Original Article Cephalalgia 2019, Vol. 39(12) 1475–1487 Non-invasive vagus nerve stimulation ! International Headache Society 2019 (nVNS) for the preventive treatment Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/0333102419876920 of episodic migraine: The multicentre, journals.sagepub.com/home/cep double-blind, randomised, sham-controlled PREMIUM trial Hans-Christoph Diener1, Peter J Goadsby2 , Messoud Ashina3, Mohammad Al-Mahdi Al-Karagholi3 , Alexandra Sinclair4, Dimos Mitsikostas5, Delphine Magis6 , Patricia Pozo-Rosich7,8, Pablo Irimia Sieira9, Miguel JA Làinez10, Charly Gaul11, Nicholas Silver12, Jan Hoffmann2,* , Juana Marin2, Eric Liebler13 and Michel D Ferrari14; on behalf of the PREMIUM Study Group Abstract Introduction: Non-invasive vagus nerve stimulation (nVNS; gammaCoreÕ ) has the potential to prevent migraine days in patients with migraine on the basis of mechanistic rationale and pilot clinical data. Methods: This multicentre study included a 4-week run-in period, a 12-week double-blind period of randomised treatment with nVNS or sham, and a 24-week open-label period of nVNS. Patients were to administer two 120-second stimulations bilaterally to the neck three times daily (6–8 hours apart). Results: Of 477 enrolled patients, 332 comprised the intent-to-treat (ITT) population. Mean reductions in migraine days per month (primary outcome) were 2.26 for nVNS (n ¼ 165; baseline, 7.9 days) and 1.80 for sham (n ¼ 167; baseline, 8.1 days) (p ¼ 0.15). Results were similar across other outcomes. Upon observation of suboptimal adherence rates, post hoc analysis of patients with  67% adherence per month demonstrated significant differences between nVNS (n ¼ 138) and sham (n ¼ 140) for outcomes including reduction in migraine days (2.27 vs. 1.53; p ¼ 0.043); therapeutic gains were greater in patients with aura than in those without aura. Most nVNS device-related adverse events were mild and transient, with application site discomfort being the most common. Conclusions: Preventive nVNS treatment in episodic migraine was not superior to sham stimulation in the ITT popu- lation. The ‘‘sham’’ device inadvertently provided a level of active vagus nerve stimulation. Post hoc analysis showed significant effects of nVNS in treatment-adherent patients. Study identification and registration: PREMIUM; NCT02378844; https://clinicaltrials.gov/ct2/show/NCT02378844 8 Headache Research Group, Vall d’Hebron Research Institute, Universitat Autonoma de Barcelona, Barcelona, Spain 9 Clinica Universidad de Navarra, Pamplona, Spain 10 1 Faculty of Medicine, University Duisburg-Essen, Essen, Germany Catholic University of Valencia, University Clinic Hospital, Valencia, 2 NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College Spain 11 London, London, UK Migraine and Headache Clinic, Königstein, Germany 12 3 Danish Headache Center, Rigshospitalet Glostrup, University of The Walton Centre, Liverpool, UK 13 Copenhagen, Copenhagen, Denmark electroCore, Inc., Basking Ridge, New Jersey, USA 14 4 Metabolic Neurology, Institute of Metabolism and Systems Research, Leiden University Medical Center, Leiden, The Netherlands University of Birmingham, Birmingham, UK *Formerly of the Department of Systems Neuroscience, University 5 1st Neurology Department, Aeginition Hospital, National and Medical Center Hamburg-Eppendorf, Hamburg, Germany (UKE); work Kapodistrian University of Athens, Athens, Greece for the current study was performed at UKE. 6 Neurology Department and Pain Clinic, CHR East Belgium, Liège, Corresponding author: Belgium Hans-Christoph Diener, Faculty of Medicine, University Duisburg-Essen, 7 Headache Unit, Neurology Department, Hospital Universitari Vall Hufelandstrasse 55, 45147 Essen, Germany. d’Hebron, Barcelona, Spain Emails: h.diener@uni-essen.de; hans.diener@uk-essen.de 1476 Cephalalgia 39(12) Keywords Neuromodulation, preventive therapy, RCT, migraine prophylaxis, non-pharmacologic treatment, vagal activation Date received: 23 July 2019; revised: 14 August 2019; 22 August 2019; accepted: 23 August 2019 randomly assigned nVNS or sham stimulation, and a Introduction 24-week open-label period of nVNS. All investigators Several alternative and emerging therapies provide an obtained approval from their local independent ethics opportunity to improve care for patients with migraine committee, and all patients provided written informed by addressing poor tolerability, adherence, and persis- consent before participating. tence with standard preventive migraine medications (1–3). Non-invasive neuromodulation therapies and injectable monoclonal antibody medications targeting Patients calcitonin gene-related peptide or its receptor are effec- Patients were 18 to 75 years of age with a diagnosis of tive and well tolerated for migraine prevention (4–10). migraine with or without aura according to The new preventive medications, including the calci- International Classification of Headache Disorders, tonin gene-related peptide monoclonal antibodies, are 3rd edition (beta version) criteria (18). The age of not effective for all patients and are currently not rec- migraine onset was <50 years, and patients had experi- ommended for patients under the age of 18 years, preg- enced 5–12 migraine days per month in the past nant patients, and older adults. There continues to be a 4 months, with at least two migraines lasting more need for additional effective, tolerable, and safe treat- than 4 hours. Complete inclusion and exclusion criteria ment options that can be used without concern about for study participation are provided in Supplemental potential adverse interactions with existing or emerging Table 1. treatments (11,12). Those who met any of the following criteria were Non-invasive vagus nerve stimulation (nVNS; excluded: Chronic migraine diagnosis; previous diagno- gammaCoreÕ ; electroCore, Inc., Basking Ridge, NJ, sis of medication overuse headache that had reverted to USA) is a neuromodulation therapy with Class I evi- episodic migraine in the past 6 