headaches. 
The data inspected for all treatments reveal consistent response rates from treatment to 
treatment with no evidence of tolerance to the therapeutic benefits. In at least two of the 
first three attacks treated with Nerivio, about 65% of patients achieved pain relief at 2 
hours post-treatment. The study also demonstrated that Nerivio relieves the associated 
symptoms of migraine, including nausea, photophobia and phonophobia and has clinical 
benefit on the MBS. 
The results of the study show that Nerivio is safe to use and is well-tolerated. The 
incidences of device-related adverse events were low with no device-related serious 

 
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adverse events. The rate of all device-related adverse events was below 2%, which 
compares favorably to the reported rates for current pharmacological treatments. 
 
4.2.5 Clinical study TCH-004 (NCT04089761)  
A multicenter study of the Nerivio device in adolescent patients (age 12-17, inclusive) 
with migraine was performed to assess the performance of Nerivio in the adolescent 
migraine population. This study has also been previously presented to FDA in the 
510k pre-market notification (K203181) and is summarized below for completeness. 
Study design and procedures 
This study was a prospective, open-label, single arm, multicenter study conducted 
across 12 clinical US sites. Participants entered a 4-week “Run-in” phase in which 
they had to report their migraine attacks and continue with their usual treatment care. 
Participants who reported at least 3 qualifying migraine headaches with pain data at 
baseline and 2 hours post-treatment were eligible to continue to the “Treatment” 
phase. During the “Treatment” phase, participants were asked to treat their migraine 
attacks at home for 8 weeks with their optimal stimulation intensity, as soon as 
possible after migraine headache began and always within one hour of attack onset. 
Participants were instructed to avoid taking rescue medications within the first two 
hours 
post-treatment. 
Pain 
scores 
(none, 
mild, 
moderate, 
or 
severe), 
absence/presence of migraine associated symptoms including nausea/vomiting, 
photophobia and phonophobia, and functional disability were recorded at baseline, 2- 
and 24-hours post-treatment in electronic diary application included in the Nerivio 
mobile application that was installed on the participants’ smartphones.  
Participants who finished the “Treatment” phase were offered to continue to an 8-
week follow-up phase in which they could incorporate the device into their usual care. 
Following the 8 weeks of “Follow up” phase, participants fill out their end of study 
questionnaire and completed the study. 
Results 
Run-in phase 
A total of 267 qualifying migraine attacks were reported during the run-in phase by 54 
of the 60 enrolled patients (6 patients did not report any migraines during the run-in 
phase), with an average of 4.9 migraine attacks per participant 
 
Treatment phase 
A total of 159 qualifying migraine headaches were treated with Nerivio for which pain 
data was recorded at baseline and at 2 hours post-treatment (average of 3.5 
treatments per participant). Pain severity of treated migraine headaches was mostly 

 
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moderate (48.4% [77/159]). 57/159 (35.8%) of the treated migraine headaches were 
severe and 25/159 (15.7%) of the treated migraine headaches were mild 
Pain relief and pain-free at 2 hours were achieved by 71.8% (28/39) and 35.9% 
(14/39) participants, respectively. Pain relief was sustained for 24 hours in 90.9% 
(20/22) of the participants, and pain freedom was sustained for 24 hours in 90.9% 
(10/11) of the participants. Nausea, photophobia, and phonophobia disappeared at 2 
hours in 54.5% (12/22), 41.9% (13/31), and 40.0% (10/25) participants, respectively. 
Furthermore, 69.7% (23/33) participants experienced improvement in functional 
ability at 2 hours and 69.0% (20/29) participants experienced improvement in 
functional ability at 24 hours. 
a consistency analyses was conducted across all treated attacks (excluding the 
training treatment). This analysis demonstrated that 66.7% (26/39) of the participants 
experienced pain relief in at least 50% of their treated attacks, and 33.3% (13/39) of 
the participants experienced pain-free in at least 50% of their treated attacks. 
Safety analyses were performed on all 45 participants who used the device at least 
once. 10 participants (22.2%) reported at least one adverse event. There was one 
device-related adverse event reported (2.2%) in which a temporary feeling of pain in 
the arm was felt. This adverse event was mild and resolved after the treatment without 
requiring medication or any other intervention. The other adverse events which were 
deemed unrelated to the device. 
The findings of the study show that Nerivio is effective for the acute treatment of migraine 
in the adolescent population. The results of the study show that Nerivio is safe to use 
and is well-tolerated by adolescence migraineurs. The incidence of device-related 
adverse events was low with no device-related serious adverse events. 
 
 
4.3. 
Clinical investigation risks and benefits  
4.3.1. 
Anticipated benefits to participants  
The clinical studies conducted in adults demonstrated that REN provides superior 
clinically meaningful relief of migraine pain and MBS compared to sham-device with a 
favorable safety profile, offering a safe and effective non-pharmacological alternative for 
acute migraine treatment. It is anticipated that the use for preventive treatment will be 
experienced with a similar safety profile.  
 
4.3.2. 
Risks and adverse effects 
The results of the pivotal study demonstrate a favorable safety profile of the device.  In 
this study, adverse event incidence was low; mainly reports of sensation of warmth, 
redness and numbness of the arm/hand. All device-related adverse events were mild, 
resolved within 24 hours and did not require medical treatment. There were no device-
related serious adverse events, no unanticipated adverse device effects and none of 

 
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the participants withdrew from the study due to adverse events. The safety profile of 
the device is favorable compared to triptans [26] and to new pharmacological agents, 
such as centrally acting serotonin (5-HT1F) agonists that lack cardiac vasoconstrictive 
activity [27]. Furthermore, the device has comparable or superior efficacy to 
commercially available neuromodulation devices [21,24]. 
   
