How Does Nerivio Work?

The study was a prospective, open-label, single arm, multicenter study of the Nerivio device in adolescent patients (age 12-17, inclusive), aiming to assess the performance of Nerivio in the adolescent migraine population. study was conducted from October 2019 to May 2020 (Clinicaltrials.gov number – NCT04089761).

Study design and procedures

Eligible participants were enrolled based on the inclusions/exclusions criteria. Following enrollment, participants entered a 4-week “Run-in” phase in which they had to report their migraine attacks and continue with their usual treatment care. Participants who reported at least 3 qualifying migraine headaches with pain data at baseline and 2 hours post-treatment were eligible to continue to the “Treatment” phase.

During the “Treatment” phase, participants were asked to treat their migraine attacks at home for 8 weeks with their optimal stimulation intensity, as soon as possible after migraine headache began and always within one hour of attack onset. Participants were instructed to avoid taking rescue medications within the first two hours post-treatment. Pain scores (none, mild, moderate, or severe), absence/presence of migraine associated symptoms including nausea/vomiting, photophobia and phonophobia, and functional disability were recorded at baseline, 2- and 24-hours post-treatment in electronic diary application included in the Nerivio mobile application that was installed on the participants’ smartphones.

Participants who completed the “Treatment” phase were offered to continue to an 8-week follow-up phase in which they could incorporate the device into their usual care. Following the 8 weeks of “Follow up” phase, participants fill out their end of study questionnaire and completed the study.

Safety and efficacy endpoints

The primary endpoints of this study were the safety and tolerability of Nerivio. Safety was assessed by the incidence of adverse events in general and by seriousness, severity and association to the device. Treatment tolerability was assessed by the percent of subjects who fail to complete the study because of adverse events.

The secondary endpoints were related to device efficacy and included the proportion of participants who achieved pain relief at 2 hours post-treatment, defined as improvement from severe or moderate pain to mild or none, or improvement from mild pain to none; proportion of participants who achieved pain-free (improvement from mild, moderate, or severe pain to none) at 2 hours, and disappearance of associated symptoms (nausea/vomiting, photophobia, and phonophobia) at 2 hours post-treatment. Exploratory endpoints included sustained pain relief at 24 hours, sustained pain-free at 24 hours, and improvement in functional ability at 2 hours and at 24 hours. Within-subject consistency of pain relief and pain-free responses, defined as the proportion of participants achieving pain relief/pain-free at 2 hours post-treatment in at least 50% of their treated headaches, were also assessed.

Results

60 patients were enrolled, of which 1 participant was lost to follow-up during the run-in phase, and 14 completed the run-in but were not eligible to continue according to protocol specifications.

Among the 45 participants who entered the treatment phase, all participants completed at least one treatment (the training treatment) and 39 participants completed the test treatment, forming the final analysis set (two participants had missing data at 2 hours post-treatment, three participants did not have migraine headaches and one participant was a lost to follow-up).

The participants demographic information is shown in table 1.

Table 1 – Participants demographic information

Run-in phase

A total of 267 qualifying migraine attacks were reported during the run-in phase by 54 of the 60 enrolled patients (6 patients did not report any migraines during the run-in phase), with an average of 4.9 migraine attacks per participant.

The characteristics of the reported migraine headaches in the “Run-in” phase are presented in Table 2.

Table 2 – Characteristics of migraine attacks reported during the “Run-in” phase.

Treatment phase

Safety

Safety analyses were performed on all 45 participants who used the device at least once. 10 participants (22.2%) reported at least one adverse event. There was one device-related adverse event reported (2.2%) in which a temporary feeling of pain in the arm was felt. This adverse event was mild and resolved after the treatment without requiring medication or any other intervention. The other adverse events which were deemed unrelated to the device included common cold (1 participant), chest congestion (2 participants), influenza (2 patients), leg pain (1 patient), streptococcus pharyngitis (1 participant), upper respiratory infection (1 patient), and worsened migraine (1 patient). There were no device-related serious adverse events and none of the participants withdrew from the study due to device-related adverse events.