months; medical con- dence for the acute treatment of migraine attacks for dition requiring oral/injectable steroids; history of sec- patients with episodic migraine (13). nVNS has also ondary headache, aneurysm, intracranial haemorrhage, shown preliminary efficacy for migraine prevention in brain tumours, significant head trauma, substance a small double-blind study of a chronic migraine popu- abuse, addiction, syncope, or seizure; structural lation (n ¼ 59) and in open-label studies of patients with abnormality, pain, or metal cervical spine hardware chronic migraine or treatment-refractory episodic implantation near the treatment site; another significant migraine (n ¼ 20) and a menstrually related migraine pain disorder; cardiovascular/cerebrovascular disease; population (n ¼ 51) (7,14,15). The efficacy of nVNS in abnormal electrocardiogram; previous migraine pre- these and other primary headache studies combined vention surgery, cervical vagotomy, or electrical or with its established tolerability and safety profile sug- neurostimulator device implantation; uncontrolled gest that nVNS could represent a valuable addition to hypertension; psychiatric/cognitive disorders; preg- available migraine prevention treatments (12,16,17). nancy; botulinum toxin injections in the past Objectives of the current study were to evaluate the 6 months; head or neck nerve blocks in the past efficacy, tolerability, and safety of nVNS for the pre- 2 months; failure of at least three classes of migraine pre- ventive treatment of episodic migraine. vention drugs; opioid use (more than 2 days per month); marijuana use (more than twice per month); simple anal- gesic or nonsteroidal anti-inflammatory drug use (more Methods than 15 days per month); or triptan, ergot, or combined analgesic use (more than 10 days per month). Study design Use of preventive migraine treatments at or within The PREMIUM trial (NCT02378844) was a phase 3, 30 days before baseline was not permitted. Patients prospective, multicentre, randomised, double-blind, were required to refrain from initiating or changing parallel-group, sham-controlled study conducted from the type, dosage, or frequency of any medications for 1 June 2015 through 21 November 2017 at 22 European other indications that were determined to potentially sites. The study included a 4-week run-in period of no interfere with the study. Those who proceeded to the study treatment, a 12-week double-blind period of double-blind period were reassessed for entry criteria. Diener et al. 1477 Randomisation and blinding but produces a low-frequency (0.1 Hz) biphasic direct After the run-in period, patients were randomly current signal (amplitude, 0.0–28 V peak to peak  10% assigned to receive nVNS or a sham control device through 15 kX  10%) that was intended to be physi- (allocation, 1:1) under variable block sizes of 4 and 6, cally perceived without actual stimulation of the vagus where 4 was chosen about 60% of the time and 6 was nerve or contraction of muscle. chosen about 40% of the time. Randomisation was stratified by study site according to independent third party–generated randomisation schedules. At each site, Preventive treatment protocol participants’ information was entered into the Merge Patients were instructed to administer preventive eClinical OSTM interactive web response system, migraine treatment with their study device using two which provided a sequential patient randomisation consecutive bilateral stimulations per treatment. These number and corresponding device serial number. two stimulations were administered three times per day A third-party distributor issued the devices to the (TID): Upon waking and at 6–8 hours after the first sites. A sponsor designee provided a copy of the ran- and second daily treatments. Acute migraine medica- domisation schemes to the unblinded trainer at each tion was permitted if needed, but preventive migraine study centre. The unblinded trainer opened the box medication was not permitted until the open-label and used the study device to provide training. The period. training was specific to each subject’s assigned random- ised treatment group and was aimed at instructing the Study procedures subject to use the device to activate the vagus nerve most efficiently (rather than to achieve a maximal cur- Patients gained access to an electronic diary at the start rent/stimulation level). After training was complete, the of the run-in period, which was used to record migraine unblinded trainer provided the device to the subject. and headache attacks, medication(s) taken for the The subjects, investigators, and study coordinators attacks, adverse events (AEs), and use of the study remained blinded to treatment assignments throughout device throughout the trial. An unblinded trainer the double-blind period. instructed the patients on correct study device use at the site before they started home use in the double- blind period; this training was revisited during each Interventions study visit. The nVNS device (Figure 1) produces a proprietary low-voltage electrical signal comprising a 5-kHz sine wave burst lasting for 1 ms (five sine waves, each lasting Study outcomes 200 ls), with such bursts repeated once every 40 ms The primary efficacy outcome was the mean reduction (25 Hz), generating a 24-V peak voltage and 60-mA in number of migraine days from the 4-week run-in peak output current. The sham device is identical to period (baseline) to the last 4 weeks of the 12-week the active nVNS device in appearance, weight, visual double-blind period. Reductions in the number of and audible feedback, user application, and control, headache days and acute medication days during the same time period were evaluated as secondary out- comes. For efficacy analysis, ‘migraine day’ was defined as a migraine headache occurring in a 24-hour period, and a ‘headache day’ was defined as any headache occurring in a single calendar day. Other secondary outcomes included 50% responder rates for migraine, headache, and acute medication days, with a ‘responder’ defined as a patient who recorded a reduc- tion of at least 50% from baseline to the last 4 weeks of the double-blind period, and migraine and headache day reductions in the open-label period. Blinding effec- tiveness was evaluated after the first week of the double-blind period and at completion by asking patients to indicate which treatment they thought Figure 1. The nVNS device. they had received (active stimulation, sham, or don’t Note: A previous model of the nVNS device was used by patients know). Device perceptions were determined from in the PREMIUM trial. Image provided courtesy of electroCore, patient responses for satisfaction (1, extremely satisfied; Inc. nVNS: non-invasive vagus nerve stimulation. 