Trial Outcomes & Findings for A Pilot Clinical Trial of a New Neuromodulation Device for Acute Attacks of Migraine in Children and Adolescents (NCT NCT05102591)

Last Updated: 2025-03-12

Results Overview

The primary outcome for this pilot study involves assessment of the feasibility of using the REN device to treat children and adolescents suffering from acute migraine attacks in the ED. The primary feasibility outcome will be determined based on the recruitment rate, defined as the number of participants enrolled per month. Our target is to have an average recruitment rate of 1.5 participants per month. Feasibility will be used as the primary outcome, along with the secondary outcomes, to provide preliminary data to help design and optimize a fully powered, phase III RCT. Recruitment rate for both phases of the study are reported to understand if changing to crossover design improved recruitment. We switched to a crossover design strictly to address participant and recruitment concerns around not receiving standard of care migraine treatment if initially randomized to receive REN treatment and such treatment was unsuccessful.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

22 participants

Primary outcome timeframe

Evaluated monthly and at the end of recruitment (i.e., 2 years or once the final participant has completed the study)

Results posted on

2025-03-12

Participant Flow

We employed a double-dummy, double-blind, pilot randomized controlled trial initially as a parallel-group design (February 22, 2022 to May 15, 2023), but switched to a crossover design (May 16, 2023 to March 1, 2024) to address participant concerns about not getting typical IV treatment if REN unsuccessful. Receiving the crossover treatment was not required as per protocol. The trial was carried out in a tertiary care pediatric ED at the Alberta Children's Hospital in Calgary, Alberta, Canada.

During the parallel-group phase, 3 participants provided written informed consent but withdrew prior to being randomized. As such, 22 participants were enrolled in the entire study but 19 of those were randomized to a study treatment. During the crossover phase, participants were not required to receive the crossover treatment if well enough to go home after the initial treatment. Only 2 participants received the crossover treatment (both REN initially and Standard of Care as crossover).

Participant milestones

Participant milestones
Measure	Standard-of-Care IV Group (Parallel Design Phase) Patients recruited during the parallel phase and randomised to the standard of care IV group will receive a single, 45-minute stimulation from a sham remote electrical neuromodulation (REN) device, which will not administer the typical electrical stimulation (modulated frequency of \~ 0.083 Hz and a modulated pulse width of 40-550 µs), and will be given a single dose IV ketorolac and IV metoclopramide, at a dose of 0.5 mg/kg and 0.15 mg/kg, respectively. Metoclopramide will be infused over 15-30 minutes and ketorolac will be administered as a direct IV push over 1-5 minutes. Ketorolac: Intervention in syringe for target dose of 0.5 mg/kg, maximum 30 mg of ketorolac (1 mL), and administer as a direct IV push over 1-5 minutes Metoclopramide: Intervention in 50 mL mini bag of normal saline (0.9% NaCl) for target dose of 0.15 mg/kg, maximum 10 mg of metoclopramide (2 mL), and administer as infusion over 15-30 minutes Sham Remote Electrical Neuromodulation Device: The sham REN device is identical to the active REN device but the stimulation parameters are different, administering a modulated symmetrical biphasic square electrical pulse, modulated frequency of \~0.083 Hz and a modulated pulse width of 40-550 µ. These sham parameters are designed to induce a sensation that will be perceptible to participants, similar to stimulation from the active REN device, but at a frequency that is low enough so as to not modulate the nociceptive sensory nerves.	REN Group (Parallel Design Phase) Patients recruited during the parallel phase and randomised to the REN group will receive a single 45-minutes stimulation from the REN device (modulated frequency of 100-120 Hz and a pulse width of 400 µs) and will also receive two doses of normal saline though an IV. Two doses of saline will be used to match the dosage, route of administration, and duration to ketorolac and metoclopramide, as described above in the standard-of-care IV group. Active Remote Electrical Neuromodulation Device: The REN device is a battery-powered, wirelessly controlled neuromodulation device that attaches via armband to the upper arm. The REN device is controlled by a smartphone application and administers electrical stimulation to the local C and Aδ nociceptive sensory nerves of the upper arm. This stimulation is achieved using a symmetrical, biphasic, square pulse, modulated at a frequency between 100-120 Hz. Each pulse has a width of 400 µs and the user, via the smartphone application, can adjust the output current to apply a maximum of 40 mA. Each stimulation session occurs over 45 minutes and each device can administer up to 12 stimulation sessions. Placebo: 0.9% NaCl will be administered to participants through IV in identical dosages, methods, and duration as the ketorolac and metoclopramide interventions described above.	Standard-of-Care IV Group First, Then REN Group if Applicable (Crossover Design Phase) Patients recruited during the crossover phase and initially randomised to the standard of care IV group during the crossover phase will receive a single, 45-minute stimulation from a sham remote electrical neuromodulation (REN) device, which will not administer the typical electrical stimulation (modulated frequency of \~ 0.083 Hz and a modulated pulse width of 40-550 µs), and will be given a single dose IV ketorolac and IV metoclopramide, at a dose of 0.5 mg/kg (for a maximum 30 mg) and 0.15 mg/kg (for a maximum 10mg), respectively. Metoclopramide will be infused over 15-30 minutes and ketorolac will be administered as a direct IV push over 1-5 minutes. At 120-minutes following the initial study intervention, participants will be assessed to see if they feel ready to go home or if they would like to receive the study treatment they did not initially receive(i.e., treatment from the REN Group). This would be a single 45-minutes stimulation from the REN device (modulated frequency of 100-120 Hz and a pulse width of 400 µs) and will also receive two doses of normal saline though an IV. Two doses of saline will be used to match the dosage, route of administration, and duration to ketorolac and metoclopramide, as described above in the standard-of-care IV group. The crossover treatment is not required if the participant is considered well enough to go home (as per protocol).	REN Group First, Then Standard-of-Care IV Group First if Applicable (Crossover Design Phase) Patients recruited during the crossover phase and initially randomised to the REN group during the crossover phase will receive a single 45-minutes stimulation from the REN device (modulated frequency of 100-120 Hz and a pulse width of 400 µs) and will also receive two doses of normal saline though an IV. Two doses of saline will be used to match the dosage, route of administration, and duration to ketorolac and metoclopramide, as described above in the standard-of-care IV group. At 120-minutes following the initial study intervention, participants will be assessed to see if they feel ready to go home or if they would like to receive the study treatment they did not initially receive(i.e., treatment from the Standard-of-Care Group). This would be a single, 45-minute stimulation from a sham remote electrical neuromodulation (REN) device, which will not administer the typical electrical stimulation (modulated frequency of \~ 0.083 Hz and a modulated pulse width of 40-550 µs), and will be given a single dose IV ketorolac and IV metoclopramide, at a dose of 0.5 mg/kg (for a maximum 30 mg) and 0.15 mg/kg (for a maximum 10mg), respectively. Metoclopramide will be infused over 15-30 minutes and ketorolac will be administered as a direct IV push over 1-5 minutes. The crossover treatment is not required if the participant is considered well enough to go home (as per protocol).
Overall Study STARTED	7	7	3	2
Overall Study COMPLETED	7	7	3	2
Overall Study NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