Efficacy

A total of 159 qualifying migraine headaches were treated with Nerivio for which pain data was recorded at baseline and at 2 hours post-treatment (average of 3.5 treatments per participant). Pain severity of treated migraine headaches was mostly moderate (48.4% [77/159]). 57/159 (35.8%) of the treated migraine headaches were severe and 25/159 (15.7%) of the treated migraine headaches were mild.

Pain relief and pain-free at 2 hours were achieved by 71.8% (28/39) and 35.9% (14/39) participants, respectively. Pain relief was sustained for 24 hours in 90.9% (20/22) of the participants, and pain freedom was sustained for 24 hours in 90.9% (10/11) of the participants. Nausea, photophobia, and phonophobia disappeared at 2 hours in 54.5% (12/22), 41.9% (13/31), and 40.0% (10/25) participants, respectively. Furthermore, 69.7% (23/33) participants experienced improvement in functional ability at 2 hours and 69.0% (20/29) participants experienced improvement in functional ability at 24 hours.

a consistency analyses was conducted across all treated attacks (excluding the training treatment). This analysis demonstrated that 66.7% (26/39) of the participants experienced pain relief in at least 50% of their treated attacks, and 33.3% (13/39) of the participants experienced pain-free in at least 50% of their treated attacks.

Safety analyses were performed on all 45 participants who used the device at least once. 10 participants (22.2%) reported at least one adverse event. There was one device-related adverse event reported (2.2%) in which a temporary feeling of pain in the arm was felt. This adverse event was mild and resolved after the treatment without requiring medication or any other intervention. The other adverse events which were deemed unrelated to the device.

The findings of the study show that Nerivio is effective for the acute treatment of migraine in the adolescent population. The results of the study show that Nerivio is safe to use and is well-tolerated by adolescence migraineurs. The incidence of device-related adverse events was low with no device-related serious adverse events.

Efficacy outcome summary is demonstrated in table 3.

Table 3 – Efficacy outcome

Conclusions

The results of the study show that Nerivio is safe and effective for the acute treatment of migraine in adolescents. There was one device-related adverse event in which a temporary feeling of pain in the arm was felt. This adverse event was mild and resolved after the treatment without requiring medication or any other intervention. This rate of device-related adverse events compares favorably to the reported rates for current pharmacological treatments. Importantly, the safety profile of Nerivio is also favorable with respect to new pharmacological developments such as ditans and gepants, though these have not been assessed in adolescents yet.

Acute treatment of migraine headaches resulted in clinically meaningful benefits. Pain relief and pain-free rates were generally similar to those found in adults, indicating that Nerivio provides an alternative acute migraine treatment independent of age.

Post HOC Analysis

In addition, a post hoc analysis (TCH-004) of comparison between the Nerivio treatment (REN) and Standard-Care Medications for Acute Treatment of Migraine was performed.

Four efficacy endpoints were tested: pain freedom and pain relief (severe to mild or no pain, or moderate to no pain—two-step improvement) after a single treatment, and pain freedom and pain relief consistency across treatments. All endpoints refer to 2 hours after treatment. For the single-treatment endpoints. The analyzed test treatment for REN was defined as the first REN treatment after a training treatment, and the test treatment for medications was defined as the first treatment in the run-in phase in which medication was used. For the consistency endpoints, consistent response was defined as response (pain freedom or relief) in at least 50% of the first four treatments. All participants had completed four evaluable REN treatments. The number of medication treatments varied among participants, and consistency was calculated on the basis of all available data (up to four treatments) for each participant.

Results

Participants

During the medication phase, eight participants (22.8%) used oral triptans only (five rizatriptan, one eletriptan,

one zolmitriptan, and one sumatriptan), two participants (5.7%) alternated between oral triptans and

OTC analgesics, and 26 participants (71.4%) used OTC analgesics only (11 ibuprofen, seven naproxen sodium,

five acetaminophen, and three acetaminophen-aspirin/caffeine combination).