5, not at all satisfied) and ease of use (1, very easy; 1478 Cephalalgia 39(12) 4, very difficult). The tolerability and safety of nVNS days in the run-in period. Two-sided p-values < 0.05 was assessed using rates of AEs, adverse device effects were considered statistically significant. (ADEs), including those considered serious, and study Responses to blinding effectiveness questions for discontinuations due to AEs. each treatment group were used to calculate the Bang blinding index (20). This measure assesses the success of blinding in clinical trials using an interval from 1 to 1, Statistical methods with 1 indicating incorrect guessing, 0 indicating per- A sample size of 320 patients (160 per treatment fect blinding, and 1 indicating complete lack of blinding arm) was determined to provide 90% power to demon- (20). Safety analyses were conducted on the ‘safety strate statistical significance for the primary outcome, population’, defined as all enrolled participants. Data assuming a treatment difference of 1 migraine day, a were analysed using SASÕ 9.4 (SAS Institute Inc., common standard deviation of 2.5, a type I error of Cary, NC, USA). 5%, and an attrition rate of 15% in the double-blind period. For each 4-week interval, statistics were summarised Results descriptively by period and by treatment group for both continuous variables (means and 95% confidence inter- Patients vals [CIs]) and categorical variables (frequency counts, Of 477 patients enrolled in the PREMIUM study, 341 percentages, and 95% CIs). Available data for patients were randomly assigned to receive nVNS (n ¼ 169) or who discontinued from the study were included in the sham (n ¼ 172) in the 12-week double-blind period analysis as far as possible. Partially completed data (Figure 2). A total of 332 patients comprised the ITT (e.g. 2 weeks of data) for the 4-week run-in period or population (nVNS, n ¼ 165; sham, n ¼ 167). Two hun- the last 4 weeks of the 12-week double-blind period dred and sixty-nine patients entered the open-label were adjusted to reflect an estimated number of days period (nVNS, n ¼ 138; sham, n ¼ 131), with 187 with the outcome of interest per 28-day interval. The patients completing the study (nVNS, n ¼ 100; sham, adjustment was made using the formula 28 x  y, where x n ¼ 87). Demographics and baseline characteristics is the number of days with observed data per 28 days were well balanced among the nVNS and sham groups and y is the number of observed days with the outcome (Table 1) and are representative of those from other of interest. If fewer than 21 days of data were observed studies of the prevention of episodic migraine (4,5,8,10). in the run-in period, the run-in value was not calculated Patients were not fully adherent to the TID treat- and was considered missing. If fewer than 70 days of ment protocol, but most (83.6% [138/165]) in the data were observed in the double-blind period, the nVNS group and 83.8% ([140/167] in the sham month 3 value was imputed to no change between treat- group) demonstrated adherence of at least 67% per ment periods. month (Supplemental Table 2). The primary efficacy analysis set was the ‘intent-to- treat (ITT) population’, defined as enrolled patients Migraine days who received 1 treatment in the double-blind period. Upon observation of suboptimal rates of adherence to The mean reduction in number of migraine days per the TID treatment protocol in the ITT population, month (primary endpoint) was 2.26 days (95% CI: a ‘modified intent-to-treat (mITT) population’ was 2.81, 1.72; baseline: 7.9 migraine days) in the defined as those with 67% adherence per month for nVNS group and 1.80 days (95% CI: 2.32, 1.27; evaluation in a post hoc analysis, which was not baseline: 8.1 migraine days) in the sham group adjusted to control for type I error. The electronic (p ¼ 0.15) (Figures 3 and 4). The percentage of patients database did not measure daily adherence, and with a 50% reduction in number of migraine days was the  67% per month threshold was selected on the 31.9% (95% CI: 23.4%, 41.8%) in the nVNS group basis of reports regarding the nVNS mechanisms of and 25.0% (95% CI: 17.8%, 34.0%) in the sham action (19), which suggest benefits lasting up to 6–8 group (absolute difference, 6.9%; odds ratio [95% hours, and for practical reasons (i.e. 67% is equivalent CI], 1.40 [0.85, 2.32]; p ¼ 0.19). A prespecified subgroup to two of the recommended three treatments per day). analysis of patients with and without aura demon- For continuous and categorical variables, p-values were strated no significant differences between treatment derived from linear regression (analysis of covariance groups, but therapeutic gains with nVNS were higher models) and logistic regression, respectively, adjusted in patients with aura (nVNS, 2.83 days; sham, 1.41 for treatment group, centre, presence/absence of aura, days; p ¼ 0.061) than in those without aura (nVNS, and number of migraine/headache/acute medication 2.22 days; sham, 1.71 days; p ¼ 0.15) (Figure 3(b)). Diener et al. 1479 Baseline period N = 477 Excluded/not randomised (n=136) • Did not meet entry criteria (96) • Withdrew consent (22) • Protocol deviation (3) Eligible for • Adverse event (1) • Othera(14) randomisation N = 341 nVNS Group Sham control group nVNS