A Pilot Clinical Trial of a New Neuromodulation Device for Acute Attacks of Migraine in Children and Adolescents

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Standard-of-Care IV Group (Parallel Design Phase) n=7 Participants Patients recruited during the parallel phase and randomised to the standard of care IV group will receive a single, 45-minute stimulation from a sham remote electrical neuromodulation (REN) device, which will not administer the typical electrical stimulation (modulated frequency of \~ 0.083 Hz and a modulated pulse width of 40-550 µs), and will be given a single dose IV ketorolac and IV metoclopramide, at a dose of 0.5 mg/kg and 0.15 mg/kg, respectively. Metoclopramide will be infused over 15-30 minutes and ketorolac will be administered as a direct IV push over 1-5 minutes. Ketorolac: Intervention in syringe for target dose of 0.5 mg/kg, maximum 30 mg of ketorolac (1 mL), and administer as a direct IV push over 1-5 minutes Metoclopramide: Intervention in 50 mL mini bag of normal saline (0.9% NaCl) for target dose of 0.15 mg/kg, maximum 10 mg of metoclopramide (2 mL), and administer as infusion over 15-30 minutes Sham Remote Electrical Neuromodulation Device: The sham REN device is identical to the active REN device but the stimulation parameters are different, administering a modulated symmetrical biphasic square electrical pulse, modulated frequency of \~0.083 Hz and a modulated pulse width of 40-550 µ. These sham parameters are designed to induce a sensation that will be perceptible to participants, similar to stimulation from the active REN device, but at a frequency that is low enough so as to not modulate the nociceptive sensory nerves.	REN Group (Parallel Design Phase) n=7 Participants Patients recruited during the parallel phase and randomised to the REN group will receive a single 45-minutes stimulation from the REN device (modulated frequency of 100-120 Hz and a pulse width of 400 µs) and will also receive two doses of normal saline though an IV. Two doses of saline will be used to match the dosage, route of administration, and duration to ketorolac and metoclopramide, as described above in the standard-of-care IV group. Active Remote Electrical Neuromodulation Device: The REN device is a battery-powered, wirelessly controlled neuromodulation device that attaches via armband to the upper arm. The REN device is controlled by a smartphone application and administers electrical stimulation to the local C and Aδ nociceptive sensory nerves of the upper arm. This stimulation is achieved using a symmetrical, biphasic, square pulse, modulated at a frequency between 100-120 Hz. Each pulse has a width of 400 µs and the user, via the smartphone application, can adjust the output current to apply a maximum of 40 mA. Each stimulation session occurs over 45 minutes and each device can administer up to 12 stimulation sessions. Placebo: 0.9% NaCl will be administered to participants through IV in identical dosages, methods, and duration as the ketorolac and metoclopramide interventions described above.	Standard-of-Care IV Group First, Then REN Group if Applicable (Crossover Design Phase) n=3 Participants Patients recruited during the crossover phase and initially randomised to the standard of care IV group during the crossover phase will receive a single, 45-minute stimulation from a sham remote electrical neuromodulation (REN) device, which will not administer the typical electrical stimulation (modulated frequency of \~ 0.083 Hz and a modulated pulse width of 40-550 µs), and will be given a single dose IV ketorolac and IV metoclopramide, at a dose of 0.5 mg/kg (for a maximum 30 mg) and 0.15 mg/kg (for a maximum 10mg), respectively. Metoclopramide will be infused over 15-30 minutes and ketorolac will be administered as a direct IV push over 1-5 minutes. At 120-minutes following the initial study intervention, participants will be assessed to see if they feel ready to go home or if they would like to receive the study treatment they did not initially receive(i.e., treatment from the REN Group). This would be a single 45-minutes stimulation from the REN device (modulated frequency of 100-120 Hz and a pulse width of 400 µs) and will also receive two doses of normal saline though an IV. Two doses of saline will be used to match the dosage, route of administration, and duration to ketorolac and metoclopramide, as described above in the standard-of-care IV group. The crossover treatment is not required if the participant is considered well enough to go home (as per protocol).	