Remote Electrical Neuromodulation for Migraine Prevention

A Double-blind, Randomized, Placebo-controlled Clinical Trial

Stewart J. Tepper MD; Liron Rabany PhD; Robert P. Cowan MD; Timothy R. Smith MD, RPh; Brian M. Grosberg MD; Bradley D. Torphy MD; Dagan Harris PhD; Maya Vizel MSc; Alon Ironi MSEE; Alit Stark-Inbar PhD

Disclosures

Headache. 2023;63(3):377-389.

Abstract and Introduction

Abstract

Objective: To assess the clinical efficacy of remote electrical neuromodulation (REN), used every other day, for the prevention of migraine.

Background: Preventive treatment is key to managing migraine, but it is often underutilized. REN, a non-pharmacological acute treatment for migraine, was evaluated as a method of migraine prevention in patients with episodic and chronic migraine.

Methods: We conducted a prospective, randomized, double-blind, placebo-controlled, multi-center trial, with 1:1 ratio. The study consisted of a 4-week baseline observation phase, and an 8-week double-blind intervention phase in which participants used either REN or a placebo stimulation every other day. Throughout the study, participants reported their symptoms daily, via an electronic diary.

Results: Two hundred forty-eight participants were randomized (128 active, 120 placebo), of which 179 qualified for the modified intention-to-treat (mITT) analysis (95 active; 84 placebo). REN was superior to placebo in the primary endpoint, change in mean number of migraine days per month from baseline, with mean reduction of 4.0 ± SD of 4.0 days (1.3 ± 4.0 in placebo, therapeutic gain = 2.7 [confidence interval −3.9 to −1.5], p < 0.001). The significance was maintained when analyzing the episodic (−3.2 ± 3.4 vs. −1.0 ± 3.6, p = 0.003) and chronic (−4.7 ± 4.4 vs. −1.6 ± 4.4, p = 0.001) migraine subgroups separately. REN was also superior to placebo in reduction of moderate/severe headache days (3.8 ± 3.9 vs. 2.2 ± 3.6, p = 0.005), reduction of headache days of all severities (4.5 ± 4.1 vs. 1.8 ± 4.6, p < 0.001), percentage of patients achieving 50% reduction in moderate/severe headache days (51.6% [49/95] vs. 35.7% [30/84], p = 0.033), and reduction in days of acute medication intake (3.5 ± 4.1 vs. 1.4 ± 4.3, p = 0.001). Similar results were obtained in the ITT analysis. No serious device-related adverse events were reported in any group.

Conclusion Applied every other day, REN is effective and safe for the prevention of migraine.

Introduction

Migraine affects more than 1 billion people worldwide causing significant disability and a huge socioeconomic burden.^[1] Preventive treatment is key in the management of migraine and mitigation of burden.^[2] The American Headache Society (AHS) Consensus Statement recommends preventive therapy in patients with frequent disabling migraine attacks (≥4 monthly headache days), or contraindication to or overuse of acute medications, or adverse events (AEs) in response to acute therapies.^[3]

Significant advances in migraine prevention have reduced the number of migraine attacks and improved the quality of life of some patients.^[4] However, suboptimal efficacy and tolerability of some of the migraine prevention treatments has led to low adherence to oral preventive treatment, and adequate migraine prevention remains an unmet need.^[5] Adherence with more novel therapies, like calcitonin gene–related peptide (CGRP) monoclonal antibodies (mAbs) injection, is better than for oral preventives, but there are still significant rates of discontinuation.^[6] The 2021 AHS Consensus Statement on integrating new migraine treatments into clinical practice states that only 3%–13% of patients with migraine use preventive treatment, even though nearly 40% of those with migraine, and all of those with chronic migraine, may benefit from preventive treatment.^[7] The Consensus Statement further asserts that the poor adherence is caused by low-to-moderate efficacy of many oral preventive treatments, moderate-to-high rates of AEs, contraindications, or drug–drug interactions that limit use. Evidence from a large US health-care database (more than 8000 patients) indicates that more than 80% of patients with chronic migraine discontinue oral preventive therapy within the first year.^[8] Thus, there is an unmet need for non-pharmacological migraine prevention that is both effective and well tolerated.

Remote electrical neuromodulation (REN) is a drug-free acute treatment for migraine^[9,10] that activates an endogenous pain management mechanism, conditioned pain modulation (CPM). CPM is a descending analgesic mechanism in which a sub–pain-threshold stimulation (e.g., in the arm) inhibits pain in remote body regions (e.g., in the head).^[11,12] The REN device (Nerivio®) is a US Food and Drug Administration (FDA)-cleared wearable, wireless, battery-operated stimulation unit, controlled by a smartphone application. For the acute treatment of migraine attacks the device is applied for 45 min to the lateral upper arm.