Efficacy Results

Single Treatment Pain freedom in the REN phase was reported by 37.1% (13/35) of the participants, vs 8.6% (3/35) in the medication phase, with a statistically significant difference: P¼0.004 (OR¼11.0, 95% CI 1.60–473).

Pain relief in the REN phase was reported by 71.4% (25/35) of the participants, vs 57.1% (20/35) in the medication phase: P¼0.225 (OR¼1.83, 95% CI 0.62–6.04). The single-treatment results are depicted in Figure 2.

Consistent Efficacy

Consistent pain freedom in the REN phase was reported by 40.0% (14/35) of the participants, vs 8.6% (3/35) in

the medication phase, with a statistically significant difference: P<0.001 (proportion difference¼0.314,

0.144–0.473). OR was not applicable because there were zero participants in the group that achieved pain freedom

with medications but not with REN, and thus the paired proportion difference was estimated instead.

Consistent pain relief in the REN phase was reported by 80.0% (28/35) of the participants, vs 57.1% (20/35)

in the medication phase, with a statistically significant difference: P¼0.033 (OR¼3.67, 95% CI 0.97–20.47).

Response Rates by Medication Class Response rates were subanalyzed by medication class. Statistical comparison was not performed because of sample size limitations of the subgroups, and response rates are presented for reporting purposes only. Twentysix participants used OTC analgesic medications, of whom 38.4% (10/26) achieved pain freedom with REN, vs 11.5% (3/26) with medications. Pain relief was achieved by 76.9% (20/26) with REN, vs 65.3% (17/26) with medications. Nine participants used oral triptans, of whom 33.3% (3/9) achieved pain freedom with REN, vs 0% (0/9) with medications. Pain relief with REN was achieved by 55.5% (5/9), vs 33.3% (3/9) with medications.

The results of the post hoc analysis provides a preliminary indication that REN may be as effective as, if not more effective than, certain standard-Care medications in adolescents with migraine. Specifically, REN was found to be superior to the tested medications (oral triptans and OTC analgesic medications) in pain freedom after a single treatment, pain freedom consistency across treatments, and pain relief.

The study was a prospective, open-label, single arm, multicenter study of the Nerivio device in adolescent patients (age 12-17, inclusive), aiming to assess the performance of Nerivio in the adolescent migraine population. study was conducted from October 2019 to May 2020 (Clinicaltrials.gov number – NCT04089761).

Study design and procedures

Eligible participants were enrolled based on the inclusions/exclusions criteria. Following enrollment, participants entered a 4-week “Run-in” phase in which they had to report their migraine attacks and continue with their usual treatment care. Participants who reported at least 3 qualifying migraine headaches with pain data at baseline and 2 hours post-treatment were eligible to continue to the “Treatment” phase.

During the “Treatment” phase, participants were asked to treat their migraine attacks at home for 8 weeks with their optimal stimulation intensity, as soon as possible after migraine headache began and always within one hour of attack onset. Participants were instructed to avoid taking rescue medications within the first two hours post-treatment. Pain scores (none, mild, moderate, or severe), absence/presence of migraine associated symptoms including nausea/vomiting, photophobia and phonophobia, and functional disability were recorded at baseline, 2- and 24-hours post-treatment in electronic diary application included in the Nerivio mobile application that was installed on the participants’ smartphones.

Participants who completed the “Treatment” phase were offered to continue to an 8-week follow-up phase in which they could incorporate the device into their usual care. Following the 8 weeks of “Follow up” phase, participants fill out their end of study questionnaire and completed the study.

Safety and efficacy endpoints

The primary endpoints of this study were the safety and tolerability of Nerivio. Safety was assessed by the incidence of adverse events in general and by seriousness, severity and association to the device. Treatment tolerability was assessed by the percent of subjects who fail to complete the study because of adverse events.

