Non-Invasive Vagus Nerve Stimulation for the ACute Treatment of Cluster Headache: Findings From the Randomized, Double-Blind, Sham-Controlled ACT1 Study

Objective To evaluate non‐invasive vagus nerve stimulation (nVNS) as an acute cluster headache (CH) treatment. Background Many patients with CH experience excruciating attacks at a frequency that is not sufficiently addressed by current symptomatic treatments. Methods One hundred fifty subjects were...

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Bibliographic Details
Published inHeadache Vol. 56; no. 8; pp. 1317 - 1332
Main Authors Silberstein, Stephen D., Mechtler, Laszlo L., Kudrow, David B., Calhoun, Anne H., McClure, Candace, Saper, Joel R., Liebler, Eric J., Rubenstein Engel, Emily, Tepper, Stewart J.
Format Journal Article
LanguageEnglish
Published United States Blackwell Publishing Ltd 01.09.2016
Wiley Subscription Services, Inc
John Wiley and Sons Inc
Subjects
acute treatment
chronic cluster headache
Cluster Headache - therapy
Double-Blind Method
episodic cluster headache
Female
Headaches
Humans
Male
Middle Aged
neuromodulation
non-invasive vagus nerve stimulation
Pain Measurement
Population
randomized controlled trial
Research Submission
Research Submissions
Response rates
Treatment Outcome
United States
Vagus Nerve Stimulation - instrumentation
Vagus Nerve Stimulation - methods
neuromodulation
chronic cluster headache
non-invasive vagus nerve stimulation
episodic cluster headache
acute treatment
randomized controlled trial
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Summary:Objective To evaluate non‐invasive vagus nerve stimulation (nVNS) as an acute cluster headache (CH) treatment. Background Many patients with CH experience excruciating attacks at a frequency that is not sufficiently addressed by current symptomatic treatments. Methods One hundred fifty subjects were enrolled and randomized (1:1) to receive nVNS or sham treatment for ≤1 month during a double‐blind phase; completers could enter a 3‐month nVNS open‐label phase. The primary end point was response rate, defined as the proportion of subjects who achieved pain relief (pain intensity of 0 or 1) at 15 minutes after treatment initiation for the first CH attack without rescue medication use through 60 minutes. Secondary end points included the sustained response rate (15‐60 minutes). Subanalyses of episodic cluster headache (eCH) and chronic cluster headache (cCH) cohorts were prespecified. Results The intent‐to‐treat population comprised 133 subjects: 60 nVNS‐treated (eCH, n = 38; cCH, n = 22) and 73 sham‐treated (eCH, n = 47; cCH, n = 26). A response was achieved in 26.7% of nVNS‐treated subjects and 15.1% of sham‐treated subjects (P = .1). Response rates were significantly higher with nVNS than with sham for the eCH cohort (nVNS, 34.2%; sham, 10.6%; P = .008) but not the cCH cohort (nVNS, 13.6%; sham, 23.1%; P = .48). Sustained response rates were significantly higher with nVNS for the eCH cohort (P = .008) and total population (P = .04). Adverse device effects (ADEs) were reported by 35/150 (nVNS, 11; sham, 24) subjects in the double‐blind phase and 18/128 subjects in the open‐label phase. No serious ADEs occurred. Conclusions In one of the largest randomized sham‐controlled studies for acute CH treatment, the response rate was not significantly different (vs sham) for the total population; nVNS provided significant, clinically meaningful, rapid, and sustained benefits for eCH but not for cCH, which affected results in the total population. This safe and well‐tolerated treatment represents a novel and promising option for eCH. ClinicalTrials.gov identifier: NCT01792817.
