6 min

Initial Assessment

of Pain Intensity

15 min

Stimulation Stimulation Stimulation

120 s 120 s 120 s

Treatment:3 Consecutive Stimulations

3 min 6 min

Stimulation Stimulation Stimulation

120 s 120 s 120 s

Optional: 3 Additional Consecutive Stimulationsd

Stimulation Protocol

2 Excluded from nVNS ITT population• 2 Missing diary

3 Discontinued • 1 Protocol violation• 2 Other

Safety Population N=102 (30 eCH, 72 cCH)

Shamn=52

(15 eCH, 37 cCH)

nVNSn=45 (13 eCH,

32 cCH)

nVNSn=38 (12 eCH,

26 cCH)

Not randomized• 1 Personal reasons

Open-label Period2 Weeks

Double-blind Period2 Weeks

nVNSn=43 (12 eCH,

31 cCH)

nVNSn=36 (12 eCH,

24 cCH) End of Study

nVNS Group Sham Group

Enrolledn=103

8 Excluded from shamITT population • 6 Missing diary• 2 No attacks treated

6 Discontinued • 2 Withdrawal• 2 LTFU• 2 AE

2 Discontinued • 1 AE• 1 Other

2 Discontinued• 2 LTFU

ITTn=48

(14 eCH, 34 cCH)

ITTn=44

(13 eCH, 31 cCH)

nVNSn=50

(15 eCH, 35 cCH)

Run-in Period1 Week

Run-in

1-Week Run-in Perioda

nVNS

Sham

2-Week Double-blind Perioda,b

nVNS

nVNS

2-Week Open-label Periodc

a Subjects maintained their standard of care regimens for CH; no adjustments were permitted. b Subjects were randomly assigned to treatment groups (1:1 ratio). c Subjects were allowed to alter their CH treatment regimens by adding prophylactic therapies and/or changing doses of existing treatments. d Optional additional stimulations were administered if the subject did not achieve pain freedom 9 minutes after initiation of the first stimulation.

Non-invasive Vagus Nerve Stimulation for the Acute Treatment of Episodic and Chronic Cluster Headache:Findings From the Randomized, Double-blind, Sham-Controlled ACT2 Study

P.J. Goadsby, MD, PhD1; I.F. de Coo, MD2; N. Silver, MBBS, PhD3; A. Tyagi, MD4; F. Ahmed, MD5; C. Gaul, MD6; R. H. Jensen, MD, DrMedSci7;H.-C. Diener, MD8; A. Straube, MD9; E. Liebler10; J. Marin, MD1; and M.D. Ferrari, MD, PhD2 on Behalf of the ACT2 Study Group

1NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College, London, UK; 2Leiden University Medical Centre, Leiden, the Netherlands; 3Walton Centre for Neurology and Neurosurgery, Liverpool, UK; 4Queen Elizabeth University Hospital Glasgow, Glasgow, UK; 5Hull Royal Infirmary, Hull, UK; 6Migraine and Headache Clinic, Königstein, Germany; 7Glostrup Hospital, Glostrup, Denmark; 8West German Headache Centre, Essen, Germany; 9University of Munich, Munich, Germany; 10electroCore, LLC, Basking Ridge, NJ, USA

IntroductionCluster Headache (CH)• Primary headache disorder characterized by recurrent attacks of intense unilateral pain commonly accompanied by restlessness and/or other autonomic symptoms1,2

▪ Characterized by painful, disabling attacks of 15 minutes to 3 hours • Subtypes2

▪ Episodic cluster headache (eCH): attack periods lasting between 1 week and 1 year, separated by ≥1 month ▪ Chronic cluster headache (cCH): attack periods of ≥1 year without remission or with remission lasting <1 month

Vagus Nerve Stimulation (VNS)• Well-established neuromodulation therapy for epilepsy and medication-resistant depression3,4