The secondary endpoints were related to device efficacy and included the proportion of participants who achieved pain relief at 2 hours post-treatment, defined as improvement from severe or moderate pain to mild or none, or improvement from mild pain to none; proportion of participants who achieved pain-free (improvement from mild, moderate, or severe pain to none) at 2 hours, and disappearance of associated symptoms (nausea/vomiting, photophobia, and phonophobia) at 2 hours post-treatment. Exploratory endpoints included sustained pain relief at 24 hours, sustained pain-free at 24 hours, and improvement in functional ability at 2 hours and at 24 hours. Within-subject consistency of pain relief and pain-free responses, defined as the proportion of participants achieving pain relief/pain-free at 2 hours post-treatment in at least 50% of their treated headaches, were also assessed.

Results

60 patients were enrolled, of which 1 participant was lost to follow-up during the run-in phase, and 14 completed the run-in but were not eligible to continue according to protocol specifications.

Among the 45 participants who entered the treatment phase, all participants completed at least one treatment (the training treatment) and 39 participants completed the test treatment, forming the final analysis set (two participants had missing data at 2 hours post-treatment, three participants did not have migraine headaches and one participant was a lost to follow-up).

The participants demographic information is shown in table 1.

Table 1 – Participants demographic information

Run-in phase

A total of 267 qualifying migraine attacks were reported during the run-in phase by 54 of the 60 enrolled patients (6 patients did not report any migraines during the run-in phase), with an average of 4.9 migraine attacks per participant.

The characteristics of the reported migraine headaches in the “Run-in” phase are presented in Table 2.

Table 2 – Characteristics of migraine attacks reported during the “Run-in” phase.

Treatment phase

Safety

Safety analyses were performed on all 45 participants who used the device at least once. 10 participants (22.2%) reported at least one adverse event. There was one device-related adverse event reported (2.2%) in which a temporary feeling of pain in the arm was felt. This adverse event was mild and resolved after the treatment without requiring medication or any other intervention. The other adverse events which were deemed unrelated to the device included common cold (1 participant), chest congestion (2 participants), influenza (2 patients), leg pain (1 patient), streptococcus pharyngitis (1 participant), upper respiratory infection (1 patient), and worsened migraine (1 patient). There were no device-related serious adverse events and none of the participants withdrew from the study due to device-related adverse events.

Efficacy

A total of 159 qualifying migraine headaches were treated with Nerivio for which pain data was recorded at baseline and at 2 hours post-treatment (average of 3.5 treatments per participant). Pain severity of treated migraine headaches was mostly moderate (48.4% [77/159]). 57/159 (35.8%) of the treated migraine headaches were severe and 25/159 (15.7%) of the treated migraine headaches were mild.

Pain relief and pain-free at 2 hours were achieved by 71.8% (28/39) and 35.9% (14/39) participants, respectively. Pain relief was sustained for 24 hours in 90.9% (20/22) of the participants, and pain freedom was sustained for 24 hours in 90.9% (10/11) of the participants. Nausea, photophobia, and phonophobia disappeared at 2 hours in 54.5% (12/22), 41.9% (13/31), and 40.0% (10/25) participants, respectively. Furthermore, 69.7% (23/33) participants experienced improvement in functional ability at 2 hours and 69.0% (20/29) participants experienced improvement in functional ability at 24 hours.

a consistency analyses was conducted across all treated attacks (excluding the training treatment). This analysis demonstrated that 66.7% (26/39) of the participants experienced pain relief in at least 50% of their treated attacks, and 33.3% (13/39) of the participants experienced pain-free in at least 50% of their treated attacks.

Safety analyses were performed on all 45 participants who used the device at least once. 10 participants (22.2%) reported at least one adverse event. There was one device-related adverse event reported (2.2%) in which a temporary feeling of pain in the arm was felt. This adverse event was mild and resolved after the treatment without requiring medication or any other intervention. The other adverse events which were deemed unrelated to the device.

