A Prospective, Single Arm, Open Label Study of the Safety and Efficacy of Nerivio™ for the Acute Treatment of New Daily Headache Persistence (NDHP) in Adolescents
Phase: NA
Conditions: New Daily Persistent Headache (NDPH)
Sponsor: Children's National Research Institute

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A prospective, single arm, open label study of the safety and 
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Headache Persistence (NDHP) in adolescents 
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CLINICAL INVESTIGATION PLAN 
STUDY TITLE: 
A prospective, single arm, open label study of the safety 
and efficacy of Nerivio™ for the acute treatment of New 
Daily Headache Persistence (NDHP) in adolescents 
PROTOCOL NUMBER: 
00016835 
REVISION: 
1.0 
RELEASE DATE: 
01/Feb/2022 
DEVICE: 
Nerivio, a Neuromodulator device for the acute treatment of 
migraine 
INVESTIGATOR: 
Marc DiSabella, DO 
CONTACT DETAILS: 
Marc DiSabella, Do 
Tel: 202-476-2120 
Fax: 202-476-2864 
EMAIL: MDISABEL@CHILDRENSNATIONAL.ORG 
 
 
 
 
 
 
 
 
 
 
 
 
APPROVED BY: 
POSITION: 
  
_ 
DATE: (DD/MM/YY) 
_ _ /_ _ /_ _ 
SIGNATURE: 
  
  
_ 
_ _ /_ _ /_ _ 
  

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The Principal investigator states the following: 
 
a) 
This study will be conducted in compliance with the protocol (after being 
approved by the local IRB/EC and, if required, by the relevant health care 
agencies), US 21 CFR Parts 50, 54, 56 and 812, 45 CFR Part 46, national laws and 
regulation concerning clinical trials, the Good Clinical Practices (GCP) set forth in 
ISO 14155 (2011) standard and the ethical principles that have their origin in the 
Declaration of Helsinki. 
b) 
The Protocol, Informed Consent Form (ICF), patient's information material, and 
advertising material (if applicable) will be submitted and approved by the ethics 
and regulatory authorities, and any request by the IRB/EC or regulatory agencies 
will be complied with. Approval will be obtained prior to enrollment of any 
patients. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator’s Signature 
Date 
 
 
 
 
Investigator’s Printed Name 

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A prospective, single arm, open label study of the safety and efficacy of Nerivio™ 
for the acute treatment of New Daily Headache Persistence (NDHP) in adolescents 
 
 
Table of contents 
1. 
Synopsis ................................................................................................................................... 5 
2. 
Background .............................................................................................................................. 8 
3. 
Identification and description of the device information ............................................................ 8 
3.1. 
Intended use ............................................................................................................................. 8 
.3.2 
Device description .................................................................................................................... 8 
3.3. 
The application ......................................................................................................................... 9 
4. 
Objectives & hypotheses ........................................................................................................ 10 
4.1. 
Study objectives ..................................................................................................................... 10 
4.2. 
Study hypothesis .................................................................................................................... 10 
5. 
Study design ........................................................................................................................... 10 
5.1. 
Participants ............................................................................................................................. 10 
5.1.1. 
Inclusion criteria ...................................................................................................................... 10 
5.1.2. 
Exclusion criteria .................................................................................................................... 10 
5.1.3. 
Withdrawal/discontinuation ..................................................................................................... 11 
5.2. 
Procedures ............................................................................................................................. 12 
.5.2.1 
Study duration ........................................................................................................................ 13 
5.3. 
Study endpoints ...................................................................................................................... 13 
5.3.1. 
Primary endpoints ................................................................................................................... 13 
5.3.2. 
Secondary endpoints .............................................................................................................. 13 
5.3.3. 
Exploratory endpoints ............................................................................................................. 14 
5.3.4. 
Safety endpoints ..................................................................................................................... 14 
6. 
Statistical Considerations ....................................................................................................... 14 
6.1. 
Study design and aim ............................................................................................................. 14 
6.2. 
Sample size ............................................................................................................................ 14 
6.3. 
Analysis sets........................................................................................................................... 15 
6.4. 
Statistical analysis .................................................................................................................. 15 
6.4.1. 
General considerations ........................................................................................................... 15 
6.4.2. 
Demographic and other baseline variables ............................................................................. 15 
6.4.3. 
Safety analysis ....................................................................................................................... 16 
6.4.4. 
Efficacy analysis ..................................................................................................................... 16 
7. 
Data management .................................................................................................................. 16 
7.1. 
Data capture ........................................................................................................................... 16 
7.2. 
Records and data retention .................................................................................................... 17 