Double-blind Sham n = 169 period n = 172 4 did not treat ITT (12 weeks) ITT 5 did not treat (not in ITT) n = 165 n = 167 (not in ITT) Discontinued (n = 27) Discontinued (n = 36) • Withdrew consent (16) • Adverse event (9) • Protocol deviation (5) • Withdrew consent (8) • Adverse event (2) • Protocol deviation (8) Othera(4) • Lost to follow-up (4) • nVNS Open-label nVNS • Withdrawn by Investigator (1) n = 138 period n = 131 • Othera(6) Discontinued (n = 38) • Withdrew consent (16) (24 weeks) Discontinued (n = 44) • Lost to follow-up (7) • Withdrew consent (17) • Adverse event (3) • Lost to follow-up (4) • Protocol deviation (2) • Adverse event (7) • Othera(10) • Protocol deviation (3) nVNS nVNS n = 100 End of study n = 87 • Withdrawn by Investigator (2) • Othera(11) Figure 2. Patient disposition. a Other reasons for discontinuation included inability to fulfill visits because of illness, travel, or family commitments, subject decision, and noncompliance with study procedures. ITT: intent-to-treat; nVNS: non-invasive vagus nerve stimulation. Table 1. Demographics and patient characteristics. CI: 2.74, 1.49; baseline: 9.1 headache days) for the sham group (p ¼ 0.10) (Figure 5). Headache  50% nVNS Sham responder rates were 28.5% (95% CI: 20.3%, 38.6%) Characteristica (n ¼ 165) (n ¼ 167) and 25.6% (95% CI: 18.0%, 35.0%) in the nVNS and Age, years 43.5  11.1 41.4  12.3 sham groups, respectively (absolute difference, 2.9%; Age at migraine onset, years 19.6  9.6 19.4  9.8 odds ratio [95% CI], 1.16 [0.69, 1.95]; p ¼ 0.57). Female, n (%) 142 (86.1) 138 (82.6) Caucasian, n (%) 160 (97.0) 154 (92.2) Acute medication days Migraine type, n (%) Migraine with aurab 36 (21.8) 42 (25.1) Reductions in the number of acute medication days were 1.90 days (95% CI: 2.47, 1.32; baseline: 6.8 Migraine without aurab 129 (78.2) 125 (74.9) acute medication days) in the nVNS group and 1.35 Migraine days in the last 4 weeks, n 7.9  2.2 8.1  2.0 days (95% CI: 1.91, 0.79; baseline: 7.0 acute medi- Headache days in the last 4 weeks, n 8.9  2.6 9.1  2.6 cation days) in the sham group (p ¼ 0.11). The  50% Acute migraine medication 6.8  2.7 7.0  2.8 responder rate for acute medication days was 30.9% use per month, d (95% CI: 22.2%, 41.3%) with nVNS use and 23.1% a Data are mean  SD unless otherwise indicated and are from the ITT (95% CI 15.9%, 32.3%) with sham use (absolute dif- population. ference, 7.8%; odds ratio [95% CI], 1.49 [0.87, 2.54]; b Presence/absence of aura was based on diagnosis provided in subject p ¼ 0.14). medical history at enrolment. ITT: intent-to-treat; nVNS: non-invasive vagus nerve stimulation; SD: standard deviation. Modified intent-to-treat population (mITT) Upon observation of suboptimal rates of adherence to treatment (Supplemental Table 2), a post hoc analysis Headache days of patients who were  67% adherent was performed. Mean reductions in the number of headache days were Significant therapeutic gains were observed with nVNS 2.73 days (95% CI: 3.37, 2.09; baseline: 8.9 head- compared with sham for the reduction in migraine ache days) for the nVNS group and 2.11 days (95% days, headache days, and acute medication days 1480 Cephalalgia 39(12) (a) a (b) ITT mITT Aura No Aura 0 0 n =165 n = 167 n =138 n = 140 n =36 n = 42 n =129 n = 125 Change in number of migraine days Change in number of migraine days from run-in (mean ± 95% CI) from run-in (mean ± 95% CI) –1 –1.71 –1.53 –1.41 –1 –1.80 –2.83 –2.22 –2.27 –2 –2.26 –2 –3 Δ = –0.52 P = 0.15 b nVNS nVNS Sham Sham –3 Δ = –0.47 –4 P = 0.15 b Δ = –0.74 Δ = –1.42 P = 0.043 b P = 0.061b Figure 3. Changes in number of migraine days in the double-blind period in (a) the ITT and mITT populations and (b) subjects with aura and without aura (ITT population). a Post hoc analysis. b The nVNS and sham groups were compared using ANCOVA models; p-values were derived from linear regression adjusted for treatment group, centre, presence/absence of aura (based on diagnosis provided in subject medical history at enrolment), and number of migraine days in the run-in period. ANCOVA: analysis of covariance; CI: confidence interval; ITT: intent-to-treat; mITT: modified intent-to-treat; nVNS: non-invasive vagus nerve stimulation. (a) Run-in Double-blind period Open-label period (b) Run-in Double-blind period Open-label Period period (all patients on nVNS) period (all patients on nVNS) 0 0 Change in number of migraine days from run-in Change in number of migraine days from run-in P = 0.15a P = 0.25a P = 0.65a P = 0.043a P = 0.078a P = 0.28a Δ = –0.47 Δ = –0.42 Δ = –0.16 Δ = –0.74 Δ = –0.74 Δ = –0.43 –1 –1 (mean ± 95% CI) (mean ± 95% CI) –1.53 –1.82 –2 –2 –1.80 –2.01 –2.08 –2.27 –2.24 –2.26 –2.56 –2.52 –2.43 –2.41 –3 –3 nVNS (n = 165) nVNS (n = 138) Sham (n = 167) Sham (n = 140) nVNS (post-Sham) (n = 167) nVNS (post-Sham) (n = 140) –4 –4 123 123 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 Month Month Figure 4. Changes in number of migraine days over time in (a) the ITT population and (b) the mITT population. a The nVNS and sham groups were compared using ANCOVA models; p-values were derived from linear regression adjusted for treatment group, centre, presence/absence of aura (based on diagnosis provided in subject medical history at enrolment), and number of migraine days in the run-in period. ANCOVA: analysis of covariance; CI: confidence interval; ITT: intent-to-treat; mITT: modified intent-to-treat; nVNS: non-invasive vagus nerve stimulation. (Figure 3(a), Table 2). Therapeutic gains for migraine mITT population are available in Supplemental Table 3 days were more pronounced in the aura subgroup and Figures 4(b) and 5(b). (nVNS, 2.96 days; sham, 1.38 days; p ¼ 0.055) than in the no aura subgroup (nVNS, 2.29 days; Blinding. At 1 week into the double-blind period, sham, 1.47 days; p ¼ 0.049). Additional data for the patients’ guesses for the treatment they thought they Diener et al. 1481 (a) (b) Run-in Double-blind period Open-label period Run-in Double-blind period Open-label period period (all patients on nVNS) period (all