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, Alex Sinclair, Dimos Mitsikostas, Delphine Magis, Patricia Pozo-Rosich, Pablo Irimia Sieira, Miguel J. A. Làinez, Charly Gaul, Nicholas Silver, Jan Hoffmann, Juana Marin, Eric Liebler, Michel D. Ferrari

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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://clinicaltrials.gov/ct2/show/NCT02378844
Original languageEnglish
Pages (from-to)1475-1487
JournalCephalalgia
Volume39
Issue number12
DOIs
Publication statusPublished - 15 Sep 2019

Keywords

  • neuromodulation
  • preventive therapy
  • RCT
  • migrane prophylaxis
  • non-pharmacologic treatment
  • vagal activation

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