ARTICLE OPEN ACCESS CLASS OF EVIDENCE

Noninvasive vagus nerve stimulation as acutetherapy for migraineThe randomized PRESTO study

Cristina Tassorelli MD PhD Licia Grazzi MD Marina de Tommaso MD PhD Giulia Pierangeli MD PhD

Paolo Martelletti MD PhD Innocenzo Rainero MD PhD Stefanie Dorlas BMath BEd

Pierangelo Geppetti MD PhD Anna Ambrosini MD PhD Paola Sarchielli MD PhD Eric Liebler

and Piero Barbanti MD PhD On behalf of the PRESTO Study Group

Neurologyreg 201891e364-e373 doi101212WNL0000000000005857

Correspondence

Prof Tassorelli

cristinatassorelli

mondinoit

AbstractObjectiveTo evaluate the efficacy safety and tolerability of noninvasive vagus nerve stimulation (nVNSgammaCore electroCore LLC Basking Ridge NJ) for the acute treatment of migraine ina multicenter double-blind randomized sham-controlled trial

MethodsA total of 248 participants with episodic migraine withwithout aura were randomized toreceive nVNS or shamwithin 20minutes from pain onset Participants were to repeat treatmentif pain had not improved in 15 minutes

ResultsnVNS (n = 120) was superior to sham (n = 123) for pain freedom at 30 minutes (127 vs 42p = 0012) and 60 minutes (210 vs 100 p = 0023) but not at 120 minutes (304 vs 197p = 0067 primary endpoint logistic regression) after the first treated attack A post hoc repeated-measures test provided further insight into the therapeutic benefit of nVNS through 30 60 and120 minutes (odds ratio 23 95 confidence interval 12 44 p = 0012) nVNS demonstratedbenefits across other endpoints including pain relief at 120minutes andwas safe andwell-tolerated

ConclusionThis randomized sham-controlled trial supports the abortive efficacy of nVNS as early as 30minutes and up to 60 minutes after an attack Findings also suggest effective pain relieftolerability and practicality of nVNS for the acute treatment of episodic migraine

ClinicalTrialsgov identifierNCT02686034

Classification of evidenceThis study provides Class I evidence that for patients with an episodic migraine nVNS sig-nificantly increases the probability of having mild pain or being pain-free 2 hours post-stimulation (absolute difference 132)

RELATED ARTICLE

CommentNoninvasiveneurostimulation formigraine should be part ofthe general neurologistrsquostherapeuticarmamentarium

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Class of EvidenceCriteria for ratingtherapeutic and diagnosticstudies

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From the Headache Science Centre (CT) IRCCS C Mondino Foundation Pavia University of Pavia (CT) Headache Center (LG) Carlo Besta Neurological Institute and FoundationMilan Neurophysiology and Pain Unit (MdT) University of Bari Aldo Moro Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) (GP) Istituto delle Scienze Neurologiche diBologna Department of Clinical and Molecular Medicine (PM) Sapienza University Rome Department of Neuroscience (IR) University of Turin Italy MedLogix CommunicationsLLC (SD) Itasca IL Headache Centre (PG) University Hospital of Careggi Florence IRCCS Neuromed (AA) Pozzilli (IS) Neurologic Clinic (PS) Santa Maria della MisericordiaHospital Perugia Italy electroCore LLC (EL) Basking Ridge NJ and Headache and Pain Unit (PB) IRCCS San Raffaele Pisana Rome Italy

Go to NeurologyorgN for full disclosures Funding information and disclosures deemed relevant by the authors if any are provided at the end of the article

The Article Processing Charge was funded by electroCore LLC

Coinvestigators are listed at linkslwwcomWNLA593

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloadingand sharing the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal

e364 Copyright copy 2018 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology

The multiple pharmacologic classes that are effective for theacute treatment of migraine are sometimes limited by lack ofavailability or risks of drug interactions medication overuseand adverse events (AEs)12 Results from the American Mi-graine Prevalence and Prevention study revealed no furthertherapeutic gains of adding or switching to different triptansor other existing treatment classes13 and some patients maybe dissatisfied with the inconsistency of triptans in adequatelytreating their attacks45 Practical alternatives such as non-invasive neuromodulation therapies that are effective safeand well-tolerated are attractive for early adjunct or frequentuse when standard pharmacologic interventions are largelyunavailable or ineffective15ndash7

Noninvasive vagus nerve stimulation (nVNS gammaCoreelectroCore LLC Basking Ridge NJ) has shown efficacy inpilot studies of acute migraine treatment and is highly prac-tical and convenient due to its strong safety and tolerabilityprofile8ndash11 Results from a small open-label study demon-strated 2-hour responder rates of 21 for pain freedom and47 for pain relief after the first treated attack9 Findingsindicated that a large randomized controlled study of nVNS asan acute migraine treatment was warranted Conducting thistrial according to International Headache Society (IHS)guidelines was critical in ensuring appropriate scientific rigorand consistency with other comparable studies12 In align-ment with these guidelines objectives of the current studywere to (1) compare clinically meaningful outcomes of acutenVNS treatment with those of a sham device in participantswith episodic migraine and (2) evaluate the safety and toler-ability of nVNS