patients on nVNS) Change in number of headache days from run-in 0 0 Change in number of headache days from run-in P = 0.10a P = 0.22a P = 0.045a P = 0.15a P = 0.070a P = 0.42a Δ = –0.62 Δ = –0.33 Δ = –0.86 Δ = –0.65 Δ = –0.84 Δ = –0.51 –1 –1 (mean ± 95% CI) (mean ± 95% CI) –2 –2 –1.99 –2.43 –2.11 –2.53 –3 –2.85 –2.55 –3 –2.59 –3.08 –2.73 –3.37 –2.87 –4 –3.10 –4 nVNS (n = 165) nVNS (n = 138) Sham (n = 167) Sham (n = 140) nVNS (post-Sham) (n = 167) 123 123 nVNS (post-Sham) (n = 140) –5 123 –5 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 Month Month Figure 5. Changes in number of headache days over time for (a) the ITT population and (b) the mITT population. a The nVNS and sham groups were compared using ANCOVA models; p-values were derived from linear regression adjusted for treatment group, centre, presence/absence of aura (based on diagnosis provided in subject medical history at enrolment), and number of migraine days in the run-in period. ANCOVA: analysis of covariance; CI: confidence interval; ITT: intent-to-treat; nVNS: non-invasive vagus nerve stimulation. had received were higher in the ‘don’t know’ category consistent for those who continued receiving nVNS (nVNS, 43.6%; sham, 51.5%) than in the ‘active stimu- (78.2%) and increased for double-blind sham subjects lation’ (nVNS, 33.3%; sham, 29.3%) or ‘sham’ (nVNS, after they switched to open-label nVNS (85.4%). Most 9.7%; sham, 10.8%) category. Bang blinding index esti- patients in each treatment group (nVNS, 95%; sham, mates for nVNS (0.27; 95% CI: 0.20, 0.35) and sham 93%) reported that their device was somewhat or very (0.20; 95% CI: 0.28, 0.13) indicated that both easy to use. groups more commonly thought they were receiving active rather than sham treatment. Blinding was suc- cessful at the end of the double-blind period, as demon- Tolerability and safety strated by well-balanced guesses among categories Preventive nVNS therapy was well tolerated and safe (active stimulation: nVNS, 33.9%; sham, 26.9%; sham: (Table 3). Across all study periods, the most common nVNS, 29.1%; sham, 27.5%; don’t know: nVNS, ADEs were rash, pain, erythema, discomfort at the 21.8%; sham, 24.6%) and blinding estimates of 0.06 application site, and dizziness. No serious ADEs were (95% CI: 0.05, 0.16) for nVNS and 0.01 (95% CI: reported during the study. 0.09, 0.11) for sham, where zero was within the 95% CI. Discussion In this large, randomised, double-blind, sham-con- Open-label period trolled trial, nVNS was not superior to sham stimula- Treatment responses to nVNS during the double-blind tion in the ITT population, with migraine reductions of period were maintained with further nVNS treatment 2.26 days with nVNS and 1.80 days with sham during the open-label period for migraine and headache (p ¼ 0.15). To better understand the role of adherence days (Figures 3(b) and 4). in the findings of this neutral study, we conducted a post hoc analysis of patients who were  67% adherent. In the mITT population, nVNS demonstrated statisti- Device perceptions cally significant benefits versus sham in the prevention The percentages of patients who were at least a little of migraine, headache, and acute medication days. satisfied with their treatment at the end of the double- Adverse events were mostly mild and transient. blind period were similar between the nVNS group Findings from previous clinical and mechanistic (77.5%) and the sham group (73.5%). At the end of studies provide the rationale for evaluating nVNS the open-label period, patient satisfaction remained for migraine prevention. Migraine/headache day 1482 Cephalalgia 39(12) Table 2. Efficacy outcomes (mITT populationa). Outcome nVNS (n ¼ 138) Sham (n ¼ 140) Reduction in migraine daysb Mean (95% CI) 2.27 (2.89, 1.65) 1.53 (2.13, 0.93) Difference (95% CI) 0.74 (1.45, 0.02) p-value 0.043 Migraine  50% responder ratec % (95% CI) 33.6 (23.7, 45.1) 23.4 (15.7, 33.5) Odds ratio (95% CI) 1.65 (0.95, 2.87) p-value 0.074 Reduction in headache daysb Mean (95% CI) 2.85 (3.58, 2.12) 1.99 (2.70, 1.29) Difference (95% CI) 0.86 (1.70, 0.02) p-value 0.045 Headache  50% responder ratec % (95% CI) 31.5 (21.9, 43.1) 25.9 (17.5, 36.5) Odds ratio (95% CI) 1.32 (0.75, 2.32) p-value 0.34 Reduction in acute medication daysb Mean (95% CI) 1.94 (2.60, 1.28) 1.14 (1.77, 0.50) Difference (95% CI) 0.80 (1.56, 0.04) p-value 0.039 Acute medication  50% responder ratec,d % (95% CI) 34.4 (24.5, 45.9) 25.1 (16.9, 35.5) Odds ratio (95% CI) 1.57 (0.88, 2.79) p-value 0.13 a Post hoc analysis. b Results are from linear regression adjusted for treatment group, centre, presence/absence of aura (based on diagnosis provided in subject medical history at enrolment), and number of migraine days in the run-in period. c Results are from logistic regression adjusted for treatment group, centre, presence/absence of aura (based on diagnosis provided in subject medical history at enrolment), and number of migraine days in the run-in period. d nVNS, n ¼ 134; sham, n ¼ 134. CI: confidence interval; mITT: modified intent-to-treat; nVNS: non-invasive vagus nerve stimulation. reductions with nVNS were previously reported in a aura with every attack, the occurrence of aura might smaller randomised, double-blind, sham-controlled be underrepresented in subjects’ existing diagnoses. The study of chronic migraine and an open-label study of consideration and use of alternative definitions to cat- menstrual and menstrually related migraine (7,14). The egorize subjects as experiencing migraine with aura mechanism of action of nVNS in migraine is probably (e.g. the documentation of 1 attack with symptoms multifactorial. In the current study, therapeutic gains consistent with aura during a study) might allow for a with nVNS were greater for patients with aura than for more robust understanding of the effect of nVNS on those without aura, which is consistent with the subjects with aura as well as the effects of nVNS spe- reported effects of nVNS on cortical spreading depres- cifically on attacks with aura. sion (CSD), a