REN Group First, Then Standard-of-Care IV Group First if Applicable (Crossover Design Phase) n=2 Participants Patients recruited during the crossover phase and initially randomised to the REN group during the crossover phase will receive a single 45-minutes stimulation from the REN device (modulated frequency of 100-120 Hz and a pulse width of 400 µs) and will also receive two doses of normal saline though an IV. Two doses of saline will be used to match the dosage, route of administration, and duration to ketorolac and metoclopramide, as described above in the standard-of-care IV group. At 120-minutes following the initial study intervention, participants will be assessed to see if they feel ready to go home or if they would like to receive the study treatment they did not initially receive(i.e., treatment from the Standard-of-Care Group). This would be a single, 45-minute stimulation from a sham remote electrical neuromodulation (REN) device, which will not administer the typical electrical stimulation (modulated frequency of \~ 0.083 Hz and a modulated pulse width of 40-550 µs), and will be given a single dose IV ketorolac and IV metoclopramide, at a dose of 0.5 mg/kg (for a maximum 30 mg) and 0.15 mg/kg (for a maximum 10mg), respectively. Metoclopramide will be infused over 15-30 minutes and ketorolac will be administered as a direct IV push over 1-5 minutes. The crossover treatment is not required if the participant is considered well enough to go home (as per protocol).	Total n=19 Participants Total of all reporting groups
Age, Categorical <=18 years	7 Participants n=5 Participants	7 Participants n=7 Participants	3 Participants n=5 Participants	2 Participants n=4 Participants	19 Participants n=21 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Age, Continuous	13.7 years STANDARD_DEVIATION 2.1 • n=5 Participants	15 years STANDARD_DEVIATION 1.2 • n=7 Participants	15.3 years STANDARD_DEVIATION 2.1 • n=5 Participants	13 years STANDARD_DEVIATION 0 • n=4 Participants	14.4 years STANDARD_DEVIATION 1.8 • n=21 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	5 Participants n=7 Participants	2 Participants n=5 Participants	1 Participants n=4 Participants	10 Participants n=21 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	9 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) White	7 Participants n=5 Participants	6 Participants n=7 Participants	2 Participants n=5 Participants	2 Participants n=4 Participants	17 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Region of Enrollment Canada	7 participants n=5 Participants	7 participants n=7 Participants	3 participants n=5 Participants	2 participants n=4 Participants	19 participants n=21 Participants
Current attack baseline pain severity	7 units on a scale n=5 Participants	5 units on a scale n=7 Participants	7 units on a scale n=5 Participants	8 units on a scale n=4 Participants	7 units on a scale n=21 Participants
Current attack duration in hours	96 Hours n=5 Participants	168 Hours n=7 Participants	72 Hours n=5 Participants	168 Hours n=4 Participants	96 Hours n=21 Participants
Current attack with aura	4 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	6 Participants n=21 Participants
History of prior attacks with aura	5 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	9 Participants n=21 Participants
Headache frequency in days/month	6 Days per Month n=5 Participants	7 Days per Month n=7 Participants	4 Days per Month n=5 Participants	5 Days per Month n=4 Participants	6 Days per Month n=21 Participants
Number of participants with continuous headache at baseline	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Number of past headache-related ED visits None	3 Counts n=5 Participants	1 Counts n=7 Participants	1 Counts n=5 Participants	0 Counts n=4 Participants	5 Counts n=21 Participants
Number of past headache-related ED visits 1	0 Counts n=5 Participants	0 Counts n=7 Participants	0 Counts n=5 Participants	1 Counts n=4 Participants	1 Counts n=21 Participants
Number of past headache-related ED visits 2	1 Counts n=5 Participants	0 Counts n=7 Participants	0 Counts n=5 Participants	0 Counts n=4 Participants	1 Counts n=21 Participants
Number of past headache-related ED visits 3	0 Counts n=5 Participants	3 Counts n=7 Participants	1 Counts n=5 Participants	1 Counts n=4 Participants	5 Counts n=21 Participants
Number of past headache-related ED visits 4	0 Counts n=5 Participants	1 Counts n=7 Participants	1 Counts n=5 Participants	0 Counts n=4 Participants	2 Counts n=21 Participants
Number of past headache-related ED visits 5	2 Counts n=5 Participants	0 Counts n=7 Participants	0 Counts n=5 Participants	0 Counts n=4 Participants	2 Counts n=21 Participants
Number of past headache-related ED visits >=6	1 Counts n=5 Participants	2 Counts n=7 Participants	0 Counts n=5 Participants	0 Counts n=4 Participants	3 Counts n=21 Participants
Took acute intervention at home prior to ED visit	7 Participants n=5 Participants	7 Participants n=7 Participants	3 Participants n=5 Participants	2 Participants n=4 Participants	19 Participants n=21 Participants
On a migraine preventive intervention at home	4 Participants n=5 Participants	4 Participants n=7 Participants	2 Participants n=5 Participants	0 Participants n=4 Participants	10 Participants n=21 Participants
PedMIDAS Score	80 units on a scale n=5 Participants	39 units on a scale n=7 Participants	61 units on a scale n=5 Participants	49.5 units on a scale n=4 Participants	49 units on a scale n=21 Participants
Duration of time with headaches in months	48 Months n=5 Participants	3 Months n=7 Participants	72 Months n=5 Participants	2.5 Months n=4 Participants	24 Months n=21 Participants