The efficacy of REN in acute treatment of migraine was established in adults and adolescents with chronic and episodic migraine, with and without aura.^[11,13–15] These data, as well as additional studies indicating REN's efficacy,^[16–22] were further supported by a real-world evidence analysis of more than 23,000 treatments^[23] indicating that REN provides a safe and effective acute treatment for migraine. Two recent systematic reviews and meta-analyses found REN effective for acute treatment of migraine.^[24,25] Furthermore, neuromodulation treatment (including REN) is recommended by the recent AHS Consensus Statement as an adjunct to the existing treatment plan for patients with an inadequate response to a migraine-specific acute medication, as well as for those with frequent attacks who may be at risk of developing medication-overuse headache and/or chronic migraine due to overuse of acute medication.^[7]

Given that CPM is an endogenous central nervous system mechanism,^[12] and as its deficiency was related to prevalence of migraine^[26] it was hypothesized that repeated activation ("training") of this mechanism using an external stimulus may potentially strengthen the associated neural networks. Considering previous findings indicating that the effect of a single REN treatment may persist for (at least) 48 h,^[14] it was hypothesized that repeated treatment sessions, applied every other day, could activate the CPM in a sustained manner, thus exerting a preventive effect and reducing the monthly number of migraine attacks. The aim of the present clinical trial was to evaluate the efficacy and safety of REN, applied every other day, for the preventive treatment of migraine in a large, multi-center, randomized, double-blind, placebo-controlled study.

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Abstract and Introduction
Methods
Results
Discussion
Conclusions
References

Table 1. Demographic and clinical characteristics of the ITT dataset.
		All (n = 248)	Active (n = 128)	Placebo (n = 120)	p-value^a
Age (years)	Average ± SD	41.7 ± 12.9	41.0 ± 12.0	42.6 ± 13.6	0.299
Sex	Female	213 (85.9%)	110 (85.9%)	103 (85.8%)	0.585
	Male	35 (14.1%)	18 (14.1%)	17 (14.2%)
Race	White	222 (89.5%)	116 (90.6%)	106 (88.3%)	0.484
	Asian	4 (1.6%)	1 (0.8%)	3 (2.5%)
	Black/African American	15 (6.0%)	6 (4.7%)	9 (7.5%)
	Native Hawaiian	1 (0.4%)	1 (0.8%)	0 (0.0%)
	Other	6 (2.4%)	4 (3.1%)	2 (1.7%)
Height (cm)	Average ± SD	166 ± 8.3	166 ± 8.4	165 ± 8.2	0.315
Weight (kg)	Average ± SD	84.5 ± 25.0	84.0 ± 25.6	85.0 ± 25.2	0.815
BMI (kg/m²)	Average ± SD	30.4 ± 7.7	30.7 ± 8.3	31.2 ± 8.4	0.572
Chronic migraine^b	N (%) (in baseline)	130 (52.4%)	67 (52.3%)	63 (52.5%)	0.981
Migraine with aura^b (%)	N (%)	62 (25.0%)	33 (25.8%)	29 (24.1%)	0.799
On preventive medication (%)	N (%)	102 (41.1%)	46 (35.9%)	56 (46.7%)	0.094
Type of preventive	Generic oral (e.g., amitriptyline, topiramate)	43 (17.3%)	23 (18.0%)	20 (16.7%)	0.242
	mAbs	22 (8.9%)	8 (6.3%)	14 (11.7%)
	OnabotulinumtoxinA	13 (5.2%)	5 (3.9%)	8 (6.7%)
	Gepants	6 (2.4%)	2 (1.6%)	4 (3.3%)
	Other	18 (7.3%)	8 (6.3%)	10 (8.3%)
Baseline migraine days^b	Average ± SD, in baseline	12.2 ± 4.5	12.1 ± 4.3	12.4 ± 4.9	0.546
Baseline headache days^b	Average ± SD, in baseline	15.6 ± 4.6	15.6 ± 4.5	15.5 ± 4.8	0.833

Abbreviations: BMI, body mass index; ITT, intention to treat; mABs, monoclonal antibodies; SD, standard deviation.
^a T-test for continuous variables, chi-square test for nominal variables.
^bDetermined based on the 28-days baseline phase.