MethodsPrimary research questionIs nVNS effective for the acute treatment of migraine attacksin episodic migraine This study provides Class I evidencethat for patients with an episodic migraine nVNS significantlyincreases the probability of havingmild pain or being pain-free2 hours poststimulation (absolute difference 132)

Study designThis multicenter randomized double-blind parallel-groupsham-controlled study took place across 10 Italian sites fromJanuary 11 2016 through March 31 2017 The study wasdesigned to compare nVNS to sham treatment and includedthree 4-week periods (1) a run-in period (2) a double-blindperiod and (3) an open-label period In the observational

run-in period participants treated their migraine attacks withstandard medications according to their individual pre-scriptions Participants treated up to 5 migraine attacks withnVNS or sham in the double-blind period and up to 5 addi-tional attacks with nVNS in the open-label period only 1attack could be treated in a 48-hour period

Standard protocol approvals registrationsand participant consentsInvestigators obtained local ethics committee approval ofthe protocol which was registered at ClinicalTrialsgov(NCT02686034) All participants provided written in-formed consent before study initiation

ParticipantsStudy sites enrolled participants who were 18ndash75 years of agewith a previous diagnosis of migraine with or without auraaccording to ICHD-3 beta criteria13 Participants were lt50years of age at migraine onset and had an attack frequency of3ndash8 attacks per month with lt15 headache days per monthover the last 6 months

Key exclusion criteria were as follows history of secondaryheadache aneurysm intracranial hemorrhage brain tumors sig-nificant head trauma substance abuse addiction syncope orseizure another significant pain disorder cardiovascularcerebrovascular disease uncontrolled hypertension psychiatriccognitive disorders pregnancy medical condition requiring oralinjectable steroids botulinum toxin injections in the past 6months head or neck nerve blocks in the past 2months previousmigraine prevention surgery cervical vagotomy electrical deviceor metal cervical spine hardware implantation current use ofopioids for more than 2 days per month current use of simpleanalgesics or nonsteroidal anti-inflammatory drugs for more than15 days per month current use of triptans ergots or combinedanalgesics for more than 10 days per month and initiation ofpreventive migraine medications in the past 2 months Partic-ipants who entered the double-blind period were reassessed forentry criteria

Participants receiving preventivemigrainemedications at baseline(or other preventive medications determined to potentially in-terfere with the study) were required to have maintained a stabledose and frequency of these medications during the 2 monthsbefore enrollment and throughout the study initiation of newpreventive medications was not permitted during this period

Randomization and blindingParticipants were randomly assigned (11) to receive nVNS orsham (variable block design [4 and 6] stratified by site)

GlossaryAE = adverse eventCI = confidence interval ICHD-3 beta = International Classification of Headache Disorders 3rd edition (betaversion) IHS = International Headache Society ITT = intent-to-treat nVNS = noninvasive vagus nerve stimulationPRESTO = Prospective Study of nVNS for the Acute Treatment of Migraine SAE = serious adverse event

NeurologyorgN Neurology | Volume 91 Number 4 | July 24 2018 e365

according to independent statistician-generated randomiza-tion schedules A third-party distributor allocated the devicesto the sites Devices were labeled with a serial number and notoutwardly identified as active or sham The Merge eClinicalOS Interactive Web Response system provided study sitepersonnel (investigator or designee) with a sequential par-ticipant randomization number and corresponding deviceserial number A sponsor designee provided the randomiza-tion schedule to a site-identified unblinded trainer Thetrainer was unblinded to provide participants with instruc-tions that were specific to the assigned device and had nofurther interaction with participants This allowed for inves-tigators and participants to remain blinded to treatmentassignments throughout the study in order to minimize po-tential bias related to the device-specific training instructions

InterventionsThe nVNS device produces a proprietary low-voltage elec-trical signal comprising a 5-kHz sine wave burst lasting for 1ms (5 sine waves each lasting 200 μs) with such bursts re-peated once every 40 ms (25 Hz) generating a 24-V peakvoltage and 60-mA peak output current The sham deviceproduces a low-frequency (01 Hz) biphasic signal that wasintended to be physically perceived without actually stimu-lating the vagus nerve or generally causingmuscle contraction

An unblinded trainer instructed the participants on electronicdiary completion and correct study device use A follow-upphone call at 5 days into each study period ensured adherence to

the instructions Within 20 minutes from migraine pain onsetparticipants self-administered bilateral 120-second stimulationsto the right and left sides of the neck Participants recorded post-treatment assessments in their diaries at 15 30 60 and 120minutes and 24 and 48 hours after completion of the initialbilateral stimulations Participants were instructed to repeat thebilateral stimulations if pain had not improved at the 15-minuteassessment and participants who were not pain-free at the 120-minute assessment had the option of administering an additionalset of bilateral stimulations Participants were asked to wait 120minutes before using acute rescue medication