PRIMARY outcome

Timeframe: Evaluated monthly and at the end of recruitment (i.e., 2 years or once the final participant has completed the study)

Population: Number of participants who were screened, deemed eligible, and subsequently enrolled. Three (3) participants during the parallel-group design phase withdrew after consent but before being randomized/receiving study treatments. No other participants withdrew during the study.

Outcome measures

Outcome measures
Measure	Parallel-group Design n=17 Participants A parallel-group design was used between February 22, 2022 to May 15, 2023 where participants were randomized to receive either the SoC or REN arm.	Crossover Design n=5 Participants We switched to a crossover design between May 16, 2023 and March 1, 2024 whereby participants who did not feel well enough to go home 2 hours after study intervention administration was initiated could cross over and receive the interventions of the other group.	Standard-of-Care IV (Crossover Treatment; Crossover Phase) Patients who initially received stimulation from the REN device and two doses of saline, and then crossed over to receive the standard of care IV and a single, 45-minute stimulation from a sham remote electrical neuromodulation (REN) device, which will not administer the typical electrical stimulation (modulated frequency of \~ 0.083 Hz and a modulated pulse width of 40-550 µs), and will be given a single dose IV ketorolac and IV metoclopramide, at a dose of 0.5 mg/kg (for a maximum 30 mg) and 0.15 mg/kg (for a maximum 10mg), respectively. Metoclopramide will be infused over 15-30 minutes and ketorolac will be administered as a direct IV push over 1-5 minutes. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, would be given the crossover treatment. As such, the crossover treatment was not required.	REN (Crossover Treatment; Crossover Phase) Patients randomised to initially receive the Standard of Care IV and stimulation from the sham REN device, and then crossed over to receive a single 45-minutes stimulation from the REN device (modulated frequency of 100-120 Hz and a pulse width of 400 µs) and two doses of normal saline through an IV. Two doses of saline will be used to match the dosage, route of administration, and duration to ketorolac and metoclopramide, as described above in the standard-of-care IV group. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, would be given the crossover treatment. As such, the crossover treatment was not required.	All Participants Participants from both SoC and REN treatment groups.
Assessment of Recruitment Rate	1.1 participants per month Standard Deviation 1.5	0.6 participants per month Standard Deviation 1.0	—	—	—

SECONDARY outcome

Timeframe: Difference between baseline and 1 hour, 2 hours, and 48 hours post-intervention.

Population: Treatment data are combined across phases, separated based on treatment given and time given to be consistent with how we specified results would be reported in the protocol (i.e., "...for both the initial assigned intervention and the crossover intervention where applicable"). Participants who received SoC IV at crossover received REN initially, and vice versa. No participants received REN crossover treatment as they were well enough to go home after the initial IV treatment (as per protocol).

Reduction in pain severity between baseline and 1-hour, 2 hours, and 48 hours post-interventions. Pain measured on an 11-point Likert scale where 0 = no pain and 10 = worst pain possible, with lower values indicating no/less pain and higher values indicating more pain. Headache pain was only assessed at 48 hours if participants indicated they were currently experiencing a headache and the 48 hours reduction in pain severity outcome does not include participants who crossed over and were exposed to both interventions as we expected them to become unblinded after being exposed to both study treatments; Standard of Care (Initial Treatment) n = 7, REN (Initial Treatment) n = 5.