The findings of the study show that Nerivio is effective for the acute treatment of migraine in the adolescent population. The results of the study show that Nerivio is safe to use and is well-tolerated by adolescence migraineurs. The incidence of device-related adverse events was low with no device-related serious adverse events.

Efficacy outcome summary is demonstrated in table 3.

Table 3 – Efficacy outcome

Conclusions

The results of the study show that Nerivio is safe and effective for the acute treatment of migraine in adolescents. There was one device-related adverse event in which a temporary feeling of pain in the arm was felt. This adverse event was mild and resolved after the treatment without requiring medication or any other intervention. This rate of device-related adverse events compares favorably to the reported rates for current pharmacological treatments. Importantly, the safety profile of Nerivio is also favorable with respect to new pharmacological developments such as ditans and gepants, though these have not been assessed in adolescents yet.

Acute treatment of migraine headaches resulted in clinically meaningful benefits. Pain relief and pain-free rates were generally similar to those found in adults, indicating that Nerivio provides an alternative acute migraine treatment independent of age.

Post HOC Analysis

In addition, a post hoc analysis (TCH-004) of comparison between the Nerivio treatment (REN) and Standard-Care Medications for Acute Treatment of Migraine was performed.

Four efficacy endpoints were tested: pain freedom and pain relief (severe to mild or no pain, or moderate to no pain—two-step improvement) after a single treatment, and pain freedom and pain relief consistency across treatments. All endpoints refer to 2 hours after treatment. For the single-treatment endpoints. The analyzed test treatment for REN was defined as the first REN treatment after a training treatment, and the test treatment for medications was defined as the first treatment in the run-in phase in which medication was used. For the consistency endpoints, consistent response was defined as response (pain freedom or relief) in at least 50% of the first four treatments. All participants had completed four evaluable REN treatments. The number of medication treatments varied among participants, and consistency was calculated on the basis of all available data (up to four treatments) for each participant.

Results

Participants

During the medication phase, eight participants (22.8%) used oral triptans only (five rizatriptan, one eletriptan,

one zolmitriptan, and one sumatriptan), two participants (5.7%) alternated between oral triptans and

OTC analgesics, and 26 participants (71.4%) used OTC analgesics only (11 ibuprofen, seven naproxen sodium,

five acetaminophen, and three acetaminophen-aspirin/caffeine combination).

Efficacy Results

Single Treatment Pain freedom in the REN phase was reported by 37.1% (13/35) of the participants, vs 8.6% (3/35) in the medication phase, with a statistically significant difference: P¼0.004 (OR¼11.0, 95% CI 1.60–473).

Pain relief in the REN phase was reported by 71.4% (25/35) of the participants, vs 57.1% (20/35) in the medication phase: P¼0.225 (OR¼1.83, 95% CI 0.62–6.04). The single-treatment results are depicted in Figure 2.

Consistent Efficacy

Consistent pain freedom in the REN phase was reported by 40.0% (14/35) of the participants, vs 8.6% (3/35) in

the medication phase, with a statistically significant difference: P<0.001 (proportion difference¼0.314,

0.144–0.473). OR was not applicable because there were zero participants in the group that achieved pain freedom

with medications but not with REN, and thus the paired proportion difference was estimated instead.

Consistent pain relief in the REN phase was reported by 80.0% (28/35) of the participants, vs 57.1% (20/35)

in the medication phase, with a statistically significant difference: P¼0.033 (OR¼3.67, 95% CI 0.97–20.47).