Study endpointsAs recommended by IHS guidelines14 the primary efficacyendpoint was the proportion of participants who were pain-free without using rescue medication at 120 minutes afterstudy treatment completion for the first treated migraine at-tack of the double-blind period Key secondary and otherefficacy endpoints for the first treated attack during thedouble-blind period included pain-free rates at 30 and 60minutes pain relief at 30 60 and 120 minutes mean per-centage change in pain score from baseline to 30 60 and 120minutes and the absence of associated symptoms(ie nausea vomiting photophobia and phonophobia) at120 minutes Pain relief was defined according to the IHSguidelines for controlled studies of migraine medications asa decrease in pain intensity from moderate (2) or severe (3)to mild (1) or no (0) pain on a 4-point scale14 Consistency ofresponse another clinically meaningful outcome recommended

Figure 1 Participant disposition

AE = adverse event ITT = intent-to-treat nVNS = noninvasive vagus nerve stimulation Other reasons for discontinuation included inability to fulfill visitsbecause of injury inability to continue the study because of family commitments dissatisfaction with or discontinuedlack of use of the device andnoncompliance with study procedures

e366 Neurology | Volume 91 Number 4 | July 24 2018 NeurologyorgN

by IHS guidelines14 was evaluated during the double-blindperiod by calculating ge50 responder rates at 120 minutes forboth pain freedom and relief in those with at least 2 treatedmigraine attacks Pain freedom and pain relief were also evalu-ated at 120minutes after the first treated attack in the open-labelperiod as was the consistency of response for those who treatedat least 2 attacks during this period Additional outcomes in-cluded blinding effectiveness participant satisfaction (1 ex-tremely satisfied 5 not at all satisfied) participant willingness torecommend the device to a friend or familymember and ease ofdevice use (1 very easy 4 very difficult) The safety and tol-erability of nVNS was assessed by comparing rates of AEsadverse device effects and serious adverse events (SAEs) amongthe nVNS group and controls

Statistical methodsA sample size of 232 participants (116 per treatment arm) wasdetermined to provide 90 power to demonstrate statistical

significance for the primary endpoint assuming a sham pain-free rate of 18 a treatment difference of 20 an α value of005 and an attrition rate of 10

Descriptive statistics were used for both continuous variables(means and 95 confidence intervals [CIs]) and categoricalvariables (frequency counts percentages and 95 CIs) Eachattack was assessed separately with responder rates basedsolely on pain intensity if medication use data were missingMissing pain intensity data were imputed using the last ob-servation carried forward Participants who did not providedata on associated symptoms were excluded from symptom-specific analyses

Statistical efficacy analyses (nVNS vs control) were conductedon the intent-to-treat (ITT) population defined as all ran-domized participants who treated at least 1 migraine attack inthe double-blind period A logistic regression analysis was

Table 1 Demographics and participantattack characteristics

Characteristic nVNS (n = 120) Sham (n = 123)

At baseline

Age y 388 plusmn 110 396 plusmn 118

Age at migraine onset y 294 plusmn 112 285 plusmn 115

Female n () 95 (792) 91 (740)

Caucasian n () 120 (1000) 123 (1000)

Migraine type n ()

Migraine with aura 8 (67) 9 (73)

Migraine without aura 112 (933) 114 (927)

Attacks in the last 4 weeks n 54 plusmn 17 53 plusmn 17

Headache days in the last 4 weeks n 63 plusmn 23 62 plusmn 21

Attacks per month in the last 6 months n 54 plusmn 15 54 plusmn 15

Acute migraine medication use per month d 56 plusmn 17 53 plusmn 17

Preventive medication use n () 42 (350) 35 (285)

At attack onseta

Migraine attack severity (first treated attack) n ()b

Mild 40 (336) 46 (387)

Moderate 51 (429) 55 (462)

Severe 28 (235) 18 (151)

Migraine attack severity (all treated attacks) n ()b

Mild 113 (315) 105 (319)

Moderate 156 (435) 166 (505)

Severe 90 (251) 58 (176)

Abbreviation nVNS = noninvasive vagus nerve stimulationIntent-to-treat population Data are mean plusmn SD unless otherwise indicateda Participants with no reported severity at attack onset are excluded from this analysisb First treated attack nVNS n = 119 sham n = 119 all treated attacks nVNS n = 359 sham n = 329

NeurologyorgN Neurology | Volume 91 Number 4 | July 24 2018 e367

included in the primary endpoint (pain freedom at 120minutesfor the first attack in the double-blind period) with adjustmentfor the participantsrsquo baseline pain score use of preventivetherapies and presence of aura andwas repeated for the 30- and60-minute time points the presence of aura was not consideredin the 30-minute analysis because of model fit issues A post hocrepeated-measures analysis using generalized linear mixed-effects regression models was conducted to gain further insightfrom all of the data collected at multiple time points throughthe 120-minute time point of the primary efficacy analysis Therepeated-measures analysis was also adjusted for baseline painscore use of preventive therapies and presence of aura Meanpercentage changes in pain score were compared betweentreatment groups using 2-sample t tests The remaining sec-ondary and other analyses reported were evaluated using the χ2

test or Fisher exact test as appropriate Two-sided p valueslt005 were considered statistically significant Use of rescuemedication before the 120-minute assessment was considereda study treatment failure