Outcome measures

Outcome measures
Measure	Parallel-group Design n=10 Participants A parallel-group design was used between February 22, 2022 to May 15, 2023 where participants were randomized to receive either the SoC or REN arm.	Crossover Design n=9 Participants We switched to a crossover design between May 16, 2023 and March 1, 2024 whereby participants who did not feel well enough to go home 2 hours after study intervention administration was initiated could cross over and receive the interventions of the other group.	Standard-of-Care IV (Crossover Treatment; Crossover Phase) n=2 Participants Patients who initially received stimulation from the REN device and two doses of saline, and then crossed over to receive the standard of care IV and a single, 45-minute stimulation from a sham remote electrical neuromodulation (REN) device, which will not administer the typical electrical stimulation (modulated frequency of \~ 0.083 Hz and a modulated pulse width of 40-550 µs), and will be given a single dose IV ketorolac and IV metoclopramide, at a dose of 0.5 mg/kg (for a maximum 30 mg) and 0.15 mg/kg (for a maximum 10mg), respectively. Metoclopramide will be infused over 15-30 minutes and ketorolac will be administered as a direct IV push over 1-5 minutes. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, would be given the crossover treatment. As such, the crossover treatment was not required.	REN (Crossover Treatment; Crossover Phase) Patients randomised to initially receive the Standard of Care IV and stimulation from the sham REN device, and then crossed over to receive a single 45-minutes stimulation from the REN device (modulated frequency of 100-120 Hz and a pulse width of 400 µs) and two doses of normal saline through an IV. Two doses of saline will be used to match the dosage, route of administration, and duration to ketorolac and metoclopramide, as described above in the standard-of-care IV group. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, would be given the crossover treatment. As such, the crossover treatment was not required.	All Participants Participants from both SoC and REN treatment groups.
Reduction in Pain Severity 1 hour post-intervention	2.9 units on a scale Standard Deviation 2.9	2.1 units on a scale Standard Deviation 1.3	3 units on a scale Standard Deviation 0	—	—
Reduction in Pain Severity 2 hours post-intervention	4 units on a scale Standard Deviation 3.5	2.4 units on a scale Standard Deviation 1.6	3.5 units on a scale Standard Deviation 0.7	—	—
Reduction in Pain Severity 48 hours post-intervention	3.3 units on a scale Standard Deviation 2.7	2.6 units on a scale Standard Deviation 1.5	—	—	—

SECONDARY outcome

Timeframe: Evaluated monthly and at the end of recruitment (i.e., 2 years or once the final participant has completed the study)

This secondary feasibility outcome involves the following: The number of participants who complete all assessments at each time point (baseline, 60, 120 minutes or at discharge if before 120 minutes, and 48-hours; for both the initial assigned intervention and the crossover intervention where applicable).

Outcome measures

Outcome measures
Measure	Parallel-group Design n=10 Participants A parallel-group design was used between February 22, 2022 to May 15, 2023 where participants were randomized to receive either the SoC or REN arm.	Crossover Design n=9 Participants We switched to a crossover design between May 16, 2023 and March 1, 2024 whereby participants who did not feel well enough to go home 2 hours after study intervention administration was initiated could cross over and receive the interventions of the other group.	Standard-of-Care IV (Crossover Treatment; Crossover Phase) n=2 Participants Patients who initially received stimulation from the REN device and two doses of saline, and then crossed over to receive the standard of care IV and a single, 45-minute stimulation from a sham remote electrical neuromodulation (REN) device, which will not administer the typical electrical stimulation (modulated frequency of \~ 0.083 Hz and a modulated pulse width of 40-550 µs), and will be given a single dose IV ketorolac and IV metoclopramide, at a dose of 0.5 mg/kg (for a maximum 30 mg) and 0.15 mg/kg (for a maximum 10mg), respectively. Metoclopramide will be infused over 15-30 minutes and ketorolac will be administered as a direct IV push over 1-5 minutes. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, would be given the crossover treatment. As such, the crossover treatment was not required.	REN (Crossover Treatment; Crossover Phase) Patients randomised to initially receive the Standard of Care IV and stimulation from the sham REN device, and then crossed over to receive a single 45-minutes stimulation from the REN device (modulated frequency of 100-120 Hz and a pulse width of 400 µs) and two doses of normal saline through an IV. Two doses of saline will be used to match the dosage, route of administration, and duration to ketorolac and metoclopramide, as described above in the standard-of-care IV group. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, would be given the crossover treatment. As such, the crossover treatment was not required.	All Participants Participants from both SoC and REN treatment groups.
Number of Eligible Participants Who Are Screened, Enrolled, and Complete All Assessments	10 Participants	9 Participants	2 Participants	—	—

SECONDARY outcome

Timeframe: Evaluated for each participant at 2-hours post-intervention, and 48-hours post-intervention

This acceptability outcome involves the following: * The proportion of participants who report a global impression of change as "very much improved" or "much improved". * Measured on a 7-point Likert scale (Patient Global Impression scale in clinical status; PGI-C) where 1 = "Very much improved", 4 = "No change", and 7 = "Very much worse" * Smaller values indicate improvement of overall change while larger values indicate worsening of overall change.