4.3.3. 
 Risk-benefit balance 
The data collected in the randomized controlled clinical study in adults demonstrated 
that acute treatment of migraine with Nerivio results in most important clinical benefits 
with a very low risk to the patient. Invoking conditioned pain modulation using peripheral 
neuromodulation that induces a general analgesic effect resulted in favorable 2-hour 
pain relief and pain-free responses which are comparable with pharmacological acute 
migraine treatments such as triptans with a more favorable safety profile. Overall, the 
benefit-risk balance of Nerivio is favorable, and was not changed when frequency of 
use was increased significantly for over 15 times per month by chronic migraine 
patients. Using the device for a preventive treatment is not expected to pose any new 
risks, since the device will be used every other day, resulting in ~15 days per month. 
The overall risk posed by the device is minimal.  The device may offer an alternative 
non-pharmacological treatment that includes both acute and preventive treatments, 
without needing a variety of pharmacological agents that increases the risk of 
medication overuse, improve treatment adherence and considerably improve the 
health and quality of life of patients with migraine. 
 
 
5. 
OBJECTIVES & HYPOTHESES  
5.1. 
Study objectives 
The objective of this study is to evaluate the safety and efficacy of Nerivio for the 
preventive treatment of migraine. The goal of this study is to demonstrate a reduction in 
the number of migraine headache days per month while maintaining a favorable safety 
profile. 
 
5.2. 
Study hypothesis 
The hypothesis of this study is that treating with Nerivio every other day will reduce 
monthly migraine headache days, while maintaining a favorable safety profile. This will 
be demonstrated by a significant difference between the active and the sham groups in 
the mean change in monthly migraine days from the baseline phase to the last 4 weeks 
of treatment phase. 
 

 
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6. 
STUDY DESIGN  
6.1. 
Participants 
This study will be conducted on up to 375 participants.  
 
6.1.1. 
Inclusion criteria 
• 
Age 18-75 years old 
• 
Must have at least a 6-month history of headaches that meet the ICHD-3 diagnostic 
criteria for migraine with or without aura, either chronic or non-chronic migraine.   
• 
History of 6 to 24 headache days per 28-day period for each of the 3 months preceding 
study enrolment (based on patient report). 
• 
Subjects on prophylactic migraine treatment are permitted to remain on 1 medication 
with possible migraine-prophylactic effects if the dose has been stable for at least 2 
months prior to the screening visit, and the dose is not expected to change during the 
course of the study. 
• 
Have personal access to a smartphone (24/7). 
• 
Must be able and willing to comply with the protocol. 
• 
Must be able and willing to provide informed consent. 
 
6.1.2. 
Exclusion criteria 
• 
An active implanted electrical and/or neurostimulator device (e.g. cardiac pacemaker, 
cochlear implant). 
• 
Uncontrolled epilepsy. 
• 
History of use of opioids or barbiturates on more than 4 days per month in the last 6 
months.  
• 
Current participation in any other interventional clinical study. 
• 
Participants without basic cognitive and motor skills required for operating a 
smartphone. 
• 
Pregnant or breastfeeding.  
• 
Other significant pain, medical or psychological problems that in the opinion of the 
investigator may confound the study assessments. 
• 
Prior experience with the Nerivio device. 
 
6.1.3. 
Withdrawal / Discontinuation 
Participants may withdraw consent at any time and do not have to provide an 
explanation.  
 
Participant may be withdrawn from the study by the PI or sponsor due to one or more 
of the following reasons: 
• Participant is lost to follow-up 
• Refusal of the participant to continue treatment and/or follow-up observations 

 
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• Serious adverse event 
• Participants encountering difficulties with the investigational product (IP) (e.g. 
cannot tolerate the treatment, unable to operate the application) 
• Significant protocol deviation/violation or noncompliance, either by the patient or 
the investigator 
• Decision made by the investigator that termination is in the patient’s best medical 
interest 
• Device malfunction 
• Other ethical or clinical considerations upon investigator discretion 
 
6.2. 
Stimulation program  
Nerivio device - The device produces a proprietary electrical signal comprising a 
modulated symmetrical biphasic square pulse with a modulated frequency of 100-120Hz, 
pulse width of 400μs, and up to 40mA output current (adjusted by the participant). The 
duration of the treatment is 45 minutes.  
 
Sham device- The device produces electrical pulses of similar width and intensity, but 
much lower frequency compared to the active device. It produces an electrical signal 
comprising a modulated symmetrical biphasic and rectangular pulse with a modulated 
frequency of 0.11-0.2Hz, pulse width of 300-1700μs, and up to 34mA output current 
(adjusted by the participant). The duration of the treatment is 45 minutes. This sham 
program produces pulses that are perceivable by the user, thus maintaining the blinding, 
but on the other hand do not intend to activate the CPM as a pain relief mechanism. 
 
6.3. 
Procedures 
This study includes up to four visits. Each visit can be performed either on-site or 
remotely, using a teleconference software. The means of remote visits will be 
documented in the site binder prior to site initiation. Each visit will have a time window of 
10 days after the perspective visit date to complete the study visit. 
 
Pre visit evaluation- 
A candidate patient for the study will be asked by the clinic to complete an online 
questionnaire that will assess the patient compliance to participate in the study. A 
summary of the questionnaire will be sent to the clinic for review. The PI will use the data 
from the questionnaire to evaluate the patient ability to comply with the study 
requirements.  
 
First visit –  
The first visit will include screening, enrollment and training on the application. 
 
Enrollment: The screening process will include an eligibility assessment and a urine 
pregnancy test. Following successful screening, the site staff will provide the participants 

 
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with study related information, perform an enrollment interview and receive an informed 
consent from the participants. During this visit, participants will complete baseline 
questionnaires that includes information on frequency of migraine attacks, typical 
associated symptoms, use of preventive and acute treatments, and the effect that their 
migraine attacks have on their daily routine and quality of life (HIT-6 and MSQ 
questionnaires). 
 
Application training: Eligible participants who enroll to the study will be trained to use 
the application that will be installed on their own smartphones. The participants will be 
instructed to complete a daily diary that included information on, headache with time of 
onset, migraine symptoms, and medication use. The site personnel will be required to 
document the training session in the CRF. 
 