▪ Initially delivered via surgically implanted devices; associated with inherent risks of infection and other surgery-related complications and costs• Non-invasive vagus nerve stimulation (nVNS; gammaCore®) ▪ Transcutaneous stimulation of the cervical branch of the vagus nerve5

▪ Previously established as efficacious for CH in randomized sham-controlled studies6,7

MethodsStudy Design and Treatment• Pivotal, randomized, double-blind, sham-controlled prospective study conducted in 4 European countries at 9 tertiary care centers, subject to local ethics committee approval• Included adults diagnosed with eCH or cCH according to ICHD (2nd edition) criteria8 who agreed not to start a new CH treatment or change the dose of an existing treatment during the run-in and double-blind periods• At onset of a CH attack, subjects administered treatment with the study device (Figure 1) • Subjects were asked to refrain from use of rescue treatments (ie, medications and/or inhaled oxygen) for 15 minutes after beginning stimulation• CH attack data recorded in subject diaries

ResultsSubjects• A total of 102 subjects (nVNS, n=50; sham, n=52) were randomly assigned and treated (Figure 2) ▪ 73 subjects (72%) were men ▪ Mean subject age was 45.4 years (standard deviation, 10.7 years) ▪ 30 subjects (29%) had eCH; 72 (71%) had cCH ▪ Demographic and baseline characteristics were generally similar between treatment groups (data not shown)

Abbreviations: ITT, intent-to-treat; LTFU, lost to follow-up.

P values were determined from the chi-square or Fisher exact test, as appropriate.

a Number of subjects from the safety population who entered the open-label study period. Abbreviation: ADE, adverse device effect.

a Rated on a 5-point pain scale (0=none, 1=mild, 2=moderate, 3=severe, 4=very severe). All patients who had at least 1 treated attack for which rescue treatments were not used and had a pain score at attack onset and at the specified post–attack-onset time periods were included in the analysis. Δ values represent the averages of the mean change (from attack onset to 15 minutes post-stimulation) in pain intensity for each subject. Only treated attacks without the use of rescue treatment were evaluated. P values are from 2-sided t tests.

The n values denote the numbers of treated CH attacks. ORs (95% CIs) are 1.22 (0.42, 3.51) for all CH, 9.19 (1.77, 47.80) for eCH, and 0.41 (0.13, 1.30) for cCH. ORs and P values are from the generalized estimating equations model, which was adjusted for site in the total cohort and cCH subgroups but was not adjusted for site in the eCH subgroup. OR >1 favors nVNS. a Type 3 test of fixed effects revealed significant interaction between treatment groups and CH subtype. Abbreviations: CI, confidence interval; OR, odds ratio.

Safety• Two subjects reported 4 serious adverse events (SAEs) during the study, none of which were considered treatment related (Table 1) ▪ One nVNS-treated subject had severe lower abdominal and back pain during the double-blind period, which resolved without intervention ▪ One sham-treated subject reported severe depression and anxiety during the double-blind period; the subject discontinued from the study, and both SAEs resolved