common mechanistic target of preventive The effect of nVNS on CSD may be complemented migraine treatments and the underlying triggering event by other acute mechanisms, including the inhibition of of migraine with aura (21,22). In adult rats, nVNS has dural-intracranial evoked trigeminocervical neuronal been found to suppress CSD (22), which suggests that responses (23,24). Taken together, the preventive and nVNS benefits in patients who have migraine with aura acute mechanistic effects may provide a greater syner- might be related to the suppression of CSD. In the gistic effect. More recently, nVNS was shown to exert a PREMIUM study, the presence/absence of migraine significant bilateral inhibitory effect on parasympa- with aura was based on the diagnosis provided in thetic functions within the trigeminal autonomic reflex each subject’s medical history at the time of enrolment. (25). This effect has been shown to relieve symptoms of Considering that patients typically do not experience migraine and the trigeminal autonomic cephalalgias Diener et al. 1483 Table 3. AE summary. Double-blind period Open-label period AEs and ADEsa nVNS (n ¼ 169) Sham (n ¼ 172) (n ¼ 269) Subjects with 1 AE 74 (43.8) 91 (52.9) 118 (43.9) Subjects with 1 SAE 2 (1.2) 1 (0.6) 2 (0.7) Subjects with 1 ADE 31 (18.3) 57 (33.1) 29 (10.8) Subjects with 1 AE leading to discontinuation 2 (1.2) 9 (5.2) 10 (3.7) All study periods Most common AEs and ADEsa nVNS (n ¼ 169) Sham (n ¼ 172) AEs Nasopharyngitis 29 (17.2) 17 (9.9) Influenza 16 (9.5) 12 (7.0) Application site pain 6 (3.6) 10 (5.8) Oropharyngeal pain 9 (5.3) 7 (4.1) Dizziness 8 (4.7) 4 (2.3) ADEs Application site rash 1 (0.6) 12 (7.0) Application site pain 5 (3.0) 10 (5.8) Application site erythema 3 (1.8) 8 (4.7) Application site discomfort 7 (4.1) 5 (2.9) Dizziness 5 (3.0) 3 (1.7) a Data are n (%) of patients with the event and are from the safety population. ADE: adverse device effect; AE: adverse event; nVNS: non-invasive vagus nerve stimulation; SAE: serious adverse event. and could complement the previous mechanistic find- (once per side). In subsequent research by de Morais ings (25–27). et al. (32) presented at the 12th European Headache Federation Congress, the effect of two unilateral stimu- lations on CSD suppression was greater than the effect Study limitations of several other stimulation paradigms, including the This study had three notable limitations: a) the vagal treatment paradigm used in this study. This suggests activity of the sham device, b) the use of bilateral stimu- that the use of bilateral stimulations could have also lations, and c) suboptimal subject adherence to the TID mitigated the overall efficacy reported in this study. treatment regimen. Subsequent to the PREMIUM trial, The inability of some patients to use nVNS consistently another study revealed parasympathetic activity caused was likely due to its TID treatment protocol. by the sham device used in this study, indicating vagal Adherence to the TID treatment regimen was activation and representing a key limitation of the cur- directly examined in a post hoc analysis of the mITT rent study (28). The vagal activity of the sham device population and appears to be a factor in the success likely decreased the therapeutic gain seen in this study. of nVNS for migraine prevention. nVNS may there- This is also consistent with the finding that the group fore be particularly attractive for use by patients that received sham treatment during the double-blind who are highly motivated to consistently treat on a phase had little additional improvement during TID basis because of overall headache burden and/or active nVNS therapy during the open-label phase (see more convenient times of stimulation during the day Figure 4(a) and Figure 5). (i.e. morning, noon, and before bed) (2,7). An ad- Determining optimal dosing for neuromodulatory ditional randomised controlled trial of nVNS for devices is challenging. For nVNS, several stimula- migraine prevention that is currently under way in tion paradigms – including right-side, bilateral, and the United States (NCT03716505) addresses the limita- ipsilateral-to-pain stimulations and varying numbers tions identified in this study through the use of an of stimulations – have been evaluated in multiple inactive sham device and unilateral stimulations (ipsi- studies of primary headache (7,13,29–31). The lateral to the pain) in patients with a greater headache PREMIUM study called for bilateral stimulations burden. 1484 Cephalalgia 39(12) in this study (2.7 days) in which patients received pre- Application of findings ventive nVNS only. These clinical data are consistent Results of the PREMIUM study demonstrate a with the mechanistic evidence supporting the potential favourable risk-benefit ratio for nVNS in the preven- synergy of acute and preventive nVNS treatment in tion of migraine, as the apparent benefits of the ther- migraine (15,22–24,34). The ability of nVNS to provide apy outweigh the minimal risks. Efficacy findings from acute and preventive benefits would represent a novel this study are comparable to those reported in other clinical option, as pharmacologic migraine therapies studies of non-invasive neuromodulation therapies are indicated only as either preventive or acute (6,7,9). The International Headache Society– treatment. recommended primary outcome for the reduction in migraine days from run-in to 3 months was 2.26 Conclusions days with nVNS and 2.06 days with supraorbital transcutaneous stimulation (6,33). The clinical benefit Preventive effects of nVNS in episodic migraine were of nVNS in this study, which may have been under- not superior to sham stimulation (ITT). The ‘‘sham’’ stated because of the partially active effects of the device used in this study, however, produced a level of sham device (28), complements the good tolerability active vagus nerve stimulation (28) that likely affected and safety profile of nVNS. the therapeutic gain observed in the study. A post hoc The proven benefits of