A Prospective, Single Arm, Open Label Post Market Study Assessing the Safety and Efficacy of Nerivio for the Treatment of Migraine in Children Under the Age of 12
Conditions: Migraine
Sponsor: Theranica

 
RWE-009  
Clinical Study Protocol 
Doc ID:  
Revision #:1.0 
Page: 1 of 6 
 
Proprietary and confidential information of Theranica Bio-Electronics Ltd.  
Template ID: COM-I00205 Rev: 2.0 
 
Approval 
 
Name 
Position 
Date 
Signature 
Revised by 
 
Dagan Harris 
VP Clinical and 
Regulatory affairs 
10-Feb-2024 
 
Reviewed by 
 
Alit Stark Inbar 
VP Medical 
Information 
10-Feb-2024 
 
Approved by 
 
Alon Ironi 
CEO 
 
10-Feb-2024 
 
              
Effective date of the document is from the date of approval. 
 
 
Change History 
Rev 
Rev. Date 
Revised by 
Change description and reason for change 
1.0  
01-Oct-2023 
Dagan Harris 
Initial version 
2.0 
10-Feb-2024 
Dagan Harris 
Increase sample size, add additional analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
RWE-009  
Clinical Study Protocol 
Doc ID:  
Revision #:1.0 
Page: 2 of 6 
 
Proprietary and confidential information of Theranica Bio-Electronics Ltd.  
Template ID: COM-I00205 Rev: 2.0 
                                                                      
 
 
 
 
Clinical Study Protocol 
 
 
 
A prospective, single arm, open label post market study assessing the 
safety and efficacy of Nerivio for the treatment of migraine in children 
under the age of 12 
 
 
 
 
 
ClinicalTrials.gov Identifier: NCT06138756 
 
 
 
Feb 01, 2024. Rev. 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
 
 

 
RWE-009  
Clinical Study Protocol 
Doc ID:  
Revision #:1.0 
Page: 3 of 6 
 
Proprietary and confidential information of Theranica Bio-Electronics Ltd.  
Template ID: COM-I00205 Rev: 2.0 
 
 
1 
TITLE PAGE 
 
Study title: 
A prospective, single arm, open label post market study assessing the 
safety and efficacy of Nerivio for the treatment of migraine in children 
under the age of 12 
  
  
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-009 
 
Clinical Phase: 
Post market study 
 
 
Study period: 
First user first treatment - May 2020 
 
 
Last user last treatment - October 2023 
 
Investigators: 
Dr Alit Stark Inbar  
 
Statistician: 
Dr. Nira Morag-Koren.  
 
Koren Statistics 
 
Yahadut Hadmama 6a, Herzlia Pituch, Israel 
 
 
 

 
RWE-009  
Clinical Study Protocol 
Doc ID:  
Revision #:1.0 
Page: 4 of 6 
 
Proprietary and confidential information of Theranica Bio-Electronics Ltd.  
Template ID: COM-I00205 Rev: 2.0 
2 
RWE-009 Study Protocol 
 
Title 
A prospective, single arm, open label post market study assessing the safety 
and efficacy of Nerivio for the treatment of migraine in children under the age of 
12 
Investigational 
Device 
Nerivio is an FDA-approved remote electrical neuromodulation (REN) device for 
the acute and/or preventive treatment of migraine with or without aura in patients 
12 years of age or older.  
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.  
Objectives 
The study assessed the safety and efficacy of Nerivio for acute treatment of 
migraine in children under the age of 12. 
Participant 
Population 
Children who were prescribed with the Nerivio device for the treatment of 
migraine and were under the age of 12.  
 
Sample size 
The sample size was defined as all Nerivio users in the Nerivio database under 
the age of 12 in the day of their first treatment 
Inclusion 
Criteria 
• Prescribed with Nerivio device for the treatment of migraine 
• Age under 12 at their first Nerivio treatment 
• Treat with Nerivio at least once 
Exclusion 
Criteria 
• Treatments shorter than 30 minutes 
Study Design  
A prospective, data analysis of users that met the inclusion criteria was 
performed. All data that were reported prior and following the treatments by the 
users using the electronic diary within the Nerivio application were downloaded 
from Theranica server in an unidentified manner.   
Primary 
endpoint - 
Safety 
Rate of Device Related Adverse Events 
Incidence of device-related adverse events (DRAEs) reported by subjects. 
a) Percentage of patients reporting DRAEs 
b) Severity of reported DRAEs 

 
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Clinical Study Protocol 
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Secondary 
endpoints -
efficacy  
 
Consistent Headache Relief at 2 Hours Post-treatment. 
The proportion of subjects reporting headache relief at 2 hours post-treatment in 
at least 50% of all their treatments. 
 
