Non-invasive vagus nerve stimulation for prevention of migraine: The multicenter, randomized, double-blind, sham-controlled PREMIUM II trial

Aim: Evaluate the efficacy and safety of non-invasive vagus nerve stimulation for migraine prevention. Methods: After completing a 4-week diary run-in period, adults who had migraine with or without aura were randomly assigned to receive active non-invasive vagus nerve stimulation or sham therapy during a 12-week double-blind period. Results: Of 336 enrolled participants, 113 (active, n = 56; sham, n = 57) completed >= 70 days of the double-blind period and were >= 66% adherent with treatment, comprising the prespecified modified intention-to-treat population. The COVID-19 pandemic led to early trial termination, and the population was similar to 60% smaller than the statistical target for full power. Mean reduction in monthly migraine days (primary endpoint) was 3.12 for the active group and 2.29 days for the sham group (difference, 0.83; p 0.2329). Responder rate (i.e. the percentage of participants with a >= 50% reduction in migraine days) was greater in the active group (44.87%) than the sham group (26.81%; p= 0.0481). Prespecified subgroup analysis suggested that participants with aura responded preferentially. No serious device-related adverse events were reported. Conclusions: These results suggest clinical utility of non-invasive vagus nerve stimulation for migraine prevention, particularly for patients who have migraine with aura, and reinforce the well-established safety and tolerability profile of this therapy.