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8. 
Device accountability .............................................................................................................. 17 
9. 
Informed consent process ...................................................................................................... 17 
10. 
Adverse events ....................................................................................................................... 17 
10.1. 
Characteristics of AEs ............................................................................................................ 18 
10.2. 
Reporting of AEs and SAEs ................................................................................................... 19 
10.3. 
Anticipated device-related AEs ............................................................................................... 19 
11. 
Patient confidentiality & data protection .................................................................................. 19 
12. 
Guidelines and applicable documents .................................................................................... 19 
13. 
Reference ............................................................................................................................... 20 

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1. 
Synopsis 
 
 
Title 
A prospective, single arm, open label study of the safety and efficacy of 
Nerivio™ for the acute treatment of New Daily Headache Persistence (NDHP) 
in adolescents 
Principal Investigator 
Marc DiSabella, DO 
Director, Pediatric Headache Program 
Associate Professor of Pediatrics and Child Neurology, George Washington 
School of Medicine and Health Sciences 
Children’s National Hospital, Washington, DC 
Investigational 
Device 
Nerivio™ is an FDA-authorized Remote Electrical Neuromodulation (REN) 
device for the acute treatment of migraine with or without aura in patients 
12years old or above. The device delivers transcutaneous electrical 
stimulation to the upper arm to induce conditioned pain modulation (CPM) that 
activates a descending endogenous analgesic mechanism. 
Objectives 
To evaluate the safety and efficacy of Nerivio™ in the acute treatment of New 
Daily Headache Persistence (NDHP) in adolescents (12 to 17 years of age). 
Participant 
Population 
Adolescents 12-17 years old meeting the International Headache Society 
criteria for New Daily Persistent Headache (NDPH) 
Sample size 
Up to 100 participants 
Inclusion Criteria 
1. Participants age 12-17 years old at the time of informed consent, inclusive. 
2. Participants have at least a 6-month history of headaches that meet the 
diagnostic criteria for New Daily Persistent Headache (NDPH) 
3. Participants who are on stable dosing of prophylaxis agents for at least 
three months. 
4. Participants have personal access to a smartphone (24/7) 
5. Participants must be able and willing to comply with the protocol 
6. Parents/Guardians must be able and willing to provide written informed 
consent 
7. Participants must be able and willing to provide informed assent 
Exclusion Criteria 
1. Participants with an implanted electrical and/or neurostimulator device 
(e.g. cardiac pacemaker, cochlear implant). 
2. Participants with congestive heart failure (CHF), severe cardiac or 
cerebrovascular disease. 
3. Participants with epilepsy. 
4. Participants who have undergone nerve block (occipital or other) in the 
head or neck, or treatment with onabotulinum toxin A (Botox) to the head 
and/or neck in the prior four months. 
5. Current participation in any other clinical interventional study 
6. Participants without basic cognitive and motor skills required for operating 
a smartphone. 
7. Pregnant or breastfeeding females 
8. Participants who have previous experience with the device 
9. Participants with arm circumference below 7.9 inches (20 cm) 
Study Design 
A prospective, single arm, open label trial. 
The study will be conducted in two phases: 

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Phase I - Run-in: 
Eligible participants will use a smartphone headache diary application for 28 
days. Participants who report at least 22 entries (70%) AND a constant and 
unremitting headache will be included in the treatment phase. 
The C-SSRS will be administered at the screening visit and a “since last visit” 
form which will be administered at each subsequent in-clinic study visit to 
assess possible suicidal ideation and behavior. The C-SSRS will be scored by 
the investigator or Study Coordinator who has C-SSRS certification. The 
survey will be scored immediately after taken by participant. If reports of 
suicidal ideation with intent to act (endorse item 4 or 5), reports of actual, 
aborted, or interrupted suicide attempts, or reports of behavior preparatory 
for an attempt are identified, the investigator” will refer the subject for further 
examination. 
Phase II - Treatment phase: 
Participants who meet the run-in requirements will receive an active Nerivio 
device. Participants will be instructed to use the device within 60 minutes of 
awakening with a headache or upon increasing headache severityduring a 
period of 4 week. A treatment session is of 45 minutes 
The participants will use the app to record pain intensity levels at baseline and 
2-hours post-treatment, and to record the presence/absence of associated 
symptoms (nausea, photophobia, phonophobia) at baseline and 2 hours post- 
treatment. 
Qualifying NDHP 
attack 
A qualifying NDPH attack is defined as a headache that: 
1. is at an intensity above their baseline pain 
2. is present upon awakening 
Primary endpoint 
Pain relief at 2 hours post-treatment: 
The proportion of participants achieving pain relief at 2 hours post-treatment 
in the test treatment, with no use of rescue/abortive medication (Pain relief 
defined as a reduction from severe to moderate, mild or none, moderate to 
mild or none, or mild to none) 