Response Rates by Medication Class Response rates were subanalyzed by medication class. Statistical comparison was not performed because of sample size limitations of the subgroups, and response rates are presented for reporting purposes only. Twentysix participants used OTC analgesic medications, of whom 38.4% (10/26) achieved pain freedom with REN, vs 11.5% (3/26) with medications. Pain relief was achieved by 76.9% (20/26) with REN, vs 65.3% (17/26) with medications. Nine participants used oral triptans, of whom 33.3% (3/9) achieved pain freedom with REN, vs 0% (0/9) with medications. Pain relief with REN was achieved by 55.5% (5/9), vs 33.3% (3/9) with medications.

The results of the post hoc analysis provides a preliminary indication that REN may be as effective as, if not more effective than, certain standard-Care medications in adolescents with migraine. Specifically, REN was found to be superior to the tested medications (oral triptans and OTC analgesic medications) in pain freedom after a single treatment, pain freedom consistency across treatments, and pain relief.

The Retrospective Survey Study (TCH-009) evaluated the self-reported effectiveness and tolerability of the Nerivio device for the acute treatment of menstrual migraine, via a retrospective structured survey that was sent to adult female Nerivio users.

Women aged 18–55 years who experience menstrually related or pure menstrual migraine and have completed at least four Remote Electrical Neuromodulation (REN) treatments with the Nerivio device, participated in this retrospective, observational survey study. Participants completed a short online survey assessing effectiveness, satisfaction, and safety outcomes. The survey was sent to 455 female patients aged 18–55 across the United States who used Nerivio between October 1, 2019, and October 18, 2020, and completed at least four REN treatment sessions.

Before taking the survey, patients provided informed consent. The consent form appeared as the first page of the survey, and participants clicked either ‘‘agree’’ or ‘‘disagree’’ to the consent statement (those who clicked ‘‘agree’’ proceeded to the survey, and those who clicked ‘‘disagree’’ were brought to an exit page).

Figure 1 – Survey disposition chart

Results

Effectiveness

Participants were predominantly white (92.3% [84/91]), had a mean age of 35.2 ± 8.1, had an average number of 13.3 ± 8.7 headache days per month, and treated 4.9 ± 4.8 menstrual migraines with Nerivio.

74.7% (68/91) of the participants reported that the treatment was at least moderately effective (moderately effective 37.4%, very effective 26.4%, extremely effective 11.0%). The treatment was reported not effective in 25.3% (23/91) of the participant (slightly effective: 20.9%, not effective 4.4%).

45.1% (41/91) of the participants reported satisfaction from REN (slightly satisfied 33%, extremely satisfied 12.1%), while 34.1% (31/91) were neutral, and 20.9% (19/91) were not satisfied (slightly dissatisfied 16.5%, not at all satisfied 4.4%).

82.4% (75/91) of the participants indicated that they experience menstrual cramps. Out of these 75, 38.7% (29/75) reported that REN was at least moderately effective (moderately effective 28.0%, very effective 8%, extremely effective 2.7%) in treating the cramps. The treatment was reported not effective for cramps in 61.3% (46/75) of the participant (slightly effective: 29.3%, not effective 32.2%).

38 patients (41.8%) indicated that they experience pelvic pain during menstruation. Out of these 38, 36.8% (14/38) reported that REN was at least moderately effective for the pelvic pain (moderately effective 28.9%, very effective 2.6%, extremely effective 5.3%). The treatment was reported not effective for pelvic pain by 63.2% (24/38) of the participant (slightly effective: 28.9%, not effective 34.2%).

Safety

Twelve patients (13.2%) reported mild short term side effects: sore arm for several days after treatment (n = 1), bruise on the arm (n = 1), nausea (n = 2), dizziness (n = 1), drowsiness (n = 1), muscle twitching (n = 3), numbness in the arm during treatment (n = 2), and tingling in the arm and hand (n = 1).

100% (91/91) of the participants reported that the treatment was at least moderately tolerable (moderately tolerable 8.8%, very tolerable 20.9%, extremely tolerable 70.3%).

The current survey study suggests that REN may offer an effective, well-tolerated treatment option for menstrual migraine, indicates that REN may provide a safe, non-pharmacological treatment option for women with menstrual migraine