Real-World Analysis of Remote Electrical Neuromodulation (REN) for the Acute Treatment of Migraine in Adolescence
Conditions: Migraine in Adolescence
Sponsor: Theranica

 
RWE-003 
Clinical study Protocol  
 
Revision #:1.0 
Page: 2 of 7 
 
Proprietary and confidential information of Theranica Bio-Electronics Ltd.  
Template ID: COM-I00205 Rev: 2.0 
\\4124-2824-6868  v1   
 
TITLE PAGE 
 
Study title: 
Real-World Evidence (RWE) of Usage of Nerivio, a 
Remote Electrical Neurostimulation (REN) Device In 
Adolescents Patients With Migraine  
 
Test Device: 
Nerivio 
 
 
 
Indication studied: 
Acute treatment of migraine 
 
 
Study description: 
Prospective, single arm, open label post market study 
 
  
Sponsors:  
Theranica Bioelectronics Ltd 
 
 
Protocol: 
RWE-003   ver 1.0   01-Jan-2021 
 
Clinical Phase: 
Post market study 
 
 
Sponsor:  
 
Theranica Bio-Electronics Ltd. 4 Ha-Omanut st, Netanya, 
Israel 
 
Contact Details: 
  
Dagan Harris, VP Clinical & Regulatory Affairs) 
 
Tel:  
  
+972.72.390.9758 
 
Fax:  
  
+ 972.72.390.9762 
 
Mobile:  
  
+972-0542220121 
 
EMAIL:  
  
daganh@theranica.com 

 
RWE-003 
Clinical study Protocol  
 
Revision #:1.0 
Page: 3 of 7 
 
Proprietary and confidential information of Theranica Bio-Electronics Ltd.  
Template ID: COM-I00205 Rev: 2.0 
\\4124-2824-6868  v1   
Study RWE-003  
 
 
Title 
Real-World Evidence (RWE) of Usage of Nerivio, a Remote Electrical 
Neurostimulation (REN) Device In Adolescents Patients With Migraine 
Sponsor 
Theranica Bio-Electronics Ltd. 4 Ha-Omanut St., Netanya, Israel 
Investigational 
Device 
Nerivio is a Remote Electrical Neuromodulation (REN) wearable, battery-
powered medical device for the acute and/or preventive treatment of 
migraine with or without aura in patients 12 years of age or older. Nerivio 
is controlled by a mobile application. Nerivio is intended for self-
administration in a home healthcare environment. 
The device is worn on the upper arm and transmits transcutaneous remote 
electrical nerve stimulation by applying weak electrical pulses that invoke 
conditioned pain modulation (CPM) to inhibit migraine pain. Nerivio is 
intended for self-administration at the onset of a migraine episode. 
Objectives 
To evaluate the safety, utilization and efficacy of Nerivio in adolescent 
patients (Age 12-18) who used the Nerivio device for treating their migraine
Patient 
Population 
Nerivio users aged 12-18 years old who registered a Nerivio account and 
used the Nerivio device for the acute treatment of migraine.  
Sample size 
The sample size will includes all Nerivio users in the age of 12-18 in the 
Nerivio database who treated with Nerivio at least once between Jan 01, 
2021 and May 31, 2022 
Inclusion 
criteria 
 
Age between 12-18 years 
 
REN user across the United States who created Nerivio account on 
January 1st, 2021 until May 31, 2022. 
 
Had at least two evaluable treatments with the Nerivio device (for 
consistent efficacy analysis). 
Exclusion 
criteria 
 Treatments shorter than 20 minutes will not be included in the analysis

 
RWE-003 
Clinical study Protocol  
 
Revision #:1.0 
Page: 4 of 7 
 
Proprietary and confidential information of Theranica Bio-Electronics Ltd.  
Template ID: COM-I00205 Rev: 2.0 
\\4124-2824-6868  v1   
Study Design 
The analysis included patients at the age of 12-18 (at the day of opening a 
Nerivio account) with migraine across the USA who used Nerivio at least 
once between January 01, 2021, and May 31, 2022. 
Treatment data will be collected through the Nerivio app (Nerivio®) which 
is required for treatment. Device output current is set by the user to be 
strong but not painful and is equivalent to treatment dosage (max device 
current 40 mA on 0-100 units user-facing scale). Additionally, patients can 
voluntarily log details about their symptoms at both treatment onset and 2-
hours post-treatment status. Treatment efficacy will be measured by 
consistent reduction in headache pain intensity and functional disability at 
2-hours post-treatment, based on data from patients who voluntarily will 
answer the pre and post treatment questionnaires. Safety will be assessed 
by the rate of device related adverse event reported by the patients. 
Evaluable 
Treatment 
Evaluable treatment is a treatment that meets all the following criteria: 
 Baseline and 2-hour post-treatment pain intensity and functional 
disability scores were recorded. 
 The participant did not use any concomitant acute migraine 
medication during the treatment. 
Efficacy 
endpoints 
 
1. Pain Relief: Reduction in pain intensity from moderate or severe 
(baseline score of 2 or 3) to mild or no pain (score of 1 or 0) at 2 hours 
post-treatment. 
2. Pain Freedom: Reduction in pain intensity from mild, moderate, or 
severe (baseline score of 1, 2, or 3) to no pain (score of 0) at 2 hours 
post-treatment. 
3. Functional Disability Relief: Reduction in functional disability by at 
least one point from baseline at 2 hours post-treatment. 
4. Functional Disability Freedom: Reduction in functional disability 
from mild, moderate, or severe (baseline score of 1, 2, or 3) to no 
disability (score of 0) at 2 hours post-treatment. 
Utilization 
endpoints 
 