Bibliography:ark:/67375/WNG-G9ZVKB0B-4
istex:E50511417A0C197AB48651E9D8766CA033EC0202
electroCore, LLC
ArticleID:HEAD12896
Financial Support
Stephen D. Silberstein, MD, has received consultancy and advisory board fees from Alder Biopharmaceuticals Inc., Allergan, Inc., Amgen, Inc., Avanir Pharmaceuticals, Inc., Depomed, Inc., Dr. Reddy's Laboratories Ltd., electroCore, LLC, eNeura Inc., Ipsen Biopharmaceuticals Inc., Medscape, LLC, Medtronic, Inc., Mitsubishi Tanabe Pharma America, Inc., National Institute of Neurological Disorders and Stroke, St. Jude Medical, Inc., Supernus Pharmaceuticals, Inc., Teva Pharmaceutical Industries Ltd., and Trigemina, Inc.; Laszlo L. Mechtler, MD, has received speaker fees from Allergan, Inc., Depomed, Inc., and Supernus Pharmaceuticals, Inc., and research support from Celldex Therapeutics, Cincinnati Children's Hospital Medical Center, GlaxoSmithKline, PharmaNet Group Ltd., and Questcor Pharmaceuticals, Inc.; David B. Kudrow, MD, has received speaker fees from Teva Pharmaceutical Industries Ltd. and grant funding from Depomed, Inc.; Anne H. Calhoun, MD, has received advisory board fees from Allergan, Inc., Depomed, Inc., Eli Lilly and Company, and Teva Pharmaceutical Industries Ltd., and speaker fees from Depomed, Inc., Merck & Co., Inc., and Teva Pharmaceutical Industries Ltd. Dr. Calhoun has also received research support from Autonomic Technologies, Inc., electroCore, LLC, and Scion NeuroStim, LLC; Candace McClure, PhD, is an employee of NAMSA; Joel R. Saper, MD, has received consultancy fees from Alder Biopharmaceuticals Inc., Allergan, Inc., Johnson & Johnson (Ethicon, Inc.), Migraine Research Foundation, NuPathe Inc., Purdue Pharma L.P., Supernus Pharmaceuticals, Inc., Teva Pharmaceutical Industries Ltd., and Tian Pharmaceutical Co. Ltd. Dr. Saper has also received research grants from Achelios Therapeutics, Inc., Alder Biopharmaceuticals Inc., Allergan, Inc., Amgen, Inc., Astellas Pharma Inc., Autonomic Technologies, Inc., Cerephex Corporation, Daiichi‐Sankyo Co. Ltd., Dr. Reddy's Laboratories Ltd., Eli Lilly and Company, GlaxoSmithKline, Labrys Biologics, Inc., Merck & Co., Inc., Pfizer, Inc., Scion NeuroStim, LLC, Vanda Pharmaceuticals, and Winston Laboratories, Inc.; Eric J. Liebler is an employee of electroCore, LLC, and receives stock ownership; Emily Rubenstein Engel, MD, has received consultancy, speaker, and advisory board fees from Allergan, Inc., Depomed, Inc., and electroCore, LLC; and Stewart J. Tepper, MD, has received consultancy fees from Acorda Therapeutics, Inc., Allergan, Inc., Amgen, Inc., Autonomic Technologies, Inc. (ATI), Avanir Pharmaceuticals, Inc., Depomed, Inc., Dr. Reddy's Laboratories Ltd., electroCore, LLC, Impax Pharmaceuticals, Inc., Pfizer, Inc., Scion NeuroStim, LLC, Teva Pharmaceutical Industries Ltd., Theorem Clinical Research, Zogenix, Inc., and Zosano Pharma Corporation. Dr. Tepper has also received research grants/support from Allergan, Inc., Amgen, Inc., Autonomic Technologies, Inc. (ATI), Avanir Pharmaceuticals, Inc., electroCore, LLC, eNeura Inc., GlaxoSmithKline, Merck & Co., Inc., Pfizer, Inc., Optinose US Inc./Avanir Pharmaceuticals, Inc./Otsuka Pharmaceutical Co., Ltd., Teva Pharmaceutical Industries Ltd., and Zogenix, Inc. He has also received stock options from Autonomic Technologies, Inc. (ATI) and royalties from the University Press of Mississippi and Springer.
This study was sponsored by electroCore, LLC. Professional writing and editorial support from MedLogix Communications, LLC, funded by electroCore, LLC, were under the direction of authors throughout draft development and revisions in accordance with International Committee of Medical Journal Editors (ICMJE) criteria for authorship. Data analysis support from NAMSA was funded by electroCore, LLC. The authors are guarantors of this document, which expresses the opinions and conclusions of the authors and not those of their corresponding affiliations.
Conflict of Interest
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Financial Support: This study was sponsored by electroCore, LLC. Professional writing and editorial support from MedLogix Communications, LLC, funded by electroCore, LLC, were under the direction of authors throughout draft development and revisions in accordance with International Committee of Medical Journal Editors (ICMJE) criteria for authorship. Data analysis support from NAMSA was funded by electroCore, LLC. The authors are guarantors of this document, which expresses the opinions and conclusions of the authors and not those of their corresponding affiliations.