Consistent Freedom from Headache at 2 Hours Post-treatment. 
The proportion of subjects reporting freedom from headache at 2 hours post-
treatment in at least 50% of all their treatments. 
 
Freedom from a specific migraine associated symptom.  
Freedom from a specific migraine associated symptom was calculated as the 
percent of patients reporting the presence of that symptom at baseline, and the 
lack of that symptom at 2-hours post-treatment in at least 50% of all their 
treatments.  
Per the ICHD-3, migraine associated symptoms are: 
a) Hyper sensitivity to light (phonophobia) 
b) Hyper sensitivity to sound (phonophobia) 
c) Nausea (with or without vomiting) 
 
Functional disability relief  
Functional disability relief was calculated as decrease of at least one level of 
functional disability from baseline to 2-hours post-treatment in at least 50% of all 
their treatments. 
Disability levels are (0) none (full function), (1) mild disability, (2) moderate 
disability, and (3) severe disability.  
 
Freedom from functional disability  
Freedom from functional disability was calculated as decrease from any 
disability level (3, 2, or 1) at baseline to no disability (i.e., return to full function) 
at 2-hours post-treatment in at least 50% of all their treatments. 
 
Exploratory 
efficacy 
endpoints 
Use of migraine medications 
Treatment patterns of Nerivio use as a standalone treatment vs. in combination 
with medications were extracted from the 2-hours post-treatment reports, as the 
percentage of treatments in which no rescue headache medications were used 
(Nerivio standalone), or Nerivio was used with over-the-counter (OTC) 
medications, or with prescription medications (Rx). 
 
Nerivio treatment stimulation intensity  
Treatment intensity (stimulation current) is set by patients via the smartphone 
app and automatically recorded. The average intensity over all treatments per 
patient was calculated to provide personal intensity levels, which was used for 
the analyses. Average personal intensity levels and the range for 80% of the 
users were calculated over the patient cohort. 
 
Nerivio utilization  
Average (and/or median) of number of Nerivio treatments per month. A specific 
cohort of this outcome considers safety in patients who use the device at high 
frequency, close to the every-other-day regime of preventive treatment.  
 

 
RWE-009  
Clinical Study Protocol 
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Revision #:1.0 
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Template ID: COM-I00205 Rev: 2.0 
Datasets 
1. Intent to treat analysis set (ITT) 
The ITT analysis set includes all users who had at least one treatment  
 
2. Modified intent to treat analysis set (mITT) 
The mITT analysis set includes all ITT participants who had at least 2 
treatments with prospective electronic diary reports at the beginning of the 
treatment (“baseline”) and 2 hours post the beginning of the treatment.  
Data Analysis 
The ITT analysis set was used for the safety assessments and the mITT 
analysis set was used for the efficacy assessments. 
 
 

STATISTICAL CONSIDERATIONS FOR RWE-009 STUDY 
The study hypothesis was that treatments of migraine with the Nerivio device in children 
will be as safe and effective as previously described in adolescents and adults.  
 
DATA COLLECTION 
BASELINE DATA  
Baseline participant characteristics (age, gender) were collected from the Nerivio account 
of each participant. 
TREATMENT DATA  
Treatment data was 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…) 
COMPUTER SOFTWARE  
All statistical analyses and data presentations, including tabulations and listings, were 
performed using the SAS version 9.4 software.   
 
STATISTICAL ANALYSIS  
Demographic and Baseline Analysis 
Demographic and baseline condition related characteristics will be tabulated and 
compared between the participant age data type. 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) was calculated ad the number of reported 
DRAE divided by the number of participants in the study. 
 

Efficacy Endpoints Analysis 
All the endpoints will be calculated for Qualified Attacks only, Qualifies treaterent was 
defined as 
1 - Attacks treated with Nerivio for at least 30 minutes 
2 – Pre and post treatment data wasreported by the participant for the specific treatment 
3 – No rescue medications were taken before and during the 2 hours post treatment, 
according to the participant report 
 
Consistent efficacy was 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 were 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) were marked as present or not. 
Pain relief was calculated as a decrease from severe or moderate levels at baseline to mild 
or none at 2 h posttreatment. 
Functional disability relief was calculated as any improvement in disability from baseline to 
2 h posttreatment.  
Pain/functional disability freedom was calculated as a decrease from any pain/disability 
level at baseline to none at 2 h post‐treatment.  
Freedom from a specific migraine‐associated symptom was calculated as the percentage 
of patients reporting the presence of that symptom at baseline and the lack of that 
symptom at 2 h post‐treatment. Freedom from at least one associated symptom was 
calculated as the percentage of patients in which one or more associated symptom(s) were 
reported at baseline and the lack of at least one of those symptoms at 2 h post‐treatment.