Baseline phase: 
After the enrollment visit, participants will undergo a 4-week baseline phase aimed to 
collect headache days, medication use, migraine symptoms, and further assess 
eligibility. Participants will use the app daily to record headache with time of onset, 
migraine symptoms and medication use. To ensure compliance, the app will send daily 
reminders/notifications in a pre-specified time in the evening chosen by the participant, 
but the questionnaire will be available throughout the day. The daily reports will be 
transferred by the application to the electronic data capture (EDC) system, where they 
will be collected and registered. 
 
Qualification to enter into the treatment phase: Participants who complete the diary 
in at least 22 out of the 28 days during the baseline phase (80%), have between 6 to 24 
headache days during the 28-day baseline period, at  least 4 of their headache days 
during the baseline phase fulfill the ICHD-3 criteria for migraine (migraine without aura 
[code 1.1; C and D], or with aura [code 1.2; B and C], or probable migraine, or headaches 
requiring the use of migraine-specific medications such as triptans, gepants or ergot 
derivatives) will continue to the treatment phase. Participants who fail these criteria will 
be excluded from the study and considered screen failure. 
 
Second visit- 
Device training: Eligible participants who successfully complete the baseline phase will 
be randomized in a 1:1 ratio into one of the two groups: either active (treatment with 
Nerivio active device) or sham group (treatment with Nerivio sham device). During this 
visit, participants will receive general instructions on study procedures, device mode of 
operation and warnings/precautions. After the training, patients will be instructed to use 
the device at home every other day.  
The site personnel will be required to document the training session in the CRF. If the 
visit is conducted remotely, the devices will be shipped/mailed to the participant 
beforehand, with clear instructions not to open the device before the training. 
 

 
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Before the first device use, the participants will watch a short instructional video that 
includes how to pair the device, finding the optimal individual stimulation intensity level 
(perceptible but not painful, just below the pain threshold), and instruction to use the 
device every other day for 45 minutes and to complete a daily questionnaire.  
 
Treatment phase: 
During this 8-week phase, participants will be instructed to use the device every other day 
for 45 minutes. Participants will also be instructed to continue completing a daily diary with 
information on their headaches with time of onset, migraine symptoms and medication 
use, as performed in the baseline phase. Participants will be instructed to use the device 
with an intensity level that is perceptible but not painful. Adverse events will be reported 
throughout this phase of the study directly to the site staff and recorded in the CRF. 
 
Participants can treat their migraine and headaches with their usual acute treatments. 
(Nerivio will not be used for acute treatment to avoid bias between the groups). 
Blinding will be assessed at the end of the treatment phase when participants will be asked 
of their presumed group assignment (active, sham, do not know). 
 
Third visit-  
Transition to the follow-up phase (open label): 
During the visit, participants will complete the following questionnaires: 
1. Patient assessment of treatment group during the treatment phase 
2. HIT questionnaire regarding weeks 9-12 
3. MSQ regarding weeks 9-12 
At the end of the 8-week treatment phase, participants from both arms (active and sham) 
may continue to an open-label follow-up phase in which they will receive an active Nerivio 
device to use during the follow-up phase.  
Participants who meet the following conditions will be offered to enter the pre-emptive 
follow-up phase: 
• 
Between 6 to 16 headache days during the baseline phase. 
• 
Participants experience at least one prodromal symptom, within 24 hours prior to the 
onset of their migraine headache, in at least half of their migraine attacks during the 
baseline phase. 
• 
Participants completed the daily questionnaires in at least 70% of the days during the 
treatment phase  
•     Treated every other day on at least 24 and no more than 32 days during the 56 days 
of the treatment phase. 
 

 
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All other patients will be offered to receive an active device and continue in a safety follow-
up, using Nerivio for preventive treatment of migraine, as instructed in the treatment 
phase. 
 
Follow-up phase (open label): 
Participants who continue into this 4-week period of follow-up phase, will receive an active 
device. Those who do not meet the requirements (see above) will use Nerivio for 
preventive treatment of migraine, as performed during the treatment phase. Participants 
will continue to complete a daily diary and use the device every other day for 45 minutes. 
Participants who meet the requirements (see above) will receive the device for pre-
emptive treatment of migraine. Participants will be instructed to use Nerivio within 60 
minutes of prodrome symptoms onset, prior to the start of a headache, for a 45-minute 
treatment. The participants will be instructed to complete questionnaires regarding their 
headache, prodrome symptoms, and medication use at baseline (start of treatment), 2 
hours post-treatment and 24 hours post-treatment. In addition, participants will be 
instructed to continue to complete the daily diary as in the baseline and treatment phases. 
Participants will be permitted to take their usual care medications during this phase, except 
for the timepoint between starting a device treatment until 2 hours after treatment start.   
Fourth (final) visit – End of study:  
During the final visit, participants may be asked to fill additional questionnaires on their 
migraine and their experience with the device. In addition, all study devices will be returned 
to the clinic, either in person or by mail/shipment.  
 
Study design is summarized in Figure 4 below. 
 

 
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Figure 4:  Study design    
 
 
6.3.1. 
Study duration 
The duration of the study for each participant is expected to be up to 16 weeks.  
 
6.4. Study endpoints  
6.4.1. Primary efficacy endpoint 
Difference between treatment groups in the mean change in number of migraine 
headache days per month comparing the 4-week baseline phase (weeks 1 through 
4) with the last 28 days of the treatment phase (weeks 9 through 12).  
 
A 
migraine 
headache 
day 
is 
defined 
as 
a 
calendar 
day 
with  
headache that is accompanied by at least one of the following symptoms: aura, 
photophobia, phonophobia, nausea and/or vomiting; or a calendar day with a 
headache that is successfully treated with a migraine-specific acute medication. 
 
6.4.2. Secondary efficacy endpoints 
1. Difference between treatment groups in the mean change in number of 
moderate/severe headache days per month comparing the 4-week baseline 

 
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phase (weeks 1 through 4) with the last 28 days of the treatment phase (weeks 
9 through 12). 
A moderate/severe headache day is defined as a calendar day with moderate 
or severe headache. 
 
