A prospective, Randomized, double-blind, sham-controlled multi-center clinical study assessing the safety and efficacy of Nerivio for the preventive treatment of migraine (NCT04828707).
The results of the pivotal study were published in Headache. 2023 Jan 27.63(3): 377-389
This was a Randomized, Controlled Trial (RCT) of the Nerivio device in migraine patients to assess the Nerivio safety and clinical efficacy in prevention of migraine. Specifically, it assessed the capability of the Nerivio device to reduce the number of migraine days, number of headache days and number of moderate/severe headache days in patients with migraine. The study was in compliance with 21 CFR parts 50, 56, and 812.
The study was a prospective, randomized, sham-controlled, multicenter study conducted at 15 sites. Eligible participants were adults (18–75 years old) who met the International Classification of Headache Disorders (ICHD-3) criteria for migraine, with 6 to 24 headaches per month (with at least 4 days a month on which their headaches and associated symptoms meet diagnostic criteria for migraine).
Participants had a 4-weeks period of “Baseline” phase. During that phase, participants were asked to complete a daily migraine diary using the electronic diary application installed on the participants’ smartphones, while continue with their standard practice for migraine. Following the baseline period, and if were qualified to continue according to the study requirements, participants went into an 8-weeks period of “Treatment” phase. During that phase, participants were asked to treat with the Nerivio device every other day with their optimal stimulation intensity and complete a daily migraine diary using the electronic diary application installed on the participants’ smartphones, while continue with their standard practice for migraine. Participants were asked NOT to use the Nerivio for acute treatment during the Treatment phase, in order to reduce bias between the active and the sham groups. At the end of the treatment phase, participant went into a 4-weeks period of “follow-up” phase.
Efficacy outcome
The primary efficacy endpoint was the mean change in number of migraine days per month comparing the 4-week baseline phase (weeks 1-4) with the last 28 days of the treatment phase (weeks 9-12). The main secondary endpoints were the mean changes in numbers of moderate/severe headache days, and headache days per month comparing the 4-week baseline phase (weeks 1-4) with the last 28 days of the treatment phase (weeks 9-12).
Disposition of patients
248 participants were eligible for randomization at the end of the baseline phase (weeks 1-4) and were randomly assigned to receive either active Nerivio device (Active group, n=128) or sham Nerivio device (Sham (Placebo) group, n=120).
Among the randomized participants, 8 participants withdrew or were lost to follow-up during the treatment phase (n=5 and n=3 in the Active and Sham groups, respectively). During weeks 9-12, 23 participants did not complete at least 22 daily reports (n=12 and n=11 in the Active and Sham groups, respectively), 19 participants did not perform at least 12 treatments (n=7 and n=12 in the Active and Sham groups, respectively) and 19 participants did not complete both (n=9 and n=10 in the Active and Sham groups, respectively). Thus, the mITT dataset has 179 participants (n=95 and n=84 in the Active and Sham groups, respectively) that reported at least 22 daily reports and performed at least 12 treatment with the study device during weeks 9-12 of the study. 248 participants were eligible to be randomized into the treatment groups (Active 128. Sham 120), and made the ITT dataset.
Figure 1 – Participant disposition
Results:
In order to demonstrate the balance between the two groups, an analysis of the demographic and migraine history data was performed for both active and sham groups for both mITT and ITT datasets. No statistically significant differences were found between the active and the sham groups.
The findings of the study show that treatment with Nerivio every other day is significantly more effective than sham.
There was a reduction of 3.97±0.41 Vs. 1.28±0.43 of migraine days in the active and sham groups, respectively (mean±SEM, p<0.001), with a therapeutic gain of -2.69 (CI95% -3.87, -1.51) migraine days. The results indicate significant clinical benefit of the device. Importantly, the therapeutic gain is statistically significant in each one of the chronic and episodic sub-groups with gains of -3.04 (CI95% -4.88, -1.21) and -2.26 (CI95% -3.74, -0.78) migraine days in the chronic and episodic participants, respectively, indicating that Nerivio is effective for migraine preventive treatment of both chronic and episodic migraine.
Figure 2 – results of primary endpoint
Nerivio was statistically significant more effective than sham in the mean change in number of moderate/severe headache days per month in the last month of double-blind treatment phase: mean change of -3.82±0.40 days Vs. -2.23±0.39 in the Active and Sham groups, respectively (mean±SEM, p=0.005), with a therapeutic gain of -1.59 (CI95% -2.70, -0.48) moderate/severe headache days.
Nerivio was statistically significant more effective than sham in the mean change in number of total headache days per month in the last month of double-blind treatment phase: mean change of -4.46±0.42 Vs. -1.77±0.50 in the Active and Sham groups, respectively (mean±SEM. p<0.0001], with a therapeutic gain of -2.69 (CI95% -3.87, -1.51) headache days.
Nerivio was more effective than sham in the percentage of participants with at least a 50% reduction in the mean number of headache days per month in the last month of double-blind treatment phase. In the Active group, 26.3% of the participants (25 out of 95) demonstrated reduction of at least 50% in their number of headache days, compared to 11.9% of the participants in the Sham group (10 out of 84), resulted in 2.21 folds in favor of the Active group (p=0.015).
Nerivio was statistically-significantly more effective than sham in the mean change in number of acute headache/migraine medication days per month from weeks 1-4 to weeks 9-12, with a reduction of 3.5±0.42 in Active group Vs. 1.4±0.47 in the Sham group (mean±SEM, p=0.001), with a therapeutic gain of -2.08±0.63 (CI95% [-3.33, -0.83]) acute headache/migraine medications days.
There were two serious adverse events (SAEs) during the study (suicidal attempt and a case of Appendicitis), which were deemed to be non-related to the study device or study procedures. There was only one device-related adverse event, in the sham group (0.83%, [1/120]).
Conclusions
The study demonstrates the effectiveness and safety of the Nerivio as a therapy for prevention of migraine. The results are clinically meaningful and demonstrates that peripheral neurostimulation aiming can invoke conditioned pain modulation that induces a reduction in the number of monthly migraine days. No statistically significant differences were found between the Active and Sham groups in either the type or rate of adverse events during the treatment phase.