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Within-patient consistency 
The repeatability of headache reduction, as described in the primary endpoint 
definition, in subsequent treated attacks. Thus, this endpoint measures the % 
of patient responding to the primary endpoint in at least 50% of their treated 
attacks 
Disappearance of associated symptoms at 2 hours post-treatment 
Disappearance of nausea, photophobia and phonophobia at 2 hours post- 
treatment 
Functional disability at 2 hours post-treatment 
The proportion of participants achieving improvement of at least one grade in 
functional disability in the test treatment at 2 hours post-treatment with no use 
of rescue medication 
Improve of quality of life 
Reduction in average headache disability as measured by PedsMIDAS before 
and at 1 month after initiation of treatment with REN. 

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Exploratory 
endpoints 
1. Reduction in average headache intensity at 1 month after initiation of 
treatment with REN 
2. Reduction in perceived stress as it relates to headache, and adverse 
reactions experienced as measured by HIT-6. 
Safety endpoints 
1. The safety of Nerivio 
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 adverse 
events 
Datasets 
1. Intent to treat analysis set (ITT) 
The ITT analysis set includes all participants undergoing the treatment 
phase. 
2. Modified intent to treat analysis set (mITT) 
The mITT analysis set includes all participants undergoing the 
treatment phase who treat a test treatment within 60 minutes of attack 
onset. 
Data Analysis 
The ITT analysis set will be used for the primary endpoints of safety and 
tolerability assessments. Safety assessments will include spontaneously 
reported adverse events. The mITT analysis set will be used for the efficacy 
assessments. 

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2. 
Background 
REN is a novel treatment option which has successfully been shown to reduce 
migraine headaches in the adult population (Yarnitsky et al, 2020). There is now 
data to support its use in pediatrics and the device was recently FDA approved 
for use in pediatric migraine patients ages 12 years and older (Hershey et al, 
2021). New daily persistent headache is a constant, unremitting headache 
disorder with clinical symptoms of migraine and/or tension-type headache and is 
seen in as many as 14% of pediatric and adolescents patients (Strong et al, 
2021). Pediatric patients with a diagnosis of new daily persistent headache are 
typically resistant to standard pharmacologic treatments and often experience 
systemic side effects related to medications; thus, REN offers the potential for an 
exciting new treatment option for patients with refractory headache disorders. 
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 12 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 evaluate the effect of the Nerivio treatment in subjects with New 
Daily Persistent Headache (NDPH) in adolescents (12-17 years of age). 
 
3.2. 
Device description 
The device is a wireless wearable battery-operated stimulation unit controlled by a 
dedicated smartphone application. Treatments with Nerivio™ are self-administered by 
the user at the onset of a headache. 
 
The Nerivio™ (Figure 1) includes several main components: 
• 
A pair of electrodes covered with hydrogel and a removeable protective film 
• 
An electronic circuitry and a battery 
• 
A software that includes firmware and a software application for mobile platforms 
• An armband to secure the attachment of the device and enable a discreet treatment 

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A 
 
B 
 
C 
 
Figure 1 - Nerivio™ device. (A) Internal side, (B) External side, and (C) The armband 
 
 
3.3. 
The application 
 
Activation, control over stimulation intensity and termination of stimulation are 
performed via a dedicated smartphone application and installed on the user’s cell 
phone. The application has a graphical user interface (GUI)ץ 
 
The Nerivio application also includes a “headache diary” which collects information on 
the headache and the treatment (e.g. date & time, location, headache pain intensity, 
etc.). The application also provides notifications and indications on connection state 
and remaining number of treatments. 
 
The application can be installed from Google Play or the App store and supports 
Hebrew and English menu displays. 
 