2. Difference between treatment groups in the mean change in the number of 
headache days per month from the 4-week baseline phase (weeks 1 through 4) 
to the last 4 weeks of the treatment phase (weeks 9 through 12). 
A headache day is defined as a calendar day with headache (at any severity). 
 
3. Difference between treatment groups in the percentage of patients achieving at 
least 50% reduction from baseline in the mean number of headache days (all 
severities) per month in the last 4 weeks of the treatment phase (weeks 9 
through 12). 
 
4. Difference between treatment groups in the mean change from baseline in the 
HIT-6 total score in the last 4 weeks of the treatment phase (weeks 9 through 
12). 
 
5. Difference between treatment groups in the mean change from baseline in the 
MSQ role function in the last 4 weeks of the treatment phase (weeks 9 through 
12). 
 
6.4.3. 
Exploratory efficacy endpoints 
1. Difference between treatment groups in the reduction in the mean number of 
acute headache/migraine medication days per month in the last 4 weeks of the 
treatment phase (weeks 9 through 12) compared to Baseline (weeks 1 through 
4).  
An acute headache/migraine medication day is a calendar day on which the 
patient consumes at least one dose of any medication (OTC or prescribed) for 
acute treatment of headache or migraine.  
 
[Endpoints below relate to the pre-emptive follow-up phase] 
2. Percentage of patients who treat for the first treatment in the pre-emptive phase, 
during a prodrome, when they are pain free, and remain pain free during the 
following 2 hours after the treatment, without use of acute medication.  
3. Percentage of patients who treat for the first treatment in the pre-emptive phase, 
during the prodrome, when they are pain free, and remain pain free during the 
following 24 hours after the treatment, without use of acute medication.  
4. Percentage of patients who treat for the first treatment in the pre-emptive phase, 
during the prodrome, when they are pain free, and remain either pain free or 

 
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with mild pain during the following 24 hours after the treatment without use of 
acute medication.  
5. Mean change in the percentage of prodromes which were followed by a 
headache within 24 hours from baseline to the end of the pre-emptive follow-up 
phase.  
6. Mean change in the average number of moderate/severe headache days per 
month in the pre-emptive phase compared to the 4-week baseline phase. 
 
[Endpoint below relate to Health Economics analysis] 
7. Differences between active and sham groups in reduction in the means of the 
following events from baseline (weeks 1-4) to second month of treatment 
(weeks 9-12): 
a. Absenteeism – number of missed work/school days 
b. Presenteeism – number of work/school days with moderate/severe 
functional disability 
c. Healthcare provider appointments 
d. ED/ER visits 
e. Brain MRI/CT scans  
 
8. Feasibility of a migraine prediction algorithm:  
Analysis of the daily information provided by the participants for the purpose 
of developing a migraine prediction algorithm. 
 
6.4.4. Safety endpoints 
1. Device safety   
The incidence of adverse events in general and by seriousness, severity and 
association to the device.  
 
2. Treatment tolerability  
The percent of subjects who fail to complete the study because of device-related 
adverse events. 
 
6.5. Methods and timing of assessing and analysing variables 
Once the last patient completes the treatment phase of the study and all the queries will 
be resolved, the database will be locked, cleaned, and exported for final statistical 
analysis. A study report will be issued following the final database lock.  
 
6.6. Procedures to ensure blinding 
This is a double-blind study: neither the patient, nor the investigators will be aware of arm 
allocation of each study participant. Maintaining double blind design is a known challenge 
in non-invasive neuromodulation devices trials. Several means are planned to ensure the 
double-blind aspect of this trial.  

 
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• Selection of identically looking active and sham devices as control means is only a 
single step aimed at maintaining blindness.  
• Adherence to randomization procedure by clinical staff is critically important.  
• Importance of adherence to study design and procedures will be explained to 
participants during 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 ”strong but not painful” level.  
• Before the end of the treatment phase, 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.  
• Device training will be performed using a training video with minimal contact with 
the site staff to maintain the blinding. 
• The patient will use only the allocated device following the randomization 
procedure. 
To assess blinding, participants will be asked at the end of the treatment phase which 
group they think they had been assigned to (active, sham, do not know). 
 
6.7. Data management 
The data management function will be supported by a cloud-based electronic data 
capture (EDC) system developed by FlaskData.IO (Modi’in, Israel). FlaskData.IO 
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 the clinical personnel will be entered directly into pre-specified eCRF 
screens by the 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 soon as possible to its 
occurrence. Efforts will be made to identify missing or incorrect data and promptly resolve 
these issues.  
 
Data collected by the smartphone application will be directed to a secured cloud-based 
database where it will undergo analysis aimed at detecting of missing data and other 
inconsistencies. The smartphone 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, will be communicated to the 

 
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research coordinator of the corresponding site, using the 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 personnel. 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 the sponsor’s study monitor of such 
issues. Missing data will be automatically identified by a script running on the cloud of 
FlaskData.IO, and queries will be generated to the participants and the 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 will be performed. Processed data are further pushed into 
the EDC system. 
 
A daily back-up of the database will be performed. In addition, a copy of each 
participant’s ePROs and other activities will be stored in his/her smartphone memory and 
can be retrieved if needed.   
EDC tools will be used for locking the database and exporting to SAS compatible format 
for interim and final statistical analyses. Query resolution will also be performed using 
EDC tools. 
All paper-based source data and relevant medical documents that also serve as source 
documents will be maintained by the sites and will be available as eCRF attachments. 
participant identification will be removed from all data and the participants will be 
identified by their codes. The site investigator is responsible for ensuring that eCRFs are 
filled in a timely manner and that relevant paper documents are properly stored. The 
investigators will provide the documents to the sponsor either through the sponsor 
representative or by mail per the sponsor’s request. 
Access to data will be authorized and controlled, in accordance with relevant regulations 
and guidelines. 
 
The 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 CRFs supplied by the 
sponsor. 
Specifics of data query handling are given in data management and monitoring plans.  
Audit trail for data entry and corrections will be maintained. 
 
