Non-invasive vagus nerve stimulation (nVNS) for the preventive treatment of episodic migraine: The multicentre, double-blind, randomised, sham-controlled PREMIUM trial

Hans-Christoph Diener, Peter J Goadsby, Messoud Ashina, Mohammad Al-Mahdi Al-Karagholi, Alexandra Sinclair, Dimos Mitsikostas, Delphine Magis, Patricia Pozo-Rosich, Pablo Irimia Sieira, Miguel Ja Làinez, Charly Gaul, Nicholas Silver, Jan Hoffmann, Juana Marin, Eric Liebler, Michel D Ferrari, Hans-Christoph Diener, Peter J Goadsby, Messoud Ashina, Mohammad Al-Mahdi Al-Karagholi, Alexandra Sinclair, Dimos Mitsikostas, Delphine Magis, Patricia Pozo-Rosich, Pablo Irimia Sieira, Miguel Ja Làinez, Charly Gaul, Nicholas Silver, Jan Hoffmann, Juana Marin, Eric Liebler, Michel D Ferrari

Abstract

Introduction: Non-invasive vagus nerve stimulation (nVNS; gammaCore®) 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 = 165; baseline, 7.9 days) and 1.80 for sham (n = 167; baseline, 8.1 days) (p = 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 = 138) and sham (n = 140) for outcomes including reduction in migraine days (2.27 vs. 1.53; p = 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 population. 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://ichgcp.net/clinical-trials-registry/NCT02378844.

Keywords: Neuromodulation; RCT; migraine prophylaxis; non-pharmacologic treatment; preventive therapy; vagal activation.

Figures

Figure 1.
Figure 1.
The nVNS device. Note: A previous model of the nVNS device was used by patients in the PREMIUM trial. Image provided courtesy of electroCore, Inc. nVNS: non-invasive vagus nerve stimulation.
Figure 2.
Figure 2.
Patient disposition. aOther 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.
Figure 3.
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). aPost hoc analysis. bThe 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 4.
Figure 4.
Changes in number of migraine days over time in (a) the ITT population and (b) the mITT population. aThe 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 5.
Figure 5.
Changes in number of headache days over time for (a) the ITT population and (b) the mITT population. aThe 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.

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