Outcome measures

Outcome measures
Measure	Parallel-group Design n=10 Participants A parallel-group design was used between February 22, 2022 to May 15, 2023 where participants were randomized to receive either the SoC or REN arm.	Crossover Design n=9 Participants We switched to a crossover design between May 16, 2023 and March 1, 2024 whereby participants who did not feel well enough to go home 2 hours after study intervention administration was initiated could cross over and receive the interventions of the other group.	Standard-of-Care IV (Crossover Treatment; Crossover Phase) n=2 Participants Patients who initially received stimulation from the REN device and two doses of saline, and then crossed over to receive the standard of care IV and a single, 45-minute stimulation from a sham remote electrical neuromodulation (REN) device, which will not administer the typical electrical stimulation (modulated frequency of \~ 0.083 Hz and a modulated pulse width of 40-550 µs), and will be given a single dose IV ketorolac and IV metoclopramide, at a dose of 0.5 mg/kg (for a maximum 30 mg) and 0.15 mg/kg (for a maximum 10mg), respectively. Metoclopramide will be infused over 15-30 minutes and ketorolac will be administered as a direct IV push over 1-5 minutes. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, would be given the crossover treatment. As such, the crossover treatment was not required.	REN (Crossover Treatment; Crossover Phase) Patients randomised to initially receive the Standard of Care IV and stimulation from the sham REN device, and then crossed over to receive a single 45-minutes stimulation from the REN device (modulated frequency of 100-120 Hz and a pulse width of 400 µs) and two doses of normal saline through an IV. Two doses of saline will be used to match the dosage, route of administration, and duration to ketorolac and metoclopramide, as described above in the standard-of-care IV group. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, would be given the crossover treatment. As such, the crossover treatment was not required.	All Participants Participants from both SoC and REN treatment groups.
Global Impression of Change 2 Hours	5 participants	3 participants	1 participants	—	—
Global Impression of Change 48 Hours	5 participants	3 participants	1 participants	—	—

SECONDARY outcome

Timeframe: Participant feedback evaluated at 48 hours post-intervention

This acceptability outcome involves the following: \- Participant feedback regarding study acceptability. Participant feedback measured on 5-point Likert scale (1 = strongly disagree, 5 = strongly agree), where higher values indicate agreement and lower values indicate disagreement. Feedback questions related to study treatments is reported for both treatment groups and combined across treatment groups. Feedback questions related to the research staff and overall study experience is only combined and reported across both groups, rather than being reported for each group separately since these questions don't relate to specific study treatments. Feedback from clinical staff was collected after each participant's enrollment but not analyzed as this feedback was free-form and not collected using a scale.