6.8. Monitoring plan 
An independent data monitoring committee (DMC) will be responsible for providing 
oversight of the data monitoring issues. The DMC will periodically review and evaluate 
the accumulated data. The DMC will make recommendations regarding enrollment, 
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 recruitment targets, retention, 
protocol adherence, and quality of data collection procedures 

 
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• 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 and recommendations  
• Futility monitoring: futility will be assessed during the interim analysis   
 
 
7. STATISTICAL CONSIDERATIONS 
7.1. 
Study design and aim 
The study is designed as a prospective, double-blind, sham-controlled, multicenter 
study. This study aim is to evaluate the efficacy and safety of Nerivio for the preventive 
treatment of migraine. 
  
7.2. 
Endpoints  
7.2.1. Primary efficacy endpoint 
The primary efficacy endpoint of the study is the difference between the groups in the 
mean change in the average of migraine headache days per month comparing the 4-
week baseline phase (weeks 1 through 4) with the last 28 days (4 weeks) of the 
treatment phase (weeks 9 through 12). The groups will be compared with the 
independent t-test. 
 
A 
migraine 
headache 
day 
is 
defined 
as 
a 
calendar 
day 
with  
headache that is accompanied by at least one of the following symptoms: aura, 
photophobia, phonophobia, nausea and/or vomiting; or a calendar day with a headache 
that is treated with a migraine-specific acute medication. 
 
Subset Analyses 
The primary endpoint will also be evaluated stratified by center using a General Linear 
Model ANOVA test. 
A sensitivity analysis of the primary endpoint will be performed to assess the impact 
of missing data on the study outcome. This will be performed using several possible 
imputation methods. 
Adjustment for other covariates such as demographics or other baseline participant 
characteristics may be performed by adding these variables into a multivariate linear 
regression. 
 
7.2.2. Secondary efficacy endpoints 
Secondary efficacy endpoints include: 

 
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1. Difference between treatment groups of mean change in the average number of 
moderate/severe headache days per month comparing the 4-week baseline phase 
(weeks 1 through 4) with the last 28 days of the treatment phase (weeks 9 through 
12). 
A moderate/severe headache day is defined as a calendar day with 
moderate or severe headache. 
2. Difference between treatment groups in the mean change in the average number 
of headache days per month in comparing the 4-week baseline phase (weeks 1 
through 4) with the last 4 weeks of the treatment phase (weeks 9 through 12). A 
headache day is defined as a calendar day with headache (at any severity). 
3. Difference between treatment groups in the achievement of at least 50% reduction 
from baseline in the mean number of moderate to severe headache days per 
month in the last 4 weeks of the treatment phase (weeks 9 through 12). 
4. Difference between treatment groups in the the mean change from baseline in the 
HIT-6 total score.  
5. Difference between treatment groups of the mean change from baseline in the 
MSQ role function.  
 
The secondary efficacy variables will be summarized by a count and percentage and 
compared with a chi-squared test or a Fisher’s exact test. 
 
7.2.3. Exploratory efficacy endpoints 
Exploratory efficacy endpoints include: 
1. Difference between treatment groups in the reduction of mean number of 
headache/migraine acute medication days per month in the last 4 weeks of the 
treatment phase (weeks 9 through 12). An acute headache/migraine medication 
day is a calendar day on which the patient consumes at least one dose of any 
medication (OTC or prescribed) for acute treatment of headache or migraine. 
2. Percentage of patients who treat for the first treatment during a prodrome, when 
they are pain free, and remain pain free during the following 2 hours after the 
treatment, without use of acute medication.  
3. Percentage of patients who treat for the first treatment in the pre-emptive phase 
during a prodrome, when they are pain free, and remain pain free during the 
following 24 hours after the treatment, without use of acute medication.  
4. Percentage of patients who treat for the first treatment in the pre-emptive phase 
during a prodrome, when they are pain free, and remain either pain free or with 
mild pain during the following 24 hours after the treatment without use of acute 
medication.  
5. Mean change in the percentage of prodromes which were followed by a headache 
within 24 hours from baseline to the end of the follow-up phase.  
6. Mean change in the average number of moderate/severe headache days per 
month comparing the 4-week baseline phase with the follow-up phase. 

 
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7. Difference between treatment groups in the reduction of the health economics 
metrics: absenteeism days, presenteeism days, ED/ER visits, physician 
appointments visits and CT/MRI scans – from weeks 1-4 to weeks 9-12. 
8. Feasibility of a migraine prediction algorithm: 
Analysis of the daily information provided by the participants for the development 
of a prediction algorithm for the purpose of predicting a migraine attack on the 
following day. 
 
7.2.4. Safety endpoints 
The safety endpoints of adverse events and tolerability will be assessed by review of 
all safety parameters, including adverse events. 
The incidence of treatment related adverse events will be assessed as a function of 
severity and association to the device. The time of resolution of the adverse events 
and need for treatment will also be analysed.   
 
7.3. 
Statistical hypothesis 
In this study, we will test the following hypothesis: 
• H0 : MDa-MDs=0 
• H1: MDa-MDs≠0 
Where MDa is the mean change in number of migraine days in the in the active arm, and 
MDs is the mean change in number of migraine days in the sham arm. 
 
7.4. 
Sample size 
A sample size of 234 participants, 117 per each treatment arm, was determined to provide 
80% power to detect a mean (±SD) difference of 2±3.0 in the reduction in number of 
migraine headache days from the baseline to weeks 9-12 of the treatment phase, between 
the active group and the sham group at a two-sided alpha level of 0.05. With an anticipated 
discontinuation rate of about 35%, up to375 participants are planned to be enrolled. In 
case of higher dropout or non-eligible participants or missing data, enrollment may be 
extended in order to reach the desired sample size. 
 
7.5. 
Analysis sets 
Intent to treat analysis set (ITT) 
The ITT analysis set includes all randomized patients.  
  
Modified intend to treat analysis set (mITT) 

 
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The mITT analysis set includes all ITT participants who had at least 22 days of efficacy 
assessments in weeks 9-12 of the treatment phase and at least 12 treatments 
performed in weeks 9-12.  
 