 
 
 
 
 

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Figure 2: The app main screens 
 
 
4. 
Objectives & hypotheses 
4.1. 
Study objectives 
The objective of this study is to evaluate the safety and efficacy of Nerivio™ for the 
acute treatment of NDPH in adolescents. The goal of this study is to demonstrate 
headache relief without unexpected device-related adverse effects. 
 
4.2. 
Study hypothesis 
The hypothesis of this study is that in adolescents, REN with Nerivio™ will provide 
clinically meaningful relief of NDPH pain with a favorable safety profile. 
 
5. 
Study design 
5.1. 
Participants 
This study will be conducted on up to 100 eligible participants. 
 
5.1.1. Inclusion criteria 
 
• 
Participants age 12-17 years old at the time of informed consent, inclusive. 
• 
Participants have at least a 6-month history of headaches that meet the diagnostic 
criteria for New Daily Persistent Headache (NDPH) 
• 
Participants who are on stable dosing of prophylaxis agents for at least three months. 
• 
Participants have personal access to a smartphone (24/7) 
• 
Participants must be able and willing to comply with the protocol 
• 
Parents/Guardians must be able and willing to provide written informed consent 
• 
Participants must be able and willing to provide informed assent 
 
5.1.2. Exclusion criteria 
 
• Participants with an implanted electrical and/or neurostimulator device (e.g. cardiac 
pacemaker, cochlear implant). 
• Participants with congestive heart failure (CHF), severe cardiac or cerebrovascular 
disease. 
• Participants with epilepsy. 
• Participants who have undergone nerve block (occipital or other) in the head or neck, 
or treatment with onabotulinum toxin A (Botox) to the head and/or neck in the prior 
four months. 
• Current participation in any other clinical study that includes treatment 

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• Participants without basic cognitive and motor skills required for operating a 
smartphone. 
• Pregnant or breastfeeding females 
• Participants who have previous experience with the device 
• Participants with arm circumference below 7.9 inches (20 cm) 
• Patient has, in the judgement of the investigator, a psychiatric disorder as 
defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th 
Edition, that would interfere with adherence to study requirements or safe 
participation in the trial. This includes a current or historical diagnosis of a 
substance use disorder. 
• Patient is, in the judgment of the investigator, actively suicidal and 
therefore deemed to be at significant risk for suicide. 
• At Screening patient has answered “yes” to either Question 4 or Question 5 
on the “Suicidal Ideation” portion of the Columbia-Suicide Severity Rating 
Scale (C-SSRS) or has answered “ yes ” to any of the suicide-related 
behaviors on the “suicidal behavior” portion of the C-SSRS, and the ideation 
or behavior occurred within the past month. If reports of suicidal ideation 
with intent to act (endorse item 4 or 5), reports of actual, aborted, or 
interrupted suicide attempts, or reports of behavior preparatory for an 
attempt are identified, the investigator is to appropriately manage the 
subject in accordance with standard of care. 
 
5.1.3. Withdrawal/discontinuation 
 
Participants may withdraw consent at any time without and do not have to provide an 
explanation. 
 
Participant may be withdrawn from the study by the PI 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 
• Serious adverse event 
• Participants encountering difficulties with the investigational product (IP) (e.g. cannot 
tolerate the treatment, unable to operate the application) 

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• 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 
 
5.2. 
Procedures 
This open label study includes 2 phases and up to 3 visits. All visits will be conducted in 
the presence of a parent/guardian. 
 
First visit – enrollment: The first visit will include screening, enrollment and training on 
operating the headache diary within the smartphone application. The screening process 
will include an eligibility assessment and a urine pregnancy test (if required). Following 
successful screening, enrollment interview and signing an informed consent by the 
parent/guardian and an informed assent by the participant. The participants will be trained 
to use the electronic diary application, installed on their own smartphones. During this visit, 
participants will complete baseline questionnaires that included information on the 
headaches (frequency, severity, etc…), typical associated symptoms, use of preventive 
and abortive medications/treatments, and the effect that their headaches on their daily 
routine and quality of lifeThe C-SSRS will be administered at the screening visit 
and a “since last visit” form which will be administered at each subsequent in- 
clinic study visit to assess possible suicidal ideation and behavior. The C- SSRS 
will be scored by the investigator or Study Coordinator who has C- SSRS 
certification. The survey will be scored immediately after taken by participant. If 
reports of suicidal ideation with intent to act (endorse item 4 or 5), reports of 
actual, aborted, or interrupted suicide attempts, or reports of behavior 
preparatory for an attempt are identified, the investigator” will refer the subject 
for further examination. 
Phase 1 – run-in phase: After the enrollment visit, participants will undergo a 4-week 
diary phase aimed to collect baseline NDPH characteristics. Participants will be asked to 
report in the application each headache attack. These reports will be collected and 
analyzed. 
 