nVNS in the acute treatment analysis demonstrated some significant effects of nVNS of migraine attacks (13) could be complemented by pre- for patients with 67% adherence to treatment. nVNS ventive nVNS use. In a previous open-label pilot study may have clinical utility in migraine prevention, which of 20 patients with migraine who received preventive will be defined further in a second study that addresses and acute nVNS therapy for 3 months, the reduction the key limitations of this study by using an inactive in headache days per month was 5.8 days (15), which sham device, unilateral stimulation, and patients with a compares favourably with the headache day reduction higher headache burden. Clinical implications . nVNS was not superior to sham stimulation in patients with episodic migraine. . Therapeutic difference was greater in patients with aura than in those without aura. . Significant benefits were observed for migraine, headache, and acute medication reductions for those with 67% adherence with treatment (post hoc, mITT). . The sham treatment activated the vagus nerve, demonstrated by unexpected inhibitory effects on the trigeminal autonomic reflex (28). This likely decreased the therapeutic gain observed in this study. . nVNS was further established as a well tolerated and safe therapy for primary headache. Department, Wellcome Foundation Building, Denmark Hill The PREMIUM Study Group Campus, London, United Kingdom – Professor Peter J Investigators are listed by study site at the time of the trial. 1. Goadsby (principal investigator); 7. Hull Royal Infirmary, Klinik für Neurologie, Universitätsklinikum Essen, Essen, Neurology Department, Hull, United Kingdom – Dr. Germany – Professor Hans-Christoph Diener (principal inves- Fayyaz Ahmed (principal investigator); 8. The Southern tigator), Dr. Kasja Solbach (co-investigator), and Michael Hospital, Neurology Department, Glasgow, United Kleinschmidt (study coordinator); 2. Klinik für Neurologie, Kingdom – Dr. Alok Tyagi (principal investigator); 9. The Ludwig-Maximilians-University Munich, Klinikum Walton Centre, Neurology Department, Liverpool, United Grosshadern, Munich, Germany – Professor Andreas Kingdom – Dr. Nicholas Silver (principal investigator); 10. Straube (principal investigator), Dr. Katarina Kamm (co- School of Clinical and Experimental Medicine, College of investigator), and Dr. Ruth Ruscheweyh (co-investigator); 3. Medical and Dental Sciences, Institute of Biomedical Migräne- und Kopfschmerzklinik Königstein, Königstein im Research (West), University of Birmingham, Birmingham, Taunus, Germany – Privatdozent. Dr. Charly Gaul United Kingdom – Dr. Alexandra Sinclair (principal investi- (principal investigator); 4. Neurologische Klinik und gator) and Elizabeth Dwenger (study coordinator); 11. Poliklinik, Charité Campus Mitte, Berlin, Germany – Danish Headache Centre, Glostrup, Denmark – Dr. Uwe Reuter (principal investigator) and Dr. Heike Dr. Messoud Ashina (principal investigator) and Israel-Willner (co-investigator); 5. Institut für Systemische Dr. Mohammad Al-Mahdi Al-Karagholi (sub-investigator); Neurowissenschaften, Universitätsklinikum Hamburg- 12. Sandvika Nevrosenter AS, Sandvika, Norway – Eppendorf, Hamburg, Germany – Professor Arne May (prin- Dr. Anne Christine Buckley Poole (principal investigator); cipal investigator) and Priv.-Doz. Dr. Jan Hoffmann (sub- 13. DKD HELIOS Klinik Wiesbaden, Wiesbaden, Germany investigator); 6. King’s College London, Neurology – Professor Till Sprenger (principal investigator); 14. Catholic Diener et al. 1485 University of Valencia, Department of Neurology, University Council. HCD has no ownership interests and does not Clinic Hospital, Valencia, Spain – Dr. Miguel JA Làinez own any pharmaceutical company stocks. (principal investigator); 15. Leiden University Medical PJG has received grants and personal fees from Allergan; Centre, Department of Neurology, Leiden, The Netherlands Amgen; and Eli Lilly and Company. He has also received – Professor Michel D Ferrari (principal investigator) and personal fees from Akita Biomedical; Alder Dr. Ilse de Coo (co-investigator); 16. University of Liège, Biopharmaceuticals; Autonomic Technologies; Avanir CHR de la Citadelle, Neurology Department, Liège, Pharmaceuticals; Cipla Ltd; CoLucid Pharmaceuticals, Inc.; Belgium – Dr. Delphine Magis (principal investigator) and Dr. Reddy’s Laboratories; electroCore, Inc.; eNeura; Journal Romain Nonis (study coordinator); 17. Neurology Clinic, Watch; Medico-Legal Journal; Novartis; Oxford University Aeginition Hospital, Athens, Greece – Dr. Dimos Press; Pfizer Inc; Promius Pharma; Quest Diagnostics; Mitsikostas (principal investigator); 18. Servicio de Scion; Teva Pharmaceuticals; Trigemina, Inc.; and Up-to- Neurologı́a, Pamplona, Spain – Dr. Pablo Irimia Sieira (prin- Date. In addition, PJG has a patent for magnetic stimulation cipal investigator); 19. Basildon University Hospital, for headache pending assigned to eNeura. Nethermayne, Basildon, Essex, United Kingdom – MA has received honoraria for contributions to advisory Dr. Farooq Maniyar (principal investigator); 20. Zentrum boards and oral presentations sponsored by Allergan; Alder; für Neurologie und Epileptologie, Hertie-Institut für Amgen; Eli Lilly and Company; Novartis; and Teva Klinische Hirnforschung, Universitätsklinikum Tübingen, Pharmaceuticals. MA has been the primary investigator Tübingen, Germany – Dr. Tobias Freilinger (principal inves- for Alder, Amgen, electroCore, Novartis, and Teva trials. tigator); 21. Servicio de Neurologı́a, Hospital Ruber MA has no ownership interests and does not own any Internacional, Madrid, Spain – Dr. Margarita Sánchez del pharmaceutical company stocks. Rio (principal investigator); 22. Vall d’Hebron University MAA has received travel grants from electroCore, Inc. Hospital, Headache Unit, Barcelona, Spain – Dr. Patricia AS is funded by an NIHR Clinician Scientist Fellowship Pozo-Rosich (principal investigator), Marta Torres-Ferrus (NIHR-CS-011-028) and by the Medical