 
Statistical analysis of the analysis sets 
The ITT analysis set will serve as the main set for safety assessments. 
The mITT analysis set will serve as the primary set for the efficacy assessment.  
    
7.6. 
Statistical analysis  
7.6.1. General considerations 
Statistical analyses will be performed using a statistical software such as SAS® (SAS 
Institute, Cary NC, USA), or SPSS statistic program version 27.0 (or higher) software. 
Baseline demographic and other baseline characteristics, together with safety analyses 
will be performed on all participants who were randomized. Baseline values are defined 
as the last valid value prior to treatment. 
Where confidence limits are appropriate, a two-sided 95% confidence interval will be 
constructed.  
 
7.6.2. Demographic and other baseline variables 
Demographic and baseline condition related characteristics will be tabulated. 
Continuous variables will be summarized by a mean, standard deviation, minimum, 
median and maximum, and categorical variables by a count and percentage. 
 
7.6.3. Efficacy analysis 
The efficacy endpoints will be assessed on evaluable reports of daily symptoms.  
A modified intent to treat analysis set (mITT) will include all ITT participants who had at 
least 22 days of efficacy assessments in the last 4 weeks of the treatment phase (weeks 
9 through 12) and at least 12 treatments performed in the last 4 weeks of the treatment 
phase (weeks 9 through 12). The efficacy analyses will be conducted on the mITT 
analysis set. The mITT will be assessed for the mean change in migraine days from 
the 4-week baseline phase (weeks 1 through 4) to the last 4 weeks of the treatment 
phase (weeks 9 through 12) and will be compared between treatment groups with a 
significance level p<0.05.  
 
7.6.4. Safety analysis 
Safety and tolerability will be assessed on the ITT analysis set by reviewing of all safety 
parameters, including adverse events. Serious adverse events, device-related SAEs, 
adverse events (by type and overall), device-related AE, adverse device reactions and 
device malfunction rates will be documented. Treatment tolerability, the number and 
percent of subjects who fail to complete the study and the number and percent of 

 
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subjects who fail to complete the study because of adverse events will be presented. 
Time to withdrawal will also be assessed and presented by Kaplan-Meier curves. 
 
7.6.5. Treatment by sites interaction 
Poolability across centers may be assessed using logistic regression. Centers with less 
than 10 subjects will be grouped together by geographical area. If the center term is 
found significant (p<0.1), the reason for this interaction will be further explored. This 
evaluation may include demographic features, symptoms at presentation, clinical and 
treatment history, and site comparability in the features found to be associated with the 
primary endpoint variables. Adjustment for other covariates such as demographics or 
other baseline subject characteristics may be performed by adding these variables into 
a logistic regression model. The analysis may be repeated for US sites vs. out of US 
(OUS) sites, if applicable. 
 
7.6.6. Handling of missing data 
For management of missing data in the primary analysis, i.e., missing daily reports, the 
number of migraine days per each 28-day period in the Treatment phase will be prorated 
(normalized) to a 28-day. For example, if a patient had 24 reported days during weeks 9-
12, with 7 migraine days, her number of migraine days in this period will be normalized to 
(7/24) * 28 = 8.17 
 
7.6.7. Interim analysis 
One interim analysis is planned after at least 35% of the data is collected (~84 participants 
in both arms [42 per arm]). The study will continue to the originally planned sample size if 
the results are favorable (difference between groups in the mean reduction of migraine 
days of at least 1 migraine day). The interim analysis will be performed on both the mITT 
and ITT analysis sets, and the enrollment may be stopped due to futility if the interim 
effects fall below the threshold.  
 
7.6.7.1. Procedure 
After all the relevant data will be entered into the database, a soft lock to the database will 
be performed. An independent unblinded statistician will perform the assessments 
described below.  A designated decision committee will recommend whether to continue 
or stop the study once the interim results are available. 
 
In the interim analysis, the data of all evaluable subjects enrolled up to that point will be 
analyzed. 
 

 
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7.6.7.2. Blinding 
Only the unblinded statistician and the two other members of the DMC will be exposed to 
the interim report. This team may also have access to the unmasked information of the 
interim analysis. The investigators and company directors will only be informed of a 
decision to continue or to discontinue the trial, or to implement modifications in trial 
procedure and/or sample size. The unblinded statistician who is responsible for 
conducting the interim analyses should ensure that the unmasked data is not available to 
any unauthorized person within or outside the company. 
Only the decision and recommendation will be shared with the sponsor and the study 
personnel. 
  
7.7. 
Randomization 
After a subject meets the eligibility criteria, he/she will be equally allocated (with a 1:1 
ratio) to one of the following treatment groups based on a randomization scheme with 
blocks stratified by center:  
• Active 
• Sham 
 
Subjects will be stratified according to their headache days frequency reported during the 
baseline phase, to achieve approximately equal numbers of chronic and non-chronic 
participants. High frequency (HF) group will contain all subjects reported 15 headache 
days or more, and low frequency (LF) group will contain all subjects reported less than 15 
headache days. The stratified randomization will allow a balance in the number of 
headache days between treatment groups and prevent bias in the mean change of 
migraine/headache days.  
The randomization scheme will be prepared by a biostatistician using a random number 
generating procedure. 
 
7.8. 
Blinding 
This is a double-blind study, the subjects, and investigators will be blinded to the treatment 
allocated to each subject. The study personnel will be blinded to the randomization block 
size.  
 
Each device will be programmed with one of two versions of firmware that deliver either 
active or sham electrical stimulation. In all other aspects, the active and the sham 
conditions will be kept identical. 
 
 

 
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8. DATA MANAGEMENT 
8.1. 
Data capture 
Data capture will be performed using an electronic data collection (EDC) system in 
conjunction with electronic patient reported outcome (PRO) 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 FlaskData.IO. The EDC enables secure collection, transmission, 
validation, monitoring and real-time administration of the data collected at the sites and 
by the smartphone application. The system offers a 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 Investigations.” 
Except for patient reported outcomes which are directly reported by the participants in 
the smartphone application, data reported on the eCRF should be driven from source 
documents and should be consistent with these source documents. Editing of data will 
be done with a full audit trail. 
PRO data collected from the smartphone application will be saved in dedicated log files 
on the smartphones for backup purposes and transferred to the EDC system. 
  