Second visit – Device training visit: During this visit, participants and their 
parent/guardian will be trained to use the device, including finding the optimal individual 
stimulation intensity level (perceptible but not painful). 
 
Participants will be asked to treat their NDPH with the device using the identified optimal 
intensity. If the research staff recognizes that the participant cannot tolerate the feeling of 
the electrical stimulation, the participant may be withdrawn from the study. 
 
During the training, participants will also be informed on the key elements which are critical 
for the successful conduct of the study: 

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• 
Treatments of headache with Nerivio™ should be performed within 60 minutes of 
awakening with a headache or upon increasing headache severity and always within one 
hour of symptoms onset. Treatments of mild headaches are accepted. 
• 
 Avoid taking rescue medications within two hours post-treatment (2 hours from 
start of treatment), if possible. 

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• 
The treatment should be performed for 45 minutes. 
 
In addition, participants will complete study questionnaires, as required. 
 
Phase 2 –Treatment phase: Participants will be instructed to use the device within 60 minutes 
of awakening with a headache or upon increasing headache severity during a period of 4 week. 
Participants will be instructed to use the device with the intensity level identified during the 
device training visit (with a range of ±5 units) and make sure the stimulation is perceptible 
but not painful. Participants will be instructed to avoid taking rescue medications within 2 
hours post-treatment. If medications are used, participants will be instructed to record in 
the app when and which medication was taken. The participants will use the app to record 
pain intensity levels (none, mild, moderate, or severe) at baseline and 2 hours post- 
treatment, and to record the presence/absence of associated symptoms (nausea, 
photophobia, phonophobia) at baseline and 2 hours post-treatment. 
 
Participants who do not achieve satisfactory relief at 2 hours post-treatment may treat 
again with the Nerivio™ device or may treat with usual care at that time or any time 
thereafter if the headache does not resolve. 
 
 
Third (final) visit – End of study: Participants will return to the clinic following the end of 
the 4-week treatment phase, at which time they will return the device and complete the 
required questionnaires 
 
5.2.1. Study duration 
 
The duration of the study for each participant is expected to be ~ 8 weeks. 
 
5.3. 
Study endpoints 
5.3.1. Primary endpoints 
 
1. Pain relief at 2 hours post-treatment: 
The proportion of participants achieving pain relief at 2 hours post-treatment in 
the test treatment, with no use of rescue/abortive medication (Pain relief defined 
as a reduction in pain scale from severe to moderate, mild, or none)from 
moderate or severe to mild or none. 
 
5.3.2. Secondary endpoints 
 
1. Within-patient consistency 
The repeatability of headache reduction, as described in the primary endpoint 
definition, in subsequent treated attacks. Thus, this endpoint measures the % 

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of patient responding to the primary endpoint in at least 50% of their treated 
attacks. 
 
2. Disappearance of associated symptoms at 2 hours post-treatment 
Disappearance of nausea, photophobia and phonophobia at 2 hours post- 
treatment. 
 
3. Functional disability at 2 hours post-treatment 
The proportion of participants achieving improvement of at least one grade in 
functional disability in the test treatment at 2 hours post-treatment with no use 
of rescue medication. 
 
4. Improve of quality of life 
Reduction in average headache disability as measured by PedsMIDAS before 
and at 1 month after initiation of treatment with REN. 
 
 
5.3.3. Exploratory endpoints 
 
1. Reduction in average headache intensity at 1 month 
2. Reduction in perceived stress 
 
 
5.3.4. Safety endpoints 
 
1. The safety of Nerivio 
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 adverse 
events. 
 
6. 
Statistical Considerations 
6.1. 
Study design and aim 
The study is designed as a prospective, open label study. This study aims to evaluate the 
safety and efficacy of Nerivio™ for the acute treatment of NDPH in adolescents (ages 12- 
17 years). 
 
6.2. 
Sample size 
100 participants 

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6.3. 
Analysis sets 
Intent to treat analysis set (ITT) 
The ITT analysis set includes all patients undergoing the treatment phase. 
 