Conflict of Interest: Stephen D. Silberstein, MD, has received consultancy and advisory board fees from Alder Biopharmaceuticals Inc., Allergan, Inc., Amgen, Inc., Avanir Pharmaceuticals, Inc., Depomed, Inc., Dr. Reddy's Laboratories Ltd., electroCore, LLC, eNeura Inc., Ipsen Biopharmaceuticals Inc., Medscape, LLC, Medtronic, Inc., Mitsubishi Tanabe Pharma America, Inc., National Institute of Neurological Disorders and Stroke, St. Jude Medical, Inc., Supernus Pharmaceuticals, Inc., Teva Pharmaceutical Industries Ltd., and Trigemina, Inc.; Laszlo L. Mechtler, MD, has received speaker fees from Allergan, Inc., Depomed, Inc., and Supernus Pharmaceuticals, Inc., and research support from Celldex Therapeutics, Cincinnati Children's Hospital Medical Center, GlaxoSmithKline, PharmaNet Group Ltd., and Questcor Pharmaceuticals, Inc.; David B. Kudrow, MD, has received speaker fees from Teva Pharmaceutical Industries Ltd. and grant funding from Depomed, Inc.; Anne H. Calhoun, MD, has received advisory board fees from Allergan, Inc., Depomed, Inc., Eli Lilly and Company, and Teva Pharmaceutical Industries Ltd., and speaker fees from Depomed, Inc., Merck & Co., Inc., and Teva Pharmaceutical Industries Ltd. Dr. Calhoun has also received research support from Autonomic Technologies, Inc., electroCore, LLC, and Scion NeuroStim, LLC; Candace McClure, PhD, is an employee of NAMSA; Joel R. Saper, MD, has received consultancy fees from Alder Biopharmaceuticals Inc., Allergan, Inc., Johnson & Johnson (Ethicon, Inc.), Migraine Research Foundation, NuPathe Inc., Purdue Pharma L.P., Supernus Pharmaceuticals, Inc., Teva Pharmaceutical Industries Ltd., and Tian Pharmaceutical Co. Ltd. Dr. Saper has also received research grants from Achelios Therapeutics, Inc., Alder Biopharmaceuticals Inc., Allergan, Inc., Amgen, Inc., Astellas Pharma Inc., Autonomic Technologies, Inc., Cerephex Corporation, Daiichi‐Sankyo Co. Ltd., Dr. Reddy's Laboratories Ltd., Eli Lilly and Company, GlaxoSmithKline, Labrys Biologics, Inc., Merck & Co., Inc., Pfizer, Inc., Scion NeuroStim, LLC, Vanda Pharmaceuticals, and Winston Laboratories, Inc.; Eric J. Liebler is an employee of electroCore, LLC, and receives stock ownership; Emily Rubenstein Engel, MD, has received consultancy, speaker, and advisory board fees from Allergan, Inc., Depomed, Inc., and electroCore, LLC; and Stewart J. Tepper, MD, has received consultancy fees from Acorda Therapeutics, Inc., Allergan, Inc., Amgen, Inc., Autonomic Technologies, Inc. (ATI), Avanir Pharmaceuticals, Inc., Depomed, Inc., Dr. Reddy's Laboratories Ltd., electroCore, LLC, Impax Pharmaceuticals, Inc., Pfizer, Inc., Scion NeuroStim, LLC, Teva Pharmaceutical Industries Ltd., Theorem Clinical Research, Zogenix, Inc., and Zosano Pharma Corporation. Dr. Tepper has also received research grants/support from Allergan, Inc., Amgen, Inc., Autonomic Technologies, Inc. (ATI), Avanir Pharmaceuticals, Inc., electroCore, LLC, eNeura Inc., GlaxoSmithKline, Merck & Co., Inc., Pfizer, Inc., Optinose US Inc./Avanir Pharmaceuticals, Inc./Otsuka Pharmaceutical Co., Ltd., Teva Pharmaceutical Industries Ltd., and Zogenix, Inc. He has also received stock options from Autonomic Technologies, Inc. (ATI) and royalties from the University Press of Mississippi and Springer.
ISSN:0017-8748
1526-4610
DOI:10.1111/head.12896