Assessment of Safety and Efficacy of Nerivio for the Migraine Prevention

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

Migraine is a common neurologic with attacks of headache and associated symptoms such as nausea, vomiting, phono and photophobia. Migraine can lead to substantial functional impairment. This study intends to demonstrate the safety and efficacy of the Nerivio for migraine prevention.

The study is a prospective, randomized, double-blind, sham-controlled, multicenter study, conducted in three phases.

The study will consist of a screening/enrollment visit, followed by a 4-week (28 days) baseline phase, an 8-week double-blind preventive treatment phase, and a 4-week open-label phase.

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 treatment feedback during the follow-up pre-emptive phase.

The primary endpoint is 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 of the treatment phase (weeks 9 through 12).

Study Overview

• Status: Completed
• Conditions: Migraine
• Intervention / Treatment: Device: Nerivio active device; Device: Nerivio sham device

Detailed Description

Nerivio is a neuromodulation device approved for the acute treatment of migraine with or without aura in patients 12 years of age or older. The device utilizes electro stimulation to achieve conditioned pain modulation (CPM). CPM stimulate endogenous analgesic mechanism. Treatments are self-administered by the user at the onset of a migraine attack. this study intends to demonstrate the safety and efficacy of the Nwrivio for migraine prevention.

The study is a prospective, randomized, double-blind, sham-controlled, multicenter trial, conducted in three phases. The ratio between treatment and control groups will be 1:1, stratified by center and patient type (chronic/non-chronic). The study 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 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 International Classification of Headache Disorders 3rd edition (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 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.

All adverse events will be reported.

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.

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.

All adverse events will be reported.

• Study Type: Interventional
• Enrollment (Actual): 335
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Evolve Clinical Research
  • California
    • Carlsbad, California, United States, 92011
      • The Neurology Center of Southern California
    • Newport Beach, California, United States, 92663
      • Newport Beach Clinical Research Associates
  • Connecticut
    • Hartford, Connecticut, United States, 06107
      • Hartford Headache Center
  • Florida
    • Boynton Beach, Florida, United States, 33472
      • Reciomed Clinical Research
    • Cutler Bay, Florida, United States, 33157
      • Beautiful Minds Clinical Research Center
  • Illinois
    • Chicago, Illinois, United States, 60657
      • Chicago Headache Center and Research Institute
  • Indiana
    • Evansville, Indiana, United States, 47713
      • Deaconess Clinic
  • Kentucky
    • Paducah, Kentucky, United States, 42001
      • Four Rivers Clinical Research
  • Mississippi
    • Ridgeland, Mississippi, United States, 39157
      • Headache Neurology Research Institute
  • Missouri
    • Saint Peters, Missouri, United States, 63303
      • StudyMetrix Research
    • Springfield, Missouri, United States, 65810
      • Clinvest Research
  • New Jersey
    • Toms River, New Jersey, United States, 08755
      • Ocean Medical Research
  • New York
    • Amherst, New York, United States, 14226
      • Dent Neurosciences Research Center
  • South Carolina
    • Columbia, South Carolina, United States, 29203
      • Prevention & Strengthening Solutions, Inc.
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 (at least 15 days of Headache Days(HD)/ month with migraine days (migraine with or without aura) at least 8 days/ month for > 3 months) 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 participant report).
4. Subject 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).
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. Subject 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Migraine prevention treatment with active Nerivio; Participants will treat with an active Nerivio device every other day for migraine prevention.	Device: Nerivio active device; Nerivio neurostimulator of conditional pain modulation (CPM)
Sham Comparator: Migraine prevention treatment with sham Nerivio; Participants will treat with a sham (placebo) Nerivio device every other day for migraine prevention.	Device: Nerivio sham device; Nerivio neurostimulator with an electrical output not intended for neurostimulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in Migraine Days	The mean reduction in the number of migraine days per month during the last 28 days (4 weeks) of the treatment phase (weeks 9 through 12) compare to the 4-week baseline phase (weeks 1 through 4) A migraine day is defined as a calendar day with a 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.	3 months
Rate of Adverse Events (Safety and Tolerability)	Number of participants with Adverse Events (AE), Serious Adverse Events (SAE) and Device-related Adverse Events	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in Moderate/Severe Headache Days	The mean reduction in the number of moderate/severe headache days per month during the last 28 days (4 weeks) of the treatment phase (weeks 9 through 12) compare to the 4-week baseline phase (weeks 1 through 4) A moderate/severe headache day is defined as a calendar day with a moderate or severe headache.	3 months
Reduction Headache Days	The mean reduction in the number of headache days per month during the last 28 days (4 weeks) of the treatment phase (weeks 9 through 12) compare to the 4-week baseline phase (weeks 1 through 4) A headache day is defined as a calendar day with headache (at any severity).	3 months
Reduction of 50% in Headache Days	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).	3 months
Increase in Headache Impact Test-6 (HIT-6) Score at the End of the Last 28 Days (4 Weeks) of the Treatment Phase (Weeks 9 Through 12) Compare to the HIT-6 Score at the End of the 4-week Baseline Phase (Weeks 1 Through 4)	Headache Impact Test-6 (HIT-6) questionnaire is a tool used to measure the impact headaches have on your ability to function on the job, at school, at home, and in social situations. the questionnaire contains 6 questions with a total score between 36 to 78. Higher score interpret as better patient outcome.	3 months
Reduction in Migraine-Specific Quality-of-Life (MSQ) Questionnaire Score at the End of the Last 28 Days (4 Weeks) of the Treatment Phase (Weeks 9 Through 12) Compare to the MSQ Score at the End of the 4-week Baseline Phase (Weeks 1 Through 4)	The migraine Specific Quality-of-Life questionnaire (MSQ) is a tool to measure the impact of migraine on your ability to function on the job, at school, at home, and in social situations. The questionnaire contains 14 questions with a total score between 0 to 84. Lower score interprets as better patient outcome.	3 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in Migraine Medication Intake	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).	3 months
Percentage of Freedom From Headache Post 2 Hours Following Prodrome Treatment	Percentage of participants 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 2 hours after the treatment, without use of acute medication.	2 hours post treatment at follow up phase
Percentage of Freedom From Headache Post 24 Hours Following Prodrome Treatment	Percentage of participants 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.	24 hours post treatment at follow up phase
Percentage of Reduction of Headache Post 24 Hours From Prodrome Treatment	Percentage of patients who treat 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.	24 hours post treatment at follow up phase
Feasibility of Migraine Prediction Algorithm	Analysis of the daily information provided by the participants for the purpose of predicting their migraine days	3 months
Health Economic Analysis	Health economics analysis of the difference between subjects using Nerivio as a therapy and those who do not with respect to: Absenteeism - number of missed work/school days; Presenteeism - number of work/school days with moderate/severe functional disability; Healthcare provider appointments; ED visits; Brain MRI/CT scans	12 weeks

Collaborators and Investigators

• Sponsor: Theranica
• Investigators: Study Chair: Robert Cowan, MD, Stanford Health Care

Study record dates

Study Major Dates

• Study Start (Actual): April 13, 2021
• Primary Completion (Actual): August 31, 2022
• Study Completion (Actual): October 10, 2022

Study Registration Dates

• First Submitted: March 30, 2021
• First Submitted That Met QC Criteria: April 1, 2021
• First Posted (Actual): April 2, 2021

Study Record Updates

• Last Update Posted (Actual): March 15, 2023
• Last Update Submitted That Met QC Criteria: February 18, 2023
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders, Primary; Headache Disorders; Migraine Disorders
• Other Study ID Numbers: TCH008

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No