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 (i.e. patient reported outcome completed 
directly into the smartphone app). Therefore, the CRF may be used for direct data entry, 
but only in pre-defined fields. 
  
8.2. 
Data quality assurance 
To ensure the quality of clinical data across all subjects, a clinical data management 
review of the patient data in the CRF will be performed by the sponsor. During this 
review, patient data will be assessed 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 the sponsor. 
Discrepancy resolution will be documented within the database audit trail. 
 
8.3. 
Electronic signatures 
The PI will electronically sign each individual eCRF after the data has been cleaned, 
monitored and reviewed. The electronic signature asserts that the investigator reviewed 
the eCRFs, the data queries, and the site notifications, and agrees with the content. Any 
changes made to the data after an electronic signature has been applied will result in 
invalidation of the original signature, and the PI will be required to re-sign the data after 
reviewing the change(s). 

 
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8.4. 
Verification, validation and securing of electronic data capture system 
Verification and validation of the EDC and eCRFs will be performed by a team comprising 
representatives of the developer, the sponsor and at least one of the participating sites. 
A verification and validation report will be detained by the sponsor.  
 
8.5. 
Records and data retention 
A 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. 
 
The database will be retained by the EDC system provider for a minimum of 5 years. 
 
8.6. 
Other aspects of clinical quality assurance  
The site PI or a person designated by the site PI is responsible for establishing and 
maintaining compliance with the study protocol. The study PI is responsible for 
addressing quality assurance issues (e.g. correcting procedures that are not in 
compliance with the protocol). The study coordinator is responsible for quality control 
issues (e.g. correcting errors in data entry). The sponsor will 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 a monitoring 
plan. An independent DMC will be responsible for providing oversight of the data 
monitoring issues and conducting periodical reviews that may include recommendations 
regarding enrollment, continuation, modification, or termination of the study.   
Site audits by the sponsor may be conducted 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 a health authority 
audit.  
 

 
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9. 
AMENDMENTS AND DEVIATIONS FROM THE PROTOCOL 
9.1. 
Protocol amendments 
The protocol cannot be amended by the investigator without obtaining the sponsor’s 
approval. Protocol amendments will be submitted for approval to local IRB/EC and, if 
applicable, to the respective regulatory authority (RA). The amendments can be 
implemented in the study only after an IRB/EC and/or RA approval are obtained. Non-
substantial changes (e.g. minor logistical or administrative changes, change of 
monitor(s), telephone numbers, renewal of insurance) which do not affect the rights, 
safety and well-being of human subjects and/or are not related to the clinical investigation 
objectives or endpoints, may only require a notification to the IRB/EC and/or regulatory 
without protocol amendment. 
The following documents are relevant to the protocol but are not considered part of the 
protocol.  These documents 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 
 
9.2. Protocol deviations 
A protocol deviation is any noncompliance with the clinical study protocol, Good Clinical 
Practice, or related SOPs requirements. The deviation may be associated with the 
subject, the investigator, or study personnel. The investigator/co-investigators must 
obtain the sponsor’s approval for all protocol deviations, except for cases in which 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 with the protocol will be assessed by the study monitor during the monitoring 
visits as well as remotely, using designated reports provided by the EDC system. 
All protocol deviations will be addressed in study subject source documents and promptly 
reported to the site IRB, according to local requirements. 
   
9.3. Procedures for recording, reporting and analysing protocol deviations 
All protocol deviations will be documented in source documents and appropriate 
eCRFs. 
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 with the principal 
investigator. 

 
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The study monitor will ensure that major protocol deviations are discussed with the 
investigator. Major deviations include deviations that: 
• impact patient safety  
• alter the risk/benefit ratio 
• compromise the integrity of the data  
• affect willingness of the patient’s participation in the study  
 
The deviations will be reported to the IRB/EC periodically or as specified by the local 
regulations. Further documentation of any changes in research activity should be 
submitted to the sponsor and the IRB/EC if the deviations 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.  
 
In addition to the immediate reporting, the study monitor will 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 will be sent to the sponsor. The sponsor or its designee will review 
records of deviations and will consider the need for corrective and preventive action 
and further external reporting to regulatory authorities. Deviations will be summarized 
and included in the study report. The potential impact/lack of impact of the deviations 
on the study results will be assessed. 
 
9.4. Notification requirement and timelines 
Major deviations should be escalated to the sponsor within 5 business days. Protocol 
deviations must be reported to local IRB/EC according to their guidelines. The site PI or 
other designated site staff member is responsible for adhering to local IRB/EC 
requirements. 
 
10. DEVICE ACCOUNTABILITY 
The devices will be provided by Theranica Bioelectronics (sponsor), with all required 
labeling. The device number will be documented in the CRF and in the site log when 
provided to the participant. Each batch of devices delivered to the clinical sites for 
allocation to study participants will be accompanied with a shipment note. The device 
shipment records will be maintained by the sponsor as well as on site. 
 
Prior to distribution, the devices will be stored in a designated locked cabinet. The access 
to the investigational devices will be controlled by the research staff. The devices will only 
be 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 will be provided to 
the participant, it will be paired with the participant’s smartphone using Bluetooth 

 
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connection. During device allocation, application installation and device–smartphone 
pairing, a site allocated user ID will be entered by the study coordinator via the application.  
The three IDs (user ID, phone ID, device ID) provide a mean for identifying technical and 
PRO data from each participant in the electronic database while protecting participant’s 
privacy.  
 
The investigators will be responsible for the safe storage of the devices according to the 
instructions provided 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. The device accountability records will be 
reviewed during the monitoring visits.  
 
The investigator will be responsible for providing device use training to the participants 
according to the instructions for use 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 Bio-Electronics. 
 
 
11. INFORMED CONSENT PROCESS 
Informed consent must be obtained from the participant before any protocol-related 
activities are performed. Participants must be provided with a signed copy of the consent 
form. The eCRFs will be updated that the informed consent form has been signed. 
  