Outcome measures

Outcome measures
Measure	Parallel-group Design n=10 Participants A parallel-group design was used between February 22, 2022 to May 15, 2023 where participants were randomized to receive either the SoC or REN arm.	Crossover Design n=9 Participants We switched to a crossover design between May 16, 2023 and March 1, 2024 whereby participants who did not feel well enough to go home 2 hours after study intervention administration was initiated could cross over and receive the interventions of the other group.	Standard-of-Care IV (Crossover Treatment; Crossover Phase) n=2 Participants Patients who initially received stimulation from the REN device and two doses of saline, and then crossed over to receive the standard of care IV and a single, 45-minute stimulation from a sham remote electrical neuromodulation (REN) device, which will not administer the typical electrical stimulation (modulated frequency of \~ 0.083 Hz and a modulated pulse width of 40-550 µs), and will be given a single dose IV ketorolac and IV metoclopramide, at a dose of 0.5 mg/kg (for a maximum 30 mg) and 0.15 mg/kg (for a maximum 10mg), respectively. Metoclopramide will be infused over 15-30 minutes and ketorolac will be administered as a direct IV push over 1-5 minutes. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, would be given the crossover treatment. As such, the crossover treatment was not required.	REN (Crossover Treatment; Crossover Phase) Patients randomised to initially receive the Standard of Care IV and stimulation from the sham REN device, and then crossed over to receive a single 45-minutes stimulation from the REN device (modulated frequency of 100-120 Hz and a pulse width of 400 µs) and two doses of normal saline through an IV. Two doses of saline will be used to match the dosage, route of administration, and duration to ketorolac and metoclopramide, as described above in the standard-of-care IV group. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, would be given the crossover treatment. As such, the crossover treatment was not required.	All Participants n=19 Participants Participants from both SoC and REN treatment groups.
Study Feedback From Participants and Staff I would prefer to only use IV to treat future migraine attacks in the ED.	2.8 units on a scale Standard Deviation 1	2.8 units on a scale Standard Deviation 1	3 units on a scale Standard Deviation 0	—	2.8 units on a scale Standard Deviation 1
Study Feedback From Participants and Staff I would use the device to treat future migraine attacks at home instead of my usual treatment.	4.2 units on a scale Standard Deviation 0.8	3.3 units on a scale Standard Deviation 1.1	3 units on a scale Standard Deviation 1.4	—	3.8 units on a scale Standard Deviation 1
Study Feedback From Participants and Staff I would only use my usual treatment instead of the device to treat future migraine attacks at home.	2.5 units on a scale Standard Deviation 0.5	2.8 units on a scale Standard Deviation 1.1	3 units on a scale Standard Deviation 1.4	—	2.6 units on a scale Standard Deviation 0.8
Study Feedback From Participants and Staff If I could, I would bring the device home with me to treat future migraine attacks at home.	4.4 units on a scale Standard Deviation 0.5	3.7 units on a scale Standard Deviation 1	4 units on a scale Standard Deviation 0	—	4.1 units on a scale Standard Deviation 0.8
Study Feedback From Participants and Staff I understood the study procedures before providing my informed consent to participate.	—	—	—	—	4.7 units on a scale Standard Deviation 0.5
Study Feedback From Participants and Staff The research staff took the necessary amount of time to answer all my questions.	—	—	—	—	4.9 units on a scale Standard Deviation 0.3
Study Feedback From Participants and Staff I understood that participation was voluntary.	—	—	—	—	4.9 units on a scale Standard Deviation 0.3
Study Feedback From Participants and Staff I understood that I could withdraw from the study anytime.	—	—	—	—	4.7 units on a scale Standard Deviation 0.6
Study Feedback From Participants and Staff I understood the risk(s) involved with participating in the study.	—	—	—	—	4.4 units on a scale Standard Deviation 0.6
Study Feedback From Participants and Staff I understood the possible benefit(s) involved with participating in the study.	—	—	—	—	4.7 units on a scale Standard Deviation 0.5
Study Feedback From Participants and Staff I felt the research staff were approachable when I had questions or concerns.	—	—	—	—	4.8 units on a scale Standard Deviation 0.4
Study Feedback From Participants and Staff I felt the research staff were easy to contact.	—	—	—	—	4.6 units on a scale Standard Deviation 0.6
Study Feedback From Participants and Staff I felt the research staff were professional.	—	—	—	—	4.7 units on a scale Standard Deviation 0.5
Study Feedback From Participants and Staff I felt the research staff were knowledgeable.	—	—	—	—	4.6 units on a scale Standard Deviation 0.5
Study Feedback From Participants and Staff I felt the research staff were courteous.	—	—	—	—	4.7 units on a scale Standard Deviation 0.5
Study Feedback From Participants and Staff I felt the research staff were sensitive to my needs.	—	—	—	—	4.7 units on a scale Standard Deviation 0.5
Study Feedback From Participants and Staff The study went smoothly.	—	—	—	—	4.6 units on a scale Standard Deviation 0.6
Study Feedback From Participants and Staff My overall experience was positive.	—	—	—	—	4.6 units on a scale Standard Deviation 0.6
Study Feedback From Participants and Staff I would recommend to others that they consider participation in this study.	—	—	—	—	4.7 units on a scale Standard Deviation 0.6
Study Feedback From Participants and Staff If I was aware of another study at the hospital, I would participate if I was eligible and had time.	—	—	—	—	4.2 units on a scale Standard Deviation 1.1
Study Feedback From Participants and Staff I would use the device to treat future migraine attacks at home with my usual treatment.	4 units on a scale Standard Deviation 1.1	3.7 units on a scale Standard Deviation 0.9	3.5 units on a scale Standard Deviation 0.7	—	3.8 units on a scale Standard Deviation 1
Study Feedback From Participants and Staff I would be interested in using device with IV to treat future migraine attacks in the ED.	3.3 units on a scale Standard Deviation 1.1	3.3 units on a scale Standard Deviation 1	3.5 units on a scale Standard Deviation 0.7	—	3.3 units on a scale Standard Deviation 1
Study Feedback From Participants and Staff I would be interested in using device instead of IV to treat future migraine attacks in the ED.	3.9 units on a scale Standard Deviation 1	3.6 units on a scale Standard Deviation 1	3.5 units on a scale Standard Deviation 0.7	—	3.7 units on a scale Standard Deviation 1

SECONDARY outcome

Timeframe: 2 hours post-intervention

Number of participants who indicated they were pain free 2-hours post-intervention. Pain measured on an 11-point Likert scale where 0 = no pain and 10 = worst pain possible, with lower values indicating no/less pain and higher values indicating more pain.