Blinding analyses were performed using the Bang blindingindex Safety analyses were conducted on the safety

population defined as all enrolled participants All data wereanalyzed using SAS 94 (SAS Institute Inc Cary NC)

Data availabilityAny data not published within this article will be publicly avail-able at ClinicalTrialsgov with the identifier NCT02686034Individual participant data will not be shared

ResultsParticipantsIn the Prospective Study of nVNS for the Acute Treatment ofMigraine (PRESTO) 285 participants were enrolled 248were randomized and 243 formed the ITT population (figure1) A total of 237 participants from the ITT populationcompleted the open-label period with 219 of these treating atleast 1 attack during this period Demographic and baselinecharacteristics were generally well-balanced between thenVNS group and controls (table 1) A higher proportion ofparticipants in the nVNS group treated their first attack whenits intensity was severe (p = 0254) and were using preventivemedications (p = 0273) The most commonly used

Figure 2 Responder rates after the first treated attack during the double-blind period

(A) Pain freedom and (B) pain relief CI = confidenceinterval nVNS = noninvasive vagus nerve stimulationData for no of participants in (A) are unadjustednumbers Statistically significant Primary endpoint

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preventive medications were topiramate vitamin B2 magne-sium and propranolol

Pain-free responder ratesFor the first treated migraine attack the proportion of par-ticipants who became pain-free was significantly higher withnVNS than with sham at 30 and 60 minutes but not at 120minutes (primary endpoint) (figure 2A) A repeated-measures test examined the inconsistency between the 120-minute finding and the 30- and 60-minute findings and foundnVNS to be superior to sham for the pain-free outcomethrough 30 60 and 120 minutes (odds ratio 23 95 CI 1244 p = 0012)

Responder rates for pain reliefResponder rates for pain relief at 120 minutes were signifi-cantly higher with nVNS than with sham for the first treatedmigraine attack (figure 2B) Responder rates for pain reliefwere numerically higher with nVNS at 30 and 60 minutes butthese differences were not significant (figure 2B)

Percentage pain intensity reductionsMean percentage pain intensity reductions for the first attackwere significantly more pronounced with nVNS than withsham at 60 and 120 minutes (figure 3)

Consistency of responseProportions of participants who responded at 120 minutes forge50 of their attacks were significantly higher with nVNSthan with sham for both pain freedom and pain relief(figure 4)

Associated symptomsAs expected with the early treatment of attacks in this studyrelatively low percentages of participants were experiencing

an associated symptom at the time of initial treatment(vomiting 66 nausea 305 photophobia 469phonophobia 432) The number of participants who didnot report vomiting at 120 minutes after the first treatedattack was higher in the nVNS group (68 [750]) than incontrols (38 [375]) (p = 0315) Proportions of par-ticipants who became nausea-free (nVNS 1435 [400]sham 1639 [410] p = 0929) photophobia-free(nVNS 2053 [377] sham 2361 [377] p =0997) or phonophobia-free (nVNS 1648 [333]sham 2457 [421] p = 0357) at 120 minutes after thefirst treated attack were similar among the nVNS group andcontrols

BlindingAfter the first treatment and at the end of the double-blindperiod participants indicated the treatment they thoughtthey had received (nVNS sham do not know) guesseswere generally similar among the nVNS group andcontrols (figure 5) After the first treatment Bangblinding index estimates for nVNS and sham indicatedsuccessful blinding (ie inclusion of zero in the 95 CI)(figure 5)

Device use and perceptionsAlmost all participants (98) administered at least 1 stimu-lation and were adherent to the treatment instructions butmost participants did not administer repeat stimulations forthe first attack at 15 minutes as instructed (nVNS 608sham 602) or optionally at 120 minutes (nVNS 958sham 935)

The percentage of participants who rated the treatment asa little satisfying or better at the end of the double-blindperiod was higher for nVNS (720) than for sham (639)as was the percentage of participants who would recommendtheir study device to a friend or family member (nVNS602 sham 467) Approximately 96 of participants ineach treatment group reported that their device was some-what or very easy to use

Efficacy findings from the open-label periodTherapeutic benefits seen with nVNS in the double-blindperiod were sustained after an additional 4 weeks of acutenVNS use in the open-label period Findings were con-sistent after the first treated attack of the double-blind andopen-label periods for pain-free response (304 and279 respectively) and pain relief (408 and 434respectively) The consistency of response to nVNS wasalso maintained from the double-blind period (pain free-dom 324 pain relief 476) to the open-label period(pain freedom 268 pain relief 418)

Safety and tolerabilityAcute nVNS therapy demonstrated a highly favorablesafety and tolerability profile (table 2) The most commonAEs were application site discomfort and nasopharyngitis

Figure 3 Mean percentage pain score reductions

Changes are from baseline for the first treated attack in the double-blindperiod post hoc analysis CI = confidence interval nVNS = noninvasive vagusnerve stimulation Statistically significant