5. Consistent Usage of Migraine Abortive (Rescue) Medications: 
The proportion of subjects with REN treatments without the use of 
pharmacological migraine abortive (rescue) medication (either over 
the counter or prescribed), or with a combination of rescue medication 
or without any treatment at all at 2 hours post-treatment in at least 
50% of all their treatments. 
6. Treatment intensity distribution: The mean intensity of the 
stimulation collected for all treatments that were performed within the 
study 
Safety 
endpoints 
Rate of serious adverse events, adverse events and device-related 
adverse events 

 
RWE-003 
Clinical study Protocol  
 
Revision #:1.0 
Page: 5 of 7 
 
Proprietary and confidential information of Theranica Bio-Electronics Ltd.  
Template ID: COM-I00205 Rev: 2.0 
\\4124-2824-6868  v1   
Data collection 
Data will be collected prospectively through the Nerivio smartphone 
application, At the time of creating a Nerivio account on the App, patients 
(and their parents, in case of patients younger than 18) are required to sign 
a consent statement presented to them, where they agree that their 
deidentified data may be collected and used for reserve purposes.  
Prospective data was collected for Nerivio users in the United States who 
treated their migraine attacks with the Nerivio device. Nerivio utilization, 
and Nerivio treatment reports at T=0h and T=2h were extracted from the 
Nerivio server in an unidentified manner. Data will be analyzed per user 
following additional analysis per the target population. 
 
The following data will be extracted: 
 Demographics: Age at registration, gender. 
 Treatment Details: Treatment date, baseline pain intensity, pain 
intensity at 2 hours post-treatment, baseline functional disability, 
functional disability at 2 hours post-treatment. 
 Treatment Frequency: Number of treatments per month over the 12-
months period. 
 Pain Intensity: 0 (no pain), 1 (mild), 2 (moderate), 3 (severe). 
 Functional Disability: 0 (no disability), 1 (mild interference), 2 
(moderate interference), 3 (severe interference). 
 Additional migraine symptoms (Nausea/ vomiting, Photophobia, 
Phonophobia) 
Statistical 
considerations 
See at the end of the document  
Responder 
Definition 
For each efficacy endpoint, a participants will be considered a responder 
in if they achieved the defined outcome in at least 50% of their evaluable 
treatments during that study period. 
 
 
 
 
STATISTICAL CONSIDERATIONS FOR RWE-003 STUDY 
The study hypothesis was that treatments of migraine with the Nerivio device In 
adolescents will demonstrate similar results to the results previously found in adults 
 
DATA COLLECTION 
BASELINE DATA  
Baseline participant characteristics (age, gender) will be collected from the Nerivio 
account of each participant. 

 
RWE-003 
Clinical study Protocol  
 
Revision #:1.0 
Page: 6 of 7 
 
Proprietary and confidential information of Theranica Bio-Electronics Ltd.  
Template ID: COM-I00205 Rev: 2.0 
\\4124-2824-6868  v1   
UTILIZATION DATA 
Utilization information is pulled out from the Nerivio server for each treatment  
TREATMENT DATA  
Treatment data will be retrieved from the Nerivio app for each treatment. Data includes 
automatic parameters (e.g time of treatment, location, device serial number, treatment 
intensity etc…) and individual information completed by the participant (pain level 
before and after the treatments, migraine symptoms, functional disability before and 
after the treatment etc…) 
SAFETY DATA  
All safety information will be pulled out from the Nerivio support center and/or 
additional safety reports from other sourced that are register in Nerivio database.   
 
STATISTICAL ANALYSIS  
Demographic and Baseline Analysis 
Demographic and baseline condition related characteristics will be tabulated and 
compared between the participant data types. Continuous variables will be 
summarized by a mean, standard deviation, minimum, median and maximum and 
categorical variables by a count and percentage. 
Safety Endpoints Analysis 
The rate of device related adverse event (DRAE) will be calculated ad the number of 
reported DRAE divided by the number of participants in the study. 
EƯicacy Endpoints Analysis 
Generalized linear mixed model (GLMM) will be  used to compare the eƯect of treatment 
month on eƯicacy rate outcomes. 
Utilization Endpoints Analysis 
Utilization outcome will be calculated from the treatment parameters (intensity levels) 
and the treatment reports (usage of rescue medications), and will be presented in 
appropriate distribution tables. 
 
Qualiﬁes treatment was deﬁned as 
1 - Attacks treated with Nerivio for at least 20 minutes 
2 – Pre and post treatment data were reported by the participant for the speciﬁc treatment 

 
RWE-003 
Clinical study Protocol  
 
Revision #:1.0 
Page: 7 of 7 
 
Proprietary and confidential information of Theranica Bio-Electronics Ltd.  
Template ID: COM-I00205 Rev: 2.0 
\\4124-2824-6868  v1   
3 – No rescue medications were taken before and during the 2 hours post treatment, 
according to the participant report 
 
Consistent eƯicacy will be conducted in cases where at least two qualiﬁed treatments 
were performed. Patients who experienced the outcome (e.g., pain freedom) in at least 
50% of their reported treatments, during which they did not report the use of rescue 
medications, were considered responders. 
Headache pain and functional disability will be rated at baseline and at 2 h post-treatment 
on a 4-point scale: severe, moderate, mild, or none. Migraine associated symptoms 
(photophobia, phonophobia, and nausea/vomiting) will be marked as present or not. 
Pain relief will be calculated as a decrease from severe or moderate levels at baseline to 
mild or none at 2 h posttreatment. 
Functional disability relief will be calculated as any improvement in disability from 
baseline to 2 h posttreatment.  
Pain/functional disability freedom will be calculated as a decrease from any 
pain/disability level at baseline to none at 2 h post-treatment.