Modified intend to treat analysis set (mITT) 
The mITT analysis set includes all patients undergoing the treatment phase and treat at 
least one (1) treatment within 60 minutes of headache onset. Subjects with no valid post 
baseline assessment will not be included in the relevant analysis. 
 
Per-protocol analysis set (PP) 
The PP analysis set includes all patients from the mITT analysis set without major protocol 
deviations. Main protocol instructions include: 
• has started within 60 minutes of awakening with headache or increased intensity 
from baseline 
• was administered for 45 minutes 
• includes data on headache intensity at 2 hours post-treatment 
• rescue medication was not used before or within 2 hours post-treatment 
 
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. 
 
6.4. 
Statistical analysis 
6.4.1. General considerations 
 
Statistical analyses will be performed using SAS® v9.4 or higher (SAS Institute, Cary NC, 
USA). 
Baseline demographic and other baseline characteristics, together with safety analyses 
will be performed on all participants who underwent the treatment phase. 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. 
 
6.4.2. 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. 

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6.4.3. Safety analysis 
 
Safety and tolerability will be assessed by review 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 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. 
 
6.4.4. Efficacy analysis 
 
The efficacy endpoints will be assessed on evaluable treatments of qualifying attacks. The 
first use of the device is considered a training treatment and will not be included in the 
efficacy analyses. The first treatment of a qualifying attack after the training treatment is 
considered a test treatment and will be used for all efficacy assessments. If this treatment 
is not evaluable (i.e., no pain data at 2 hours post-treatment), a subsequent treatment of 
a qualifying attack with evaluable data will be considered the test treatment. 
Use of rescue medication before the 2-hours assessment will be considered a treatment 
failure for the 2-hours endpoints, and before the 24 hours assessment for the sustained 
24-hours endpoints. The percentage of participants achieving each of the efficacy 
outcomes will be presented in a tabular form along with two-sided 95% exact confidence 
intervals. 
For the associated symptoms outcomes, the observed response proportions and 
corresponding 95% exact confidence intervals for each associated symptom will be 
provided. All patients with baseline and 2 hours values will be included in the analyses. A 
response in each associated symptom (nausea, vomiting, photophobia, phonophobia) is 
defined as change from presence of a specific associated symptom at baseline to absence 
of the same associated symptom at 2 hours post-treatment. 
 
In addition, logistic regression models will be used to assess the efficacy. Baseline value 
and site will serve as covariates. 
The first secondary endpoint (pain relief at 2 hours) may also be evaluated in attacks with 
aura and attacks without aura separately. 
 
 
7. 
Data management 
7.1. 
Data capture 
Data capture will be performed using electronic patient reported outcome (PRO) collection 
tools implemented in the smartphone application. 

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Headache Persistence (NDHP) in adolescents 
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PRO data collected from the smartphone application will be saved in dedicated log files 
on the smartphones for backup purposes. 
 
7.2. 
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. 
 
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. 
 
8. 
Device accountability 
The devices will be provided by Theranica Bioelectronics (Netanya, ISRAEL). The device 
serial number will be documented when provided to the participant. 
 
The devices will only be used in the clinical investigation and according to the study 
protocol. 
 
The investigator will be responsible for providing device training to the participants 
according to the instructions for use. If the participant damages or loses the device, we 
can replace up to one device per participant, if needed. We will not request any 
compensation for that or hold any claims for that. 
9. 
Informed consent processrescue 
 
Informed consent and assent must be obtained from the parent/caregiver and participant, 
respectively, before any protocol-related activities are performed. Participants must be 
provided with a signed copy of the consent and assent forms. 
 
10. Adverse events 
Adverse event (AE) is defined as any unfavorable and unintended medical change, 
temporally associated with the use of the Nerivio, 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 device, is also an adverse experience. An adverse device effect (ADE) is 
an adverse event related to the use of the Nerivio 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 

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A prospective, single arm, open label study of the safety and 
efficacy of Nerivio™ for the acute treatment of New Daily 
Headache Persistence (NDHP) in adolescents 
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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 
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. 
 
10.1. 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. 
 
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. 
 
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. 
 
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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10.2. 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. 
 
10.3. 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 devoice-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). 
 
11. 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. 
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. 
 
12. 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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efficacy of Nerivio™ for the acute treatment of New Daily 
Headache Persistence (NDHP) in adolescents 
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13. Reference