NeurologyorgN Neurology | Volume 91 Number 4 | July 24 2018 e369

in the nVNS group and application site erythema and paindizziness flu-like symptoms and nasopharyngitis amongcontrols Participants reported no SAEs during the studyOnly 2 participants both controls discontinued from thestudy due to AEs

DiscussionThe PRESTO trial is one of the largest randomized double-blind sham-controlled studies of a noninvasive neuro-modulation device for the acute treatment of migraine2 In theabsence of guidelines for evaluating neuromodulation in mi-graine this trial was designed and conducted using stringentIHS recommendations for evaluating migraine medications14

Our adherence to the current standards for pharmacologictrials included the use of 2-hour pain freedom as the primaryendpoint which is less vulnerable to the placebosham effectcompared with pain relief41415

nVNSwas superior to sham in aborting the first treated attack at30 and 60minutes but not at 120minutes A repeated-measurestest provided additional insight into the primary endpoint bysupporting the superiority of nVNS over sham in achieving painfreedom through 30 60 and 120 minutes The pain-free re-sponder rate at 120 minutes in the nVNS group (304)was consistent with those generally seen in previous studiesevaluating the efficacy of oral triptans (14ndash42)416ndash18 and ofpotent nonsteroidal anti-inflammatory drugs (15ndash25)19ndash21

Higher 2-hour pain-free rates of oral triptans (47ndash68) havebeen reported in patients with mild-intensity migraines whoalso generally had higher 2-hour pain-free placebo rates and in

patients treated with higher-dose regimens17 which often fur-ther increase the risk of adverse effects22 Taken togetherfindings of this large rigorous well-controlled trial stronglysuggest that nVNS is effective and has benefits consistent withstandard drug options but with the added benefit of an ex-tremely benign adverse effect profile and the flexibility to beused for multiple attacks without the risk of medication overuseor drug-related adverse effects As a nonpharmacologic optionnVNS can also be utilized in combination with any existingmedication

A higher percentage of participants in the nVNS group treatedtheir first attack while it was severe in intensity This differ-ence although not statistically significant suggests a clinicallymeaningful bias toward more severe pain at the time oftreatment in the nVNS group that may have moderated thetherapeutic gain seen in the study results Associated symp-toms had not yet emerged in many participants as nVNS orsham treatment was initiated within 20 minutes from mi-graine pain onset which limits statistical power for evaluatingthese symptoms The early treatment design likely contrib-uted to the lack of superiority of nVNS in improving associ-ated symptoms consistent with challenges in othernoninvasive device studies2324 Treatment responses mayhave also been mitigated due to the limited use of repeatstimulations Additional stimulations appeared to improveefficacy in previous studies and carry minimal risks given thefavorable safety and tolerability of nVNS1125ndash29 A possibleexplanation for why most participants in the current study didnot administer repeat stimulations as instructed may involvea perceived rapid pain relief from the initial stimulations thatled to a lack of need or motivation to administer the additionalstimulations

The limitations of this study include the selection of an ap-propriate sham device which is a consistent challenge inneuromodulation studies30 The sham device in this study hadan active signal that was strong enough to be perceived butwas not intended to stimulate the vagus nerve as recom-mended in published literature30 The apparent strength ofthe sham signal helped to maintain blinding but could haveconceivably elevated the effects of sham treatment across allendpoints limiting the ability of clinically meaningful activetherapeutic gains to achieve statistical superiority We hy-pothesize that the higher-than-expected sham results couldrepresent either a psychobiological placebo effect31 ora physiologically active response potentially related to anunanticipated low level of vagal or other activity generated byan active sham signal being applied to the neck

The mechanism of action of nVNS in the treatment of mi-graine is largely elusive and likely multifactorial Preclinicaldata have demonstrated that this therapy inhibits the trige-minovascular pathway and suppresses extracellular glutamatein the central nervous system2532 A study that used a vali-dated migraine-specific animal model demonstrated that di-rect activation of the vagus nerve which has been shown to be

Figure 4 ge50 responder rates at 120 minutes during thedouble-blind period

CI = confidence interval nVNS = noninvasive vagus nerve stimulationStatistically significant Post hoc analysis

e370 Neurology | Volume 91 Number 4 | July 24 2018 NeurologyorgN

elicited by nVNS3334 suppressed the acute nociceptive acti-vation of trigeminocervical neurons25 In a separate studyusing an established rodent model of chronic trigeminalallodynia nVNS reversed the elevation in extracellular glu-tamate a marker of increased pain within the trigeminalnucleus caudalis32 These studies suggest that direct activationof the vagus nerve by nVNS treatment facilitates central in-hibition in the trigeminovascular system contributing to theclinical efficacy seen in the current study

The scientific rigor of the large PRESTO trial and its adher-ence to IHS guidelines for pharmacologic studies allow for theconsideration of nVNS in the context of currently availableacute treatment options for migraine121417 Our resultsprovide an option for both headache centers and the largermigraine community to address the need for further optimi-zation of the control of migraine attacks without anyadded adverse effects or the risk of medication overuse35