Table 2. Primary, secondary, and exploratory efficacy endpoints (mITT and ITT datasets.)
Endpoint	mITT data set		ITT data set
Endpoint	REN (N = 95)	Sham (N = 84)	REN (N = 128)	Sham (N = 120)
Primary efficacy end point
Migraine days per month
Mean no. of days at baseline (days ± SD)	11.8 ± 4.4	12.0 ± 4.4	12.1 ± 4.3	12.4 ± 4.9
Change from baseline—mean no. of days ± SD (SE)	−4.0 ± 4.0 (0.4)	−1.3 ± 4.0 (0.4)	−3.8 ± 4.5 (0.4)	−1.1 ± 4.4 (0.4)
Difference versus placebo (95% CI)	−2.7 (−3.9 to −1.5)		−2.7 (−3.8 to −1.6)
p-value	<0.001		<0.001
Effect size effect size Cohen's D (95% CI)	−0.7 (−1.0 to −0.4)		−0.6 (−0.8 to −0.3)
Secondary and exploratory efficacy endpoints
Moderate/severe headache days per month
Mean no. of days at baseline (days ± SD)	8.5 ± 3.9	8.3 ± 4.1	8.4 ± 3.8	8.5 ± 4.2
Change from baseline—mean no. of days ± SD (SE)	−3.8 ± 3.9 (0.4)	−2.2 ± 3.6 (0.4)	−3.5 ± 3.9 (0.3)	−2.1 ± 3.9 (0.4)
Difference versus placebo (95% CI)	−1.6 (−2.7 to −0.5)		−1.4 (−2.4 to −0.4)
p-value	0.005		0.005
Effect size effect size Cohen's D (95% CI)	−0.4 (−0.7 to −0.1)		−0.5 (−0.8 to −0.3)
Headache days per month
Mean no. of days at baseline (days ± SD)	15.7 ± 4.7	15.0 ± 4.5	15.6 ± 4.5	15.5 ± 4.8
Change from baseline—mean no. of days ± SD (SE)	−4.5 ± 4.1 (0.4)	−1.8 ± 4.6 (0.5)	−4.2 ± 4.5 (0.4)	−2.0 ± 4.5 (0.4)
Difference versus placebo (95% CI)	−2.7 (−3.9 to −1.5)		−2.2 (−3.3 to −1.0)
p-value	<0.001		<0.001
Effect size effect size Cohen's D (95% CI)	−0.6 (−0.9 to −0.3)		−0.4 (−0.6 to −0.1)
≥50% reduction in headache days
Participants	25	10	40	22
Percent	26.3%	11.9%	31.3%	18.3%
p-value	0.015		0.019
Effect size Cohen's W (95% CI)	0.2		0.1
≥50% reduction in moderate/severe headache days
Participants	49	30	71	48
Percent	51.6%	35.7%	55.5%	40.0%
p-value	0.033		0.015
Effect size Cohen's W (95% CI)	0.2		0.2
HIT-6 score
Baseline	64.5 ± 6.0	64.2 ± 5.6	64.0 ± 7.3	64.6 ± 6.1
Change from baseline ± SD (SE)	5.2 ± 6.2 (0.6)	4.4 ± 5.6 (0.6)	4.7 ± 7.0 (0.6)	3.9 ± 6.2 (0.6)
Difference versus placebo (95% CI)	0.8 (−1.0 to 2.5)		0.9 (−0.8 to 2.5)
p-value	0.399		0.328
Effect size effect size Cohen's D (95% CI)	0.1 (−0.2 to 0.4)		0.1 (−0.1 to 0.4)
MSQ score
Baseline	49.6 ± 13.2	49.7 ± 13.2	48.7 ± 13.7	48.7 ± 13.4
Change from baseline ± SD (SE)	−11.4 ± 13.2 (1.4)	−10.4 ± 13.5 (1.5)	−11.5 ± 12.8 (1.1)	−9.8 ± 13.6 (1.2)
Difference versus placebo (95% CI)	−1.1 (−5.0 to 2.9)		−1.7 (−5.0 to 1.7)
p-value	0.587		0.326
Effect size effect size Cohen's D (95% CI)	−0.1 (−0.4 to 0.2)		−0.1 (−0.4 to 0.1)
Medication days per month
Mean no. of days at baseline (days ± SD)	11.6 ± 4.6	11.1 ± 5.1	11.3 ± 4.8	11.4 ± 5.1
Change from baseline—mean no. of days ± SD (SE)	−3.5 ± 4.1 (0.4)	−1.4 ± 4.3 (0.5)	−3.9 ± 4.5 (0.4)	−2.2 ± 4.4 (0.4)
Difference versus placebo (95% CI)	−2.1 (−3.3 to −0.8)		−1.7 (−2.8 to −0.6)
p-value	0.001		0.005
Effect size effect size Cohen's D (95% CI)	−0.5 (−0.8 to −0.2)		−0.4 (−0.6 to −0.1)

Note: As the previous secondary endpoint was not statistically significant, the p-value was not calculated here. The next endpoint was exploratory; thus, its p-value is calculated.
Abbreviations: CI, confidence interval; HIT-6, Headache Impact Test short form; ITT, intention to treat; mITT, modified intention to treat; REN, remote electrical neuromodulation; SD, standard deviation; SE, standard error.