Research Council, and Juan B Gomez (subinvestigators), and Victor J UK (MR/K015184/1). Gallardo (study coordinator). D. Mitsikostas has received advisory fees, honoraria, research grants, or travel grants from Allergan; Amgen; Acknowledgements Biogen; Cefaly; electroCore, Inc.; Eli Lilly and Company; Merz Pharma; Novartis; Roche; Sanofi Genzyme; and Teva The authors acknowledge all patients, coinvestigators, Pharmaceuticals. research nurses, and sites for their participation in the D. Magis has received travel grants from electroCore, Inc.; study. Annelie Andersson and Emma de Launay of is a consultant for Novartis Belgium and Eli Lilly Benelux; electroCore, Inc., were responsible for coordination and execu- and is an associate editor for Cephalalgia. tion of the study. Statistical analyses for the study were con- PP-R has received honoraria as a consultant and speaker ducted by Candace McClure, PhD, and Lisa Thackeray, MS, for Allergan; Almirall; Chiesi; Eli Lilly and Company; of North American Science Associates Inc. (Minneapolis, Novartis; and Teva Pharmaceuticals. PP-R does not own MN). Editorial support was provided by Stefanie Dorlas, stocks from any pharmaceutical company. BMath, BEd, of MedLogix Communications, LLC, in cooper- PIS has received honoraria from Allergan; Novartis; and ation with the authors. Teva Pharmaceuticals. PIS has no ownership interests and Declaration of conflicting interests does not own any pharmaceutical company stocks. MJAL has received advisory fees, speaker fees, research The authors declared the following potential conflicts of inter- grants, and/or research support from ATI Pharma; Allergan; est with respect to the research, authorship, and/or publica- Amgen; Boehringer Ingelheim; electroCore, Inc.; Eli Lilly and tion of this article: HCD has received honoraria for Company; Lupin Pharmaceuticals; Medtronic; Novartis; participation in clinical trials and for contributions to advi- Otsuka; Roche; and Teva Pharmaceuticals. sory boards and oral presentations sponsored by 3M Medica; CG has received honoraria from Allergan; Bayer; Addex Pharma; Adler; Allergan; Almirall; Amgen; Boehringer Ingelheim; Desitin Arzneimittel; electroCore, AstraZeneca; Autonomic Technologies; Bayer; Berlin- Inc.; Eli Lilly and Company; Grünenthal; Hormosan Chemie; Boehringer Ingelheim; Bristol-Myers Squibb; Pharma; Novartis; Ratiopharm; Reckitt Benckiser Group; Chordate Medical; Coherex Medical; CoLucid and Teva Pharmaceuticals. CG has no ownership interests Pharmaceuticals; electroCore, Inc.; Eli Lilly and Company; and does not own any pharmaceutical company stocks. GlaxoSmithKline; Grünenthal; Janssen-Cilag; Johnson & NS has received honoraria from Allergan; electroCore, Inc.; Johnson; Labrys Biologics; La Roche; Medtronic; Menarini; Eli Lilly and Company; Novartis; and Teva Pharmaceuticals; Minster Pharmaceuticals; MSD; NeuroScore; Novartis; and investigator fees paid to the Walton Centre. Pfizer; Pierre Fabre; Sanofi; Schaper and Brümmer; St. Jude JH has consulted for and/or served on advisory boards for Medical; Vital; and Weber & Weber. HCD has also received Allergan; Autonomic Technologies Inc. (ATI); Chordate research funding from Allergan; Almirall; AstraZeneca; Medical AB; Eli Lilly and Company; Hormosan Pharma; Bayer; electroCore, Inc.; GlaxoSmithKline; Janssen-Cilag; Novartis; and Teva Pharmaceuticals. He received honoraria MSD; and Pfizer. He has received additional research support for speaking from Allergan; Chordate Medical AB; Novartis; from the European Union; the German Ministry of and Teva Pharmaceuticals. JH is an associate editor for Education and Research; and the German Research 1486 Cephalalgia 39(12) Cephalalgia and the Journal of Oral & Facial Pain and stimulator: A randomized controlled trial. Neurology Headache. JH received personal fees and/or honoraria from 2013; 80: 697–704. Oxford University Press, Quintessence Publishing, and Sage 7. Silberstein SD, Calhoun AH, Lipton RB, et al. Chronic Publishing. migraine headache prevention with noninvasive vagus JM has received honoraria and travel grants from nerve stimulation: The EVENT study. Neurology 2016; electroCore, Inc. 87: 529–538. EL is an employee of electroCore, Inc., and receives stock 8. Skljarevski V, Matharu M, Millen BA, et al. Efficacy and ownership. safety of galcanezumab for the prevention of episodic MDF has received consultancy fees from Medtronic and migraine: Results of the EVOLVE-2 phase 3 randomized research support from the Netherlands Organisation for controlled clinical trial. Cephalalgia 2018; 38: 1442–1454. Scientific Research (NWO); the European Community; 9. Starling AJ, Tepper SJ, Marmura MJ, et al. A multicen- ZonMw; and the Dutch Heart Foundation. MDF is a ter, prospective, single arm, open label, observational member of the editorial board for Cephalalgia. study of sTMS for migraine prevention (ESPOUSE Study). Cephalalgia 2018; 38: 1038–1048. 10. Stauffer VL, Dodick DW, Zhang Q, et al. Evaluation of Funding galcanezumab for the prevention of episodic migraine: The authors disclosed receipt of the following financial sup- The EVOLVE-1 randomized clinical trial. JAMA port for the research, authorship, and/or publication of this Neurol 2018; 75: 1080–1088. article: This study was sponsored by electroCore, Inc. 11. Deen M, Correnti E, Kamm K, et al. Blocking CGRP in Employees of the sponsor were involved in study design, migraine patients – a review of pros and cons. J Headache data collection, analysis, and interpretation. All authors, Pain 2017; 18: 96. including an employee of the study sponsor, drafted and/or 12. Mitsikostas DD, Belesioti I, Arvaniti C, et al. Patients’ revised the manuscript and approved the final version for sub- preferences for headache acute and preventive treatment. mission. Statistical analysis for the study conducted by North J Headache Pain 2017; 18: 102. American Science Associates Inc. (Minneapolis, MN, USA) 13. Tassorelli C, Grazzi L, de Tommaso M, et al. 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