PRESTO and a forthcoming randomized sham-controlled

Figure 5 Blinding

nVNS = noninvasive vagus nerve stimulation Inclusion ofzero in the 95 confidence interval (CI) indicates successfulblinding

Table 2 Incidence of adverse events (AEs) and adverse device effects (ADEs) (all study periods)

AEs and ADEs nVNS (n = 122) Sham (n = 126)

ge1 AE 22 (180) 23 (183)

ge1 ADE 7 (57) 10 (79)

ge1 SAE 0 0

AEs occurring in ge2 of participants in any treatment group

General disorders and administration site conditions

Application site discomfort 3 (25) 1 (08)

Application site erythema 0 3 (24)

Application site pain 0 3 (24)

Infections and infestations

Influenza 0 3 (24)

Nasopharyngitis 2 (16) 3 (24)

Nervous system disorders

Dizziness 0 3 (24)

Abbreviations nVNS = noninvasive vagus nerve stimulation SAE = serious adverse eventSafety population Data are n () of participants

NeurologyorgN Neurology | Volume 91 Number 4 | July 24 2018 e371

study of nVNS for the prevention of episodic migraine(ClinicalTrialsgov identifier NCT02378844) may also helpthe migraine community by informing future recom-mendations regarding neuromodulation trials

nVNS is a novel flexible therapeutic approach for the acutetreatment of migraine attacks The therapeutic benefit of nVNSwas consistent across several important clinically relevant end-points andwas similar to that of oral triptans as demonstrated bysimilar 2-hour pain-free responder rates41618 Its combination ofefficacy and consistent safety and tolerability established overmultiple studies1126ndash29 makes it an attractive option for earlyand frequent use nVNS may be used in conjunction withexisting treatments without any drug interactions or as mono-therapy potentially delaying or decreasing the need for medi-cations that can be limited by lack of availability inconvenienceor AEs12536 nVNS offers a convenient complementary treat-ment option that is easy to use has no pharmacologic AEs andpreserves the flexibility to use standard medications whenneeded Findings from this randomized sham-controlled trialdemonstrate the efficacy of nVNS for aborting attacks as early as30 minutes and up to 60 minutes and for relieving pain at 120minutes in the acute treatment of episodic migraine with orwithout aura This study also confirms the practicality and strongsafety and tolerability profile of nVNS

Author contributionsCristina Tassorelli Licia Grazzi and Eric Liebler contributedto the PRESTO study design and provided detailed input intothe development of the manuscript All primary investigatorswere involved in participant recruitment and treatment for thePRESTO study All authors participated in data collectioninterpretation and validation and had full access to all studydata Cristina Tassorelli and Eric Liebler were involved in dataanalysis Data analysis support from North American ScienceAssociates was funded by electroCore LLC Cristina Tas-sorelli Eric Liebler and Stefanie Dorlas drafted and revisedthe manuscript for content in cooperation with all authors Allauthors reviewed critiqued and contributed to revision of themanuscript content and provided approval of the final man-uscript draft to be submitted to Neurologyreg Professionalmedical writing and editorial support (ie technical editingcopyediting preparation of tables and figures and clericalassistance) from MedLogix Communications LLC wasfunded by electroCore LLC The principal author CristinaTassorelli takes responsibility for the data analyses and in-terpretation and conduct of the research

AcknowledgmentThe authors acknowledge all coinvestigators researchnurses study sites and electroCore study team membersStatistical analyses for the study were conducted by CandaceMcClure PhD and Lisa Thackeray MS of North AmericanScience Associates Inc (Minneapolis MN) Medical writingsupport was provided by Stefanie Dorlas BMath BEd ofMedLogix Communications LLC in cooperation with theauthors

Study fundingThis study was sponsored by electroCore LLC

DisclosureCTassorelli has received consultancy fees fromAllergan SpAelectroCore LLC Eli Lilly and Company and Novartis AGand research grants from the European Commission and theItalian Ministry of Health She is also a principal investigator orcollaborator for RCTs sponsored by Alder BioPharmaceuticalsInc Eli Lilly and Company and Teva Pharmaceutical In-dustries Ltd L Grazzi has received consultancy and advisoryfees from Allergan SpA and electroCore LLC M de Tom-maso has received advisory fees from Allergan SpANeopharmed and Pfizer Inc G Pierangeli reports no dis-closures relevant to the manuscript P Martelletti has receivedresearch grants advisory board fees or travel fees fromACRAF Allergan SpA Amgen Inc electroCore LLCNovartis AG and Teva Pharmaceutical Industries LtdI Rainero has received consultancy fees from electroCoreLLC and Mylan NV and research grants from the EuropeanCommissionmdashHorizon 2020 He is also a principal in-vestigator for RCTs sponsored by Axovant Sciences Ltd andTauRx Pharmaceuticals Ltd S Dorlas is an employee ofMedLogix Communications LLC as a senior medical writerP Geppetti has received consultancy fees from Allergan SpAelectroCore LLC Evidera Novartis AG Pfizer Inc and SanofiSpA and research grants from Chiesi Farmaceutici SpA Heis also a principal investigator for RCTs sponsored by Eli Lillyand Company Novartis AG and Teva Pharmaceutical In-dustries Ltd A Ambrosini has received consultancy fees fromAlmirall SA and travel grants from Allergan SpA andAlmirall SA P Sarchielli has received clinical study fees fromAllergan SpA E Liebler is an employee of electroCore LLCand receives stock ownership P Barbanti has received con-sultancy fees from Allergan SpA electroCore LLC JanssenPharmaceuticals Inc Lusofarmaco and Visufarma and advi-sory fees from Abbott Laboratories and Merck amp Co Inc Goto NeurologyorgN for full disclosures