Table 3. Analysis of treatment adherence (ITT dataset).
Number of treatments in intervention phase (weeks 5–12 of the study)	15–21 out of 28 treatments	22–28 out of 28 treatments
Participants in REN arm (n, [%])	7 (5.5%)	115 (89.8%)
Participants in placebo arm (n, [%])	9 (7.5%)	107 (89.2%)
Mean reduction of migraine days in REN ± SD (SE)	−1.8 ± 3.8 (1.4)	−3.8 ± 4.4 (0.4)
Mean reduction of migraine days in placebo ± SD (SE)	−1.4 ± 6.1 (2.0)	−1.0 ± 4.1 (0.4)
Net gain: diff. between REN and placebo	−0.4	−2.8
p-value	0.880	<0.001
Effect size	0.09	0.62

Note: Participants with <15 treatments per month (active n = 6, sham n = 4) are not included in the table.
Abbreviations: ITT, intention to treat; REN, remote electrical neuromodulation; SD, standard deviation; SE, standard error.

Table 4. Adverse events rate (ITT dataset).
Participants reported at least one AE	All	Active	Sham	p-value
Serious adverse events (SAE) (n, [%])	2 (0.8%)	2 (1.6%)	0 (0.0%)	0.498
Device-related SAEs (n, [%])	0 (0.0%)	0 (0.0%)	0 (0.0%)	–
All AEs (n, [%])	41 (16.5%)	20 (15.6%)	21 (17.5%)	0.730
Device-related AEs (n, [%])	1 (0.4%)	0 (0.0%)	1 (0.8%)	0.484
Discontinuation due to AE (n, [%])	2 (0.8%)	1 (0.8%)	1 (0.8%)	>0.999

Abbreviations: AE, adverse event; ITT, intention to treat.

Authors and Disclosures

Stewart J. Tepper MD¹, Liron Rabany PhD², Robert P. Cowan MD³, Timothy R. Smith MD, RPh⁴, Brian M. Grosberg MD⁵, Bradley D. Torphy MD⁶, Dagan Harris PhD², Maya Vizel MSc², Alon Ironi MSEE², Alit Stark-Inbar PhD² and Andrew M. Blumenfeld MD^7,8

¹The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA
²Theranica Bio-Electronics Ltd., Netanya, Israel
³Division of Headache Medicine, Stanford University, Palo Alto, California, USA
⁴StudyMetrix Research, St. Peters, Missouri, USA
⁵Hartford Healthcare Headache Center, Hartford, Connecticut, USA
⁶Chicago Headache Center and Research Institute, Chicago, Illinois, USA
⁷The Los Angeles Headache Center, Los Angeles, California, USA
⁸San Diego Headache Center, San Diego, California, USA

Correspondence
Liron Rabany, Theranica Bio-Electronics Ltd., Ha-Omanut 4, Netanya, Israel. Email: lironr@theranica.com

Author Contributions
Study concept and design: Robert P. Cowan, Brian M. Grosberg, Alon Ironi, Dagan Harris, Liron Rabany, Maya Vizel. Acquisition of data: Robert P. Cowan, Timothy R. Smith, Brian M. Grosberg, Bradley D. Torphy, Dagan Harris, Maya Vizel. Analysis and interpretation of data: Stewart J. Tepper, Liron Rabany, Alon Ironi, Alit Stark-Inbar, Dagan Harris, Andrew M. Blumenfeld. Drafting of the manuscript: Liron Rabany, Alon Ironi, Alit Stark-Inbar. Revising it for intellectual content: Stewart J. Tepper, Liron Rabany, Robert P. Cowan, Timothy R. Smith, Brian M. Grosberg, Bradley D. Torphy, Dagan Harris, Maya Vizel, Alon Ironi, Alit Stark-Inbar, Andrew M. Blumenfeld. Final approval of the completed manuscript: Stewart J. Tepper, Liron Rabany, Robert P. Cowan, Timothy R. Smith, Brian M. Grosberg, Bradley D. Torphy, Dagan Harris, Maya Vizel, Alon Ironi, Alit Stark-Inbar, Andrew M. Blumenfeld.