Author DisclosuresP. J. Goadsby reports grants and personal fees from Allergan; Amgen; and Eli Lilly and Company. He has received personal fees from Akita Biomedical; Alder Biopharmaceuticals; Autonomic Technologies; Avanir Pharmaceuticals; Cipla Ltd; CoLucid Pharmaceuticals, Inc.; Dr. Reddy’s Laboratories; eNeura; electroCore, LLC; Novartis; Pfizer Inc; Promius Pharma; Quest Diagnostics; Scion; Teva Pharmaceuticals; Trigemina, Inc.; Medico-Legal Journal; Journal Watch; Up-to-Date; and Oxford University Press. In addition, Dr. Goadsby has a patent for magnetic stimulation for headache pending assignment to eNeura. I. F. de Coo has received travel grants from electroCore, LLC. N. Silver has received honoraria from Allergan and electroCore, LLC, and investigator fees paid to the Walton Centre. A. Tyagi has received honoraria from Allergan and electroCore, LLC. F. Ahmed has nothing to disclose. C. Gaul has received honoraria from Allergan; electroCore, LLC; St. Jude Medical; Grünenthal; Desitin; Bayer; Boehringer Ingelheim; Autonomic Technologies; Reckitt Benckiser; Ratiopharm GmbH; Novartis; Lilly Deutschland; and Hormosan. Dr. Gaul has no ownership interests and does not own any pharmaceutical company stocks. R. H. Jensen has given lectures and conducted clinical trials for Autonomic Technologies; Neurocore; and Eli Lilly and Company. H.-C. Diener has received honoraria for participation in clinical trials and for contributions to advisory boards and oral presentations sponsored by Addex Pharma; Adler; Allergan; Almirall; Amgen; Autonomic Technologies; AstraZeneca; Bayer; Vital; Berlin-Chemie; Boehringer Ingelheim; Bristol-Myers Squibb; Chordate Medical; Coherex Medical; CoLucid Pharmaceuticals; electroCore, LLC; GlaxoSmithKline; Grünenthal; Janssen-Cilag; Labrys Biologics; Eli Lilly and Company; La Roche; 3M Medica; Medtronic; Menarini; Minster Pharmaceuticals; MSD; NeuroScore; Novartis; Johnson & Johnson; Pierre Fabre; Pfizer; Schaper and Brümmer; Sanofi; St. Jude Medical; and Weber & Weber. Dr Diener has also received research funding from Allergan; Almirall; AstraZeneca; Bayer; electroCore, LLC; GlaxoSmithKline; Janssen-Cilag; MSD; and Pfizer. He has received additional research support from the German Research Council; the German Ministry of Education and Research; and the European Union. Dr. Diener has no ownership interests and does not own any pharmaceutical company stocks. A. Straube has received honoraria from Allergan; Berlin-Chemie; Desitin; MSD; Pfizer; electroCore, LLC; Boehringer Ingelheim; and St. Jude Medical. He has also received grants from the German Science Council; the German Secretary of Education; the Else Kröner-Fresenius Foundation; and the University of Munich. E. Liebler is an employee of electroCore, LLC, and receives stock ownership. J. Marin has received honoraria and travel grants from electroCore, LLC. M. D. Ferrari has received consultancy fees from Medtronic and research support from the Netherlands Organization for Scientific Research (NWO); the European Community; ZonMw; and the Dutch Heart Foundation. Dr. Ferrari is a member of the Editorial Board for Cephalalgia.

Figure 2. Subject Disposition

Figure 5. Changes in Pain Intensitya at 15 Minutes

Figure 4. Proportions of Subjects Who Achieved Responder Status in ≥50% of Treated Attacks at 15 Minutes (ITT Population)

Figure 3. Proportions of All Treated Attacks That Achieved Pain-Free Status Within 15 Minutes (ITT Population)

Primary End Point

References1. Goadsby PJ. Pathophysiology of cluster headache: a trigeminal autonomic cephalgia. Lancet Neurol. 2002;1(4):251-257.2. Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013;33(9):629-808.3. Guberman A. Vagus nerve stimulation in the treatment of epilepsy. CMAJ. 2004;171(10):1165-1166.4. O’Reardon JP, Cristancho P, Peshek AD. Vagus nerve stimulation (VNS) and treatment of depression: to the brainstem and beyond. Psychiatry (Edgmont). 2006;3(5):54-63.5. Yuan H, Silberstein SD. Vagus nerve and vagus nerve stimulation, a comprehensive review: part II. Headache. 2016;56(2):259-266.6. Gaul C, Diener HC, Silver N, et al. Non-invasive vagus nerve stimulation for PREVention and Acute treatment of chronic cluster headache (PREVA): a randomised controlled study. Cephalalgia. 2016;36(6):534-546.7. Silberstein SD, Mechtler LL, Kudrow DB, et al. Non-invasive vagus nerve stimulation for the acute treatment of cluster headache: findings from the randomized, double-blind, sham-controlled ACT1 study. Headache. 2016;56(8):1317-1332.8. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004;24 (suppl 1):9-160.