Received January 2 2018 Accepted in final form April 11 2018

References1 Buse DC Serrano D Reed ML et al Adding additional acute medications to a triptan

regimen for migraine and observed changes in headache-related disability resultsfrom the American Migraine Prevalence and Prevention (AMPP) study Headache201555825ndash839

2 Puledda F Goadsby PJ An update on non-pharmacological neuromodulation for theacute and preventive treatment of migraine Headache 201757685ndash691

3 Serrano D Buse DC Kori SH et al Effects of switching acute treatment on disabilityin migraine patients using triptans Headache 2013531415ndash1429

4 Ferrari MD Goadsby PJ Roon KI Lipton RB Triptans (serotonin 5-HT1B1Dagonists) in migraine detailed results and methods of a meta-analysis of 53 trialsCephalalgia 200222633ndash658

5 Lipton RB Buse DC Serrano D Holland S Reed ML Examination of unmettreatment needs among persons with episodic migraine results of the AmericanMigraine Prevalence and Prevention (AMPP) study Headache 2013531300ndash1311

6 Bigal ME Serrano D Buse D Scher A Stewart WF Lipton RB Acute migrainemedications and evolution from episodic to chronic migraine a longitudinalpopulation-based study Headache 2008481157ndash1168

7 Yuan H Silberstein SD Vagus nerve stimulation and headache Headache 20175729ndash33

8 Barbanti P Grazzi L Egeo G Padovan AM Liebler E Bussone G Non-invasive vagusnerve stimulation for acute treatment of high-frequency and chronic migraine anopen-label study J Headache Pain 20151661

e372 Neurology | Volume 91 Number 4 | July 24 2018 NeurologyorgN

9 Goadsby PJ Grosberg BM Mauskop A Cady R Simmons KA Effect of noninvasivevagus nerve stimulation on acute migraine an open-label pilot study Cephalalgia201434986ndash993

10 Kinfe TM Pintea B Muhammad S et al Cervical non-invasive vagus nerve stimu-lation (nVNS) for preventive and acute treatment of episodic and chronic migraineand migraine-associated sleep disturbance a prospective observational cohort studyJ Headache Pain 201516101

11 Silberstein SDCalhounAH LiptonRB et al Chronicmigraine headache preventionwithnoninvasive vagus nerve stimulation the EVENT study Neurology 201687529ndash538

12 Hougaard A Tfelt-Hansen P Are the current IHS guidelines for migraine drug trialsbeing followed J Headache Pain 201011457ndash468

13 The International Classification of Headache Disorders 3rd edition (beta version)Cephalalgia 201333629ndash808

14 Tfelt-Hansen P Pascual J Ramadan N et al Guidelines for controlled trials of drugsin migraine third edition a guide for investigators Cephalalgia 2012326ndash38

15 Voss T Lipton RB Dodick DW et al A phase IIb randomized double-blind placebo-controlled trial of ubrogepant for the acute treatment of migraine Cephalalgia 201636887ndash898

16 Ferrari MD Roon KI Lipton RB Goadsby PJ Oral triptans (serotonin 5-HT(1B1D) agonists) in acute migraine treatment a meta-analysis of 53 trials Lancet 20013581668ndash1675

17 Marmura MJ Silberstein SD Schwedt TJ The acute treatment of migraine in adultsthe American Headache Society evidence assessment of migraine pharmacotherapiesHeadache 2015553ndash20

18 Silberstein SD Newman LC Marmura MJ Nahas SJ Farr SJ Efficacy endpoints inmigraine clinical trials the importance of assessing freedom from pain Curr Med ResOpin 201329861ndash867

19 Brandes JL Kudrow D Stark SR et al Sumatriptan-naproxen for acute treatment ofmigraine a randomized trial JAMA 20072971443ndash1454

20 Diener HC Montagna P Gacs G et al Efficacy and tolerability of diclofenac po-tassium sachets in migraine a randomized double-blind cross-over study in com-parison with diclofenac potassium tablets and placebo Cephalalgia 200626537ndash547

21 Lipton RB Grosberg B Singer RP et al Efficacy and tolerability of a new powderedformulation of diclofenac potassium for oral solution for the acute treatment ofmigraine results from the International Migraine Pain Assessment Clinical Trial(IMPACT) Cephalalgia 2010301336ndash1345