Conflict of Interest
Stewart J. Tepper: Grants for research (no personal compensation): Allergan/Abbvie, Amgen, Eli Lilly, Lundbeck, Neurolief, Novartis, Satsuma, Zosano. Consultant and/or Advisory Boards (honoraria): Eon, Allergan/Abbvie, Alphasights, Amgen, Aruene, Atheneum, Axsome Therapeutics, Becker Pharmaceutical Consulting, BioDelivery Sciences International, Biohaven, ClearView Healthcare Partners, ClickTherapeutics, CoolTech, CRG, Decision Resources, Defined Health, DRG, Eli Lilly, ExpertConnect, FCB Health, Fenix, GLG, Guidepoint Global, Health Advances, Health Science Communications, HMP Communications, Impel, InteractiveForums, Keyquest, Krog and Partners, Lundbeck, M3 Global Research, Magnolia Innovation, MJH Holdings, Miravo Healthcare, Neurofront Therapeutics, Neurolief, Novartis, P Value Communications, Pain Insights, Inc, Palion Medical, Pulmatrix, Putnam Associates, Rehaler, SAI MedPartners, Satsuma, Slingshot Insights, Spherix Global Insights, Strategy Inc, Synapse Medical Communication, System Analytic, Taylor and Francis, Teva, Theranica, Tremeau, Trinity Partners, Unity HA, XOC, Zosano. Salary: Dartmouth-Hitchcock Medical Center, Thomas Jefferson University. CME honoraria: American Academy of Neurology, American Headache Society, Annenberg Center for Health Sciences, Catamount Medical Education, Diamond Headache Clinic, Forefront Collaborative, Haymarket Medical Education, HMP Global, Medical Education Speakers Network, Medical Learning Institute Peerview, Migraine Association of Ireland, Miller Medical Education, National Association for Continuing Education, North American Center for CME, The Ohio State University, Physicians' Education Resource, PlatformQ Education, Primed, Vindico Medical Education, WebMD/Medscape. Robert P. Cowan: Royalties: Springer, Pinguin/Avery. Consultant: Teva, Alergan, Pernix, Lundbeck, Satsuma, Theranica, Lily, Amgen, Agonex, Rehailer, Percept. Grant support: Alergan, Teva. Principle: BonTriage. Timothy R. Smith: Clinical trial support: Eon Pharmaceuticals, Alder/Lundbeck, Amgen, Allergan/Abbvie, Biohaven, Boehringer Ingelheim, Charleston Labs, Electrocore, Ellem Pharmacuticals, Impel Neuropharma, Lilly, Pfizer, Nocira, Novartis, Novo Nordisk, Satsuma, Teva, Theranica, Vorso/Nesos. Advisor/consultant: Alder/Lundbeck, Amgen, Allergan/Abbvie, Biohaven, Impel Neuropharma, Lilly, Neruolief, Nocira, Teva, Theranica, Vorso/Nesos. Speaker bureau: Amgen, Allergan/Abbvie, Biohaven, Lilly. Stockholder: United Health Group. Brian M. Grosberg: Institutional research funds/educational grants from Theranica, Amgen, AbbVie, Eli Lilly, Teva, and Neurolief; Book royalties or honoraria from Wiley and Medlink neurology; serves on the Medical Advisory Board for Amgen, Lundbeck, Eli Lilly, Theranica, Biohaven Pharmaceuticals, Linpharma pharmaceuticals and Abbvie. Speaking: Abbvie, Theranica, Biohaven, Eli Lilly. Bradley D. Torphy: Abbvie: Advisory board, speaker bureau, consultant, research PI, research grant. Biohaven: Advisory board, speaker bureau, consultant, research PI. Impel: Advisory board, speaker bureau, consultant. Lilly: Speaker bureau, research PI. Lundbeck: Speaker bureau. Novartis: Consultant. Teva: Advisory board, speaker bureau, consultant, research PI. Theranica: research PI. Andrew M. Blumenfeld: Speaker bureau/advisory board: Abbvie, Allergan, Eon, Biohaven, Lilly, Impel, Collagium, Amgen, Lundbeck, Theranica, Axsone, Revance. Dagan Harris, Maya Vizel, Alon Ironi, Alit Stark-Inbar, Liron Rabany: Employee and stock options, Theranica.

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Remote Electrical Neuromodulation for Migraine Prevention

A Double-blind, Randomized, Placebo-controlled Clinical Trial

Abstract and Introduction

Abstract

Introduction

Tables

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

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