Pivotal Study - A Randomized, Double Blinded Clinical Study to Evaluate the Safety and Efficacy of the Nerivio device, Intended to Relief Pain During Migraine episode in Subjects Suffer From Migraines (NCT03361423)

This study was a prospective, randomized, double-blind, sham controlled multi-center pivotal study aiming to demonstrate the efficacy and safety of Nerivio. The study was performed in 7 sites in the USA and 5 sites in Israel. The study initiation was in December 2017. The first randomization procedure was performed at the end of January 2018. The end of the double-blind phase was in October 2018.

Eligible patients were 18–75 years old females and males who met the International Classification of Headache Disorders (ICHD) third edition criteria for migraine with or without aura, with at least two and no more than eight migraine headaches per month, with no more than 12 headache days per month, and with stable (or no) migraine preventive medications in the last two months prior to recruitment.

The study included two phases.  In the first (“roll-in”) phase, participants were asked to keep a headache diary for one month in which all migraine episodes were documented.  This phase was conducted to verify the number of migraine episodes experienced in one month (and thus, the eligibility of the patient), and to confirm the participant’s ability to use the application and comply with the migraine episode reporting requirements.  The second phase was a double-blind treatment phase, in which eligible participants were randomly allocated in a 1:1 ratio to either active stimulation (treatment group) or sham stimulation (sham group), in a double-blind manner. All participants underwent training on how to use the device for the treatment of migraine and how to provide feedback using the application.

Participants were asked to treat each migraine episode within 60 minutes of symptom onset.  The participants used the application (installed on their personal phones) to record pain scores (scale: none, mild, moderate, or severe) at baseline, 2 hours post-treatment and 48 hours post-treatment, and to record the presence/absence of associated migraine symptoms (nausea, photophobia, phonophobia).  The first reported treatment was considered a “run-in test” treatment, aimed to verify that the participants use the device properly, and was only included in the safety analysis.  The efficacy endpoints were evaluated on the first reported treatment following the “run-in test” treatment (hereby termed “Test treatment”).

Efficacy outcome

The primary efficacy endpoint was the proportion of participants who achieved pain relief at 2 hours post-treatment in the “Test” treatment. The co-secondary efficacy endpoints were the proportions of participants who achieved most bothersome symptom (MBS) relief, pain relief and MBS relief, pain-free and MBS free at 2 hours post-treatment.  Exploratory endpoints included the proportion of participants showing 48-hour sustained pain-free response with device single use, 48-hour sustained headache reduction with device single use, 48-hour sustained pain-free response with device reuse, 48-hour sustained headache reduction with device reuse, 48-hour sustained MBS relief with device single use, and 48-hour sustained MBS relief with device reuse.

Disposition of patients

296 participants were recruited to the study, 252 participants were randomized at the end of the roll-in phase. 126 of these eligible participants were randomly assigned to receive active Nerivio device (active group) and 126 were randomly assigned to receive sham Nerivio device (sham group). Among the 252 randomized participants, 7 participants withdrew from the study (4 in the active group and 3 in the sham group). 3 participants (1 from the sham group and 2 from the active group) withdrew from the study due to intolerance to the sensation of the stimulation (two participants withdrew during the randomization visit after the training, so the devices were never used at home) and 4 participants (2 in the active group and 2 in the sham group) were lost to follow up. 237 participants completed at least one treatment (the run-in treatment) and 202 participants completed the test treatment within one hour from symptom onset and reported a pain level at 2 hours (figure 1).

A modified intent to treat (mITT) group was defined as all randomized subjects who treated at least one attack (excluding the “run-in test” attack) within 1 hour from the attack onset.

Figure 1 – Participant disposition

The majority of patients were female (81%), and the mean age was 42.7±12.1 years. The demographic characteristics were generally similar among groups (table 1).

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Efficacy

Primary Endpoint

In the mITT analysis set, the proportion of participants achieving a pain-relief response 2 hours after treatment was 66.7% (66/99) in the treatment group compared to 38.8% (40/103) in the sham group (therapeutic gain 27.9%; p<0.0001). The active treatment was also superior to the sham for the reduction of pain for each one of the possible baseline pain levels (severe, moderate, and mild).

Secondary Endpoints

In the mITT dataset, the active stimulation treatment was significantly more effective than the sham treatment for the proportion of participants achieving 2 hours of MBS relief (46.3% vs. 22.2%; p=0.0.0008) and for the proportion of participants who achieved both headache relief and MBS relief at 2 hours post-treatment (40.0% vs. 15.2%; p=0.0004. For pain-free 2 hours post-treatment, the active device was superior to the sham device, with statistical significance (37.4% vs. 18.4%; p=0.0036). There was no significant difference between active and sham treatment for MBS-free 2 hours post-treatment (40.7% vs. 36.4%; p=0.0.55).

Figure 2 – Main endpoints results

Furthermore, the active treatment was significantly more effective than the sham treatment for all measures of sustained efficacy, including 48-hour sustained pain-free response with device single use (p=0.007), 48-hour sustained headache reduction with device single use (p=0.0015), 48-hour sustained pain-free response with device reuse (p=0.0148), and 48-hour sustained headache reduction with device reuse (p=0.0010).  In addition, the consistency of pain reduction over multiple treatments was also significantly higher in the treatment group (62.6%) compared to the sham group (45.6%, p=0.0154)

Safety

Safety analyses were performed on all 252 participants from the ITT population. 773 treatments were performed during the study (including the run-in treatment). The percentage of participants with at least 1 adverse event (regardless of its suspected cause) was 13.5% (34/252) and was comparable across treatment groups (15.1% (19/126) in the active group and 11.9% (15/126) in the sham group, p_Fisher’s=0.58). The incidence of device-related adverse events was low (3.6%), and similar between treatment groups (active group: 6/126 [4.8%]; sham group: 3/126 [2.4%]; pFisher’s=0.49). Notably, there were no unanticipated adverse device effects.

23 device-related adverse events were reported during 773 treatments (2.7%), 14 in the active group and 9 in the sham group. All device-related adverse events reported were mild in severity, did not require treatment and were resolved.  No serious adverse events related to the device were reported.  No statistically significant differences were found between treatment groups in either the type or rate of adverse events during the double-blind treatment phase.

Figure 3 – Device related adverse events

Conclusions

The findings of this study were robust and clinically meaningful. The study confirms that Nerivio is well tolerated and is associated with treatment efficacy and treatment satisfaction. From a risk-benefit perspective, treatment with Nerivio achieved significant pain relief without serious side effects. Therefore, Nerivio offers an alternative for current pharmacological and non-pharmacological treatments that combines efficient treatment with minimal side effects.

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