 
12. ADVERSE EVENTS 
Adverse event (AE) is defined as any unfavorable and unintended medical change, 
temporally associated with the use of the sponsor’s product, whether or not considered 
related to the use of the product. Any worsening (i.e., any clinically significant adverse 
change in frequency and/or intensity) of a preexisting condition which is temporally 
associated with the use of the sponsor’s product, is also an adverse experience. An 
adverse device effect (ADE) is an adverse event related to the use of the investigational 
device. In this study the ADE refers to side effect and complications. 
 
A serious adverse event (SAE) is defined as an adverse event that leads to 
a) death,  
b) 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 body structure or body function 

 
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c) fetal distress, fetal death or a congenital abnormality or birth defect  
 
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. 
12.1. Characteristics of AEs 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
 
Maximum intensity 
Mild: awareness of symptom, but easily tolerated 
Moderate: definitely acting like something is wrong 
Severe: extremely distressed or unable to do usual activities 
 
Duration 
Record the start and stop dates of the adverse experience. If less than 1 day, indicate 
the appropriate length of time and units. 
 
Relationship of an AE and SAE to the study device  
The relationship of the adverse event to the study device is defined as: 
 
Definitely related: There is evidence of exposure to the device. The temporal sequence 
of the AE onset relative to use of the device is reasonable. The AE is more likely 
explained by the device than by another cause. Dechallenge is positive. Rechallenge (if 
feasible) is positive. The AE shows a pattern consistent with previous knowledge of the 
device.  
Possibly related: There is evidence of exposure to the device. The temporal sequence 
of the AE onset relative to use of the device is reasonable. The AE could have been due 
to another equally or less likely cause. Dechallenge (if performed) is positive. 
Probably related: There is evidence of exposure to the device. The temporal sequence 
of the AE onset relative to use of the device is reasonable. The AE is more likely 
explained by the device than by another cause. Dechallenge (if performed) is positive.  
Unlikely related: The relationship with the use of the device seems not relevant and/or 
the event can be reasonably explained by another cause, but additional information may 
be obtained.  
Definitely not related: The subject/patient did not use the device; or temporal sequence 
of the AE onset relative to device use is not reasonable; or there is another obvious 
cause of the AE. 

 
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12.2. Reporting of AEs and SAEs 
All adverse events will be recorded in appropriate adverse events case report form. The 
adverse events will be used for the safety assessment. An on-site visit to monitor the 
adverse event will be conducted if the principal investigator determines it is needed. 
These visits will be reported using designated case report forms. If during the last visit, 
an ongoing device-related AE is present, the participant will be monitored for 
approximately 2 weeks, until the AE resolves or a steady state is achieved.   
 
The PI must report any SAE or SADE to the sponsor within 1 business day: 
Theranica Bioelectronics  
Dr. Dagan Harris 
Tel: +972.72.390.9758 
Fax: + 972.72.390.9755 
Email: daganh@theranica.com 
 
The sponsor is responsible for reporting the adverse events to regulatory agencies, 
IRB/IECs, and investigators in accordance with all applicable global laws and 
regulations. 
 
12.3. Anticipated device-related AEs 
Possible adverse events associated with remote electrical neuromodulation include, but 
are not limited to, the following: 
• 
Numbness of the hand/arm 
• 
Itching 
• 
Muscle spasms 
• 
Redness 
• 
Warmth sensation 
• 
Tingling 
• 
Pain in the arm 
 
All anticipated device-related AEs, if present, are temporary and should disappear 
shortly after the treatment. 
The following migraine symptoms are foreseeable and will not be considered as device 
related: headache, nausea, light sensitivity, sensitivity to noise, allodynia, abdominal 
pain, loss of appetite, cold or heat sensation, paleness, fatigue, dizziness, anxious mood, 
fever (rare), blurred vision, vision symptoms such as bright flashing dots or lights, blind 
spots, wavy or jagged lines (aura). 
 
12.4. Device malfunction 
Device malfunction is an inadequacy of the device with respect to its identity, quality, 
durability, reliability, safety, or performance, such as failure, use error or inadequate 
labeling. Device malfunctions may or may not be associated with an adverse event.  

 
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All device malfunctions will be reported in the eCRF. Device malfunctions 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 and needed, the 
device(s) associated with malfunction or failure will be retained until arrangements for its 
collection are made by the sponsor. 
 
All device malfunctions will be summarized and reported in the clinical study report and 
will be reported to the regulatory authorities according to local reporting requirements. 
 
 
13. EARLY TERMINATION 
13.1. Criteria and procedures 
The study may be discontinued if: 
 
The sponsor decides to terminate the study due to company considerations (e.g. the 
data monitoring committee recommends terminating the study based on the interim 
analysis)  
 
If in the opinion of study PI, the study presents an unreasonable medical risk to the 
patients, the PI may close the site under his/her responsibility. 
 
If the clinical investigation terminated early or suspended, the sponsor will send a report 
justifying this decision 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. Enrolled 
subjects will be followed according to the institution’s standards and guidelines. 
 
13.2. Requirements for patient follow-up in case of withdrawal 
If a patient withdraws consent, all efforts will be made to collect the final visit observations 
as soon as possible. 
 
 
14. PUBLICATION POLICY 
The publication policy is defined in the sponsor-investigator agreement. 
 
 
15. PATIENT CONFIDENTIALITY & DATA PROTECTION 
The privacy of the participants and the confidentiality of all personal data will be 
maintained in reports and publications and will not be otherwise published in any way. 

 
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The 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 the authenticity of the 
data collected, as documented in the informed consent form. 
 
 
16. GUIDELINES AND APPLICABLE DOCUMENTS 
• 
EN ISO 14155; (2011): Clinical investigation of medical devices for human patients  
• 
EN ISO 14971; (2012): Medical devices – Application of risk management to medical 
devices 
• 
International Conference of Harmonization Good Clinical Practice guidelines 
• 
FDA Guidance for Industry: Computerized Systems Used in Clinical Investigations 
 
 

 
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