Acknowledgments and FundingThis study was sponsored by electroCore, LLC. Professional writing and editorial support was provided by Elizabeth S. O. Barton, MS, of MedLogix Communications, LLC, Schaumburg, Illinois, under the direction of the authors and was funded by electroCore, LLC. Clinicaltrials.gov identifier: NCT01958125All CH eCH cCH

0

1

2

3

4

Pain

Inte

nsity

Scor

e(m

ean)

nVNS (attack onset)

nVNS (post-stimulation)

= -1.3

n=36 n=31 n=11

P=0.06

Sham (attack onset)

Sham (post-stimulation)

= -0.9 = -1.7

= -0.6

= -1.2

= -1.0

P=0.01

P=0.52

n=36 n=31 n=11 n=8 n=8 n=25 n=25 n=23 n=23

All CH eCH cCH0

20

40

60

80

100

CHAt

tack

s(%

)

nVNS

Sham

13.5% 11.5%

47.5%

6.2% 4.8%

12.9%

n=495 n=400 n=101 n=81 n=394 n=319

P=0.71

P<0.01

P=0.13

All CH eCH cCH0

20

40

60

80

100

Subj

ects

(%)

nVNS

Sham

39.6%

13.6%

64.3%

15.4%

29.4%

12.9%

n=48 n=44 n=14 n=13 n=34 n=31

P=0.01

P=0.01

P=0.11

AEs and ADEsDouble-blind Period Open-label Period

nVNS (n=50) Sham (n=52) nVNS (n=83a)

Subject with ≥1 AE, No. (%) 20 (40.0) 14 (26.9) 23 (27.7)

Total number of AEs 65 39 72

Subjects with ≥1 ADE, No. (%) 9 (18.0) 10 (19.2) 12 (14.5)

ADEs Occuring in >1 Subject in Any Treatment Group, No. (%)

General disorders and administration site conditions

Application site irritation 2 (4.0) 0 1 (1.2)

Application site paresthesia 2 (4.0) 1 (1.9) 1 (1.2)

Musculoskeletal and connective tissue disorders

Myalgia 0 1 (1.9) 2 (2.4)

Myokymia 0 0 2 (2.4)

Skin and subcutaneous tissue disorders

Rash 1 (2.0) 2 (3.8) 0

Skin irritation 2 (4.0) 0 0

002

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End Points• Primary efficacy end point ▪ Proportion of all treated attacks that achieved pain-free status (pain score=0) within 15 minutes after initiation of stimulation• Additional efficacy end points ▪ Proportions of subjects who achieved responder status (pain score=0-1) within 15 minutes for ≥50% of attacks ▪ Change in pain intensity score from attack onset to 15 minutes after initiation of stimulation• If rescue treatment was used at any point after stimulation for an attack, that attack was counted as a treatment failure (ie, non–pain-free/non-responder)• Safety end points ▪ Occurrence of AEs, including type, number, and relationship to study device

Additional End Points

Table 1. Incidence of AEs and ADEs (Safety Population)

Figure 1. Study Design and Stimulation Protocol

Presented at the American Academy of Neurology 2017 Annual Meeting • Boston, Massachusetts • April 22-28, 2017

Conclusions • In the current study, nVNS was ▪ Superior to sham therapy for acute treatment of attacks in patients with eCH but not those with cCH, which likely affected the results for the total population ▪ Safe and well tolerated in all subjects • These results are consistent with those of the ACT1 study7 and indicate that nVNS ▪ Is an effective acute treatment option in patients with eCH but not cCH ▪ Has a favorable risk/benefit profile ▪ Can be safely and easily incorporated into existing therapeutic regimens

Interaction Test: P=0.04a