22 Hougaard A Tfelt-Hansen P Review of dose-response curves for acute antimigrainedrugs triptans 5-HT1F agonists and CGRP antagonists Expert Opin Drug MetabToxicol 2015111409ndash1418

23 Lipton RB Dodick DW Silberstein SD et al Single-pulse transcranial magneticstimulation for acute treatment of migraine with aura a randomised double-blindparallel-group sham-controlled trial Lancet Neurol 20109373ndash380

24 Schoenen J Vandersmissen B Jeangette S et al Migraine prevention with a supra-orbital transcutaneous stimulator a randomized controlled trial Neurology 201380697ndash704

25 Akerman S Simon B Romero-Reyes M Vagus nerve stimulation suppresses acutenoxious activation of trigeminocervical neurons in animal models of primary head-ache Neurobiol Dis 201710296ndash104

26 Gaul C Diener HC Silver N et al Non-invasive vagus nerve stimulation for pre-vention and acute treatment of chronic cluster headache (PREVA) a randomisedcontrolled study Cephalalgia 201636534ndash546

27 Goadsby PJ de Coo IF Silver N et al Non-invasive vagus nerve stimulation for theacute treatment of episodic and chronic cluster headache a randomized double-blind sham-controlled ACT2 study Cephalalgia 201838959ndash969

28 Grazzi L Egeo G Calhoun AH McClure CK Liebler E Barbanti P Non-invasivevagus nerve stimulation (nVNS) as mini-prophylaxis for menstrualmenstrually re-lated migraine an open-label study J Headache Pain 20161791

29 Silberstein SD Mechtler LL Kudrow DB et al Non-invasive vagus nerve stimulationfor the acute treatment of cluster headache findings from the randomized double-blind sham-controlled ACT1 study Headache 2016561317ndash1332

30 Asano E Goadsby PJ How do we fashion better trials for neurostimulator studies inmigraine Neurology 201380694

31 Benedetti F Carlino E Pollo A How placebos change the patientrsquos brain Neuro-psychopharmacology 201136339ndash354

32 Oshinsky ML Murphy AL Hekierski H Jr Cooper M Simon BJ Noninvasivevagus nerve stimulation as treatment for trigeminal allodynia Pain 20141551037ndash1042

33 Frangos E Komisaruk BR Access to vagal projections via cutaneous electricalstimulation of the neck fMRI evidence in healthy humans Brain Stimul 20171019ndash27

34 Nonis R DrsquoOstilio K Schoenen J Magis D Evidence of activation of vagal afferents bynon-invasive vagus nerve stimulation an electrophysiological study in healthy vol-unteers Cephalalgia 2017371285ndash1293

35 Westergaard ML Steiner TJ MacGregor EA et al The Headache Under-Response toTreatment (HURT) Questionnaire assessment of utility in headache specialist careCephalalgia 201333245ndash255

36 Puledda F Messina R Goadsby PJ An update on migraine current understandingand future directions J Neurol 20172642031ndash2039

NeurologyorgN Neurology | Volume 91 Number 4 | July 24 2018 e373

DOI 101212WNL0000000000005857201891e364-e373 Published Online before print June 15 2018Neurology

Cristina Tassorelli Licia Grazzi Marina de Tommaso et al PRESTO study

Noninvasive vagus nerve stimulation as acute therapy for migraine The randomized

This information is current as of June 15 2018

0028-3878 Online ISSN 1526-632XKluwer Health Inc on behalf of the American Academy of Neurology All rights reserved Print ISSN1951 it is now a weekly with 48 issues per year Copyright copy 2018 The Author(s) Published by Wolters

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Supplementary Material

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0028-3878 Online ISSN 1526-632XKluwer Health Inc on behalf of the American Academy of Neurology All rights reserved Print ISSN1951 it is now a weekly with 48 issues per year Copyright copy 2018 The Author(s) Published by Wolters

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

ServicesUpdated Information amp

httpnneurologyorgcontent914e364fullincluding high resolution figures can be found at

Supplementary Material

857DC1httpnneurologyorgcontentsuppl20180730WNL0000000000005Supplementary material can be found at

References httpnneurologyorgcontent914e364fullref-list-1

This article cites 36 articles 3 of which you can access for free at

Citations httpnneurologyorgcontent914e364fullotherarticles

This article has been cited by 3 HighWire-hosted articles

Subspecialty Collections

httpnneurologyorgcgicollectionvagus_nerve_stimulationVagus nerve stimulation

httpnneurologyorgcgicollectionmigraineMigraine

lled_consort_agreementhttpnneurologyorgcgicollectionclinical_trials_randomized_controClinical trials Randomized controlled (CONSORT agreement)

httpnneurologyorgcgicollectionclass_1Class I

httpnneurologyorgcgicollectionall_painAll Painfollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online

0028-3878 Online ISSN 1526-632XKluwer Health Inc on behalf of the American Academy of Neurology All rights reserved Print ISSN1951 it is now a weekly with 48 issues per year Copyright copy 2018 The Author(s) Published by Wolters

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology