Acute Treatment of Migraine in Pre-Adolescents: Real-World Analysis of Remote Electrical Neuromodulation (REN)

The REN device (Nerivio by Theranica, Israel) is a neuromodulation device approved by the FDA for acute and/or preventive treatment of migraine in patients 12 years old and above. It is a wearable device applied to the upper arm. It stimulates C and Aδ noxious fibers using a modulated, symmetrical, biphasic, square pulse with a pulse width of 400 μs, modulated frequency of 100-120 Hz, and up to 40 mA output current which the patient can adjust.

The REN device is operated by a designated smartphone application that is downloaded to the user's phone prior first use of the Nerivio device. As part of the sign-up process for the Nerivio app, all patients accept the terms of use which specify that providing personal information is done on their own free will and that their de-identified data may be used for research purposes. Users are not obligated to provide personal information and could treat without providing any feedback. The app includes a secure, personal migraine diary, which enables patients to record and track their migraines attacks and other headaches. At the beginning of each treatment, and again 2 hours after the start of treatment, patients are prompted to record their symptoms, including the presence or absence of aura, pain level (none, mild, moderate, severe), functional disability (none, mild limitation, moderate limitation, severe limitation), presence of associated symptoms (photophobia, phonophobia, and nausea), and an indication of which medications, if any, were taken within that 2-hour time window.

Post-marketing surveillance is designed to assess the safety and efficacy of REN in larger and more diverse populations than in clinical trials and in various real-world environments and situations. As a digital therapeutic device (i.e., electroceutical), the REN device enables prospective collection of electronic patient-reported outcomes in real-world clinical practice.

This post-marketing RWE study investigates the safety and efficacy of the Nerivio treatment in pre-adolescence migraine patients who used the Nerivio device. The following outcomes will be assessed:

1. \- Safety - Adverse events that were reported during the study's period
2. \- Efficacy - Pain relief, freedom from pain, improvement in functional disability, and improvement in migraine-associated symptoms following the treatment

Together, these objectives provide a comprehensive evaluation of the effect of REN as a treatment for migraine in this target population.

• Nerivio (Device): Nerivio is a remote electrical neuromodulation (REN) device for the treatment of migraine

Primary outcomes

• Rate of Device Related Adverse Events [Up to 6 months]: Incidence of device-related adverse events reported by subjects throughout the study period

Secondary outcomes

• Consistent Headache Relief at 2 Hours Post-treatment [up to 6 months]: The proportion of subjects reporting headache relief at 2 hours post-treatment in at least 50% of all their treatments. Headache relief is defined as an improvement from severe or moderate pain to mild or no pain.
• Consistent Freedom From Headache at 2 Hours Post-treatment [up to 6 months]: The proportion of subjects reporting freedom from headache at 2 hours post-treatment in at least 50% of all their treatments. Pain freedom is defined as the disappearance of headache from severe, moderate, or mild headache at treatment initiation to no headache 2 hours later
• Consistent Migraine Associated Symptoms Disappearance at 2 Hours Post-treatment [up to 6 months]: The proportion of subjects reporting the presence of each of the migraine-associated symptoms (nausea/vomiting, photophobia, phonophobia) at the beginning of treatment and reported their absence 2 hours following the treatment in at least 50% of their attacks.
• Consistent Functional Disability Relief at 2 Hours Post-treatment [up to 6 months]: The proportion of subjects who reported having Functional Disability at the beginning of the treatment and reported improvement of at least one level of Functional Disability at 2 hours post-treatment in at least 50% of all their treatments.
• Consistent Functional Disability Disappearance at 2 Hours Post-treatment [up to 6 months]: The proportion of subjects who reported having Functional Disability at the beginning of the treatment and reported no Functional Disability at 2 hours post-treatment in at least 50% of all their treatments.

Sex: All, ages: 6 Years to 12 Years

Inclusion Criteria:

* Subject age is between 6 to 12 at the date of the REN treatment
* Subject used the Nerivio device at least once

Exclusion Criteria:

* None

Participant flow

Outcome results

• Rate of Device Related Adverse Events (Primary), Count of participants, Participants: Pre-adolescence With Migraine 0
• Consistent Headache Relief at 2 Hours Post-treatment (Secondary), Count of participants, Participants: Pre-adolescence With Migraine 13
• Consistent Freedom From Headache at 2 Hours Post-treatment (Secondary), Count of participants, Participants: Pre-adolescence With Migraine 9
• Consistent Migraine Associated Symptoms Disappearance at 2 Hours Post-treatment (Secondary), Count of participants, Participants: Pre-adolescence With Migraine 7
• Consistent Functional Disability Relief at 2 Hours Post-treatment (Secondary), Count of participants, Participants: Pre-adolescence With Migraine 15
• Consistent Functional Disability Disappearance at 2 Hours Post-treatment (Secondary), Count of participants, Participants: Pre-adolescence With Migraine 7

Adverse events

Time frame: Up to 7 months

Limitations and caveats: A post-marketing cohort study without a control group; not all participants provided data for efficacy calculations; age among the cohort of children is not uniformly distributed.

• Study Protocol and Statistical Analysis Plan (PDF, 2024-02-10)

• Alit Stark-Inbar, PhD, Principal investigator, Theranica