Outcome measures

Outcome measures
Measure	Parallel-group Design n=10 Participants A parallel-group design was used between February 22, 2022 to May 15, 2023 where participants were randomized to receive either the SoC or REN arm.	Crossover Design n=9 Participants We switched to a crossover design between May 16, 2023 and March 1, 2024 whereby participants who did not feel well enough to go home 2 hours after study intervention administration was initiated could cross over and receive the interventions of the other group.	Standard-of-Care IV (Crossover Treatment; Crossover Phase) n=2 Participants Patients who initially received stimulation from the REN device and two doses of saline, and then crossed over to receive the standard of care IV and a single, 45-minute stimulation from a sham remote electrical neuromodulation (REN) device, which will not administer the typical electrical stimulation (modulated frequency of \~ 0.083 Hz and a modulated pulse width of 40-550 µs), and will be given a single dose IV ketorolac and IV metoclopramide, at a dose of 0.5 mg/kg (for a maximum 30 mg) and 0.15 mg/kg (for a maximum 10mg), respectively. Metoclopramide will be infused over 15-30 minutes and ketorolac will be administered as a direct IV push over 1-5 minutes. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, would be given the crossover treatment. As such, the crossover treatment was not required.	REN (Crossover Treatment; Crossover Phase) Patients randomised to initially receive the Standard of Care IV and stimulation from the sham REN device, and then crossed over to receive a single 45-minutes stimulation from the REN device (modulated frequency of 100-120 Hz and a pulse width of 400 µs) and two doses of normal saline through an IV. Two doses of saline will be used to match the dosage, route of administration, and duration to ketorolac and metoclopramide, as described above in the standard-of-care IV group. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, would be given the crossover treatment. As such, the crossover treatment was not required.	All Participants Participants from both SoC and REN treatment groups.
Number of Participants Reporting Pain Freedom	4 Participants	1 Participants	0 Participants	—	—

SECONDARY outcome

Timeframe: 48 hours post-intervention

Number of participants who indicated they were pain free 2-hours post-intervention and again 48-hours post-intervention. Pain measured on an 11-point Likert scale where 0 = no pain and 10 = worst pain possible, with lower values indicating no/less pain and higher values indicating more pain.

Outcome measures

Outcome measures
Measure	Parallel-group Design n=10 Participants A parallel-group design was used between February 22, 2022 to May 15, 2023 where participants were randomized to receive either the SoC or REN arm.	Crossover Design n=9 Participants We switched to a crossover design between May 16, 2023 and March 1, 2024 whereby participants who did not feel well enough to go home 2 hours after study intervention administration was initiated could cross over and receive the interventions of the other group.	Standard-of-Care IV (Crossover Treatment; Crossover Phase) n=2 Participants Patients who initially received stimulation from the REN device and two doses of saline, and then crossed over to receive the standard of care IV and a single, 45-minute stimulation from a sham remote electrical neuromodulation (REN) device, which will not administer the typical electrical stimulation (modulated frequency of \~ 0.083 Hz and a modulated pulse width of 40-550 µs), and will be given a single dose IV ketorolac and IV metoclopramide, at a dose of 0.5 mg/kg (for a maximum 30 mg) and 0.15 mg/kg (for a maximum 10mg), respectively. Metoclopramide will be infused over 15-30 minutes and ketorolac will be administered as a direct IV push over 1-5 minutes. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, would be given the crossover treatment. As such, the crossover treatment was not required.	REN (Crossover Treatment; Crossover Phase) Patients randomised to initially receive the Standard of Care IV and stimulation from the sham REN device, and then crossed over to receive a single 45-minutes stimulation from the REN device (modulated frequency of 100-120 Hz and a pulse width of 400 µs) and two doses of normal saline through an IV. Two doses of saline will be used to match the dosage, route of administration, and duration to ketorolac and metoclopramide, as described above in the standard-of-care IV group. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, would be given the crossover treatment. As such, the crossover treatment was not required.	All Participants Participants from both SoC and REN treatment groups.
Number of Participants Reporting Sustained Pain Freedom	1 Participants	1 Participants	0 Participants	—	—

SECONDARY outcome

Timeframe: 2 hours post-intervention

Number of participants who experienced a pain reduction from "severe" or "moderate" severity down to a "mild" or "no pain" severity, or those participants who experienced a pain reduction from "mild" to "no pain" severity between baseline and 2 hours post-intervention. Measured using the 4-point pain severity scale where 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Smaller values indicate no/less severe pain and higher values indicate more severe pain.

Outcome measures

Outcome measures
Measure	Parallel-group Design n=10 Participants A parallel-group design was used between February 22, 2022 to May 15, 2023 where participants were randomized to receive either the SoC or REN arm.	Crossover Design n=9 Participants We switched to a crossover design between May 16, 2023 and March 1, 2024 whereby participants who did not feel well enough to go home 2 hours after study intervention administration was initiated could cross over and receive the interventions of the other group.	Standard-of-Care IV (Crossover Treatment; Crossover Phase) n=2 Participants Patients who initially received stimulation from the REN device and two doses of saline, and then crossed over to receive the standard of care IV and a single, 45-minute stimulation from a sham remote electrical neuromodulation (REN) device, which will not administer the typical electrical stimulation (modulated frequency of \~ 0.083 Hz and a modulated pulse width of 40-550 µs), and will be given a single dose IV ketorolac and IV metoclopramide, at a dose of 0.5 mg/kg (for a maximum 30 mg) and 0.15 mg/kg (for a maximum 10mg), respectively. Metoclopramide will be infused over 15-30 minutes and ketorolac will be administered as a direct IV push over 1-5 minutes. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, would be given the crossover treatment. As such, the crossover treatment was not required.	REN (Crossover Treatment; Crossover Phase) Patients randomised to initially receive the Standard of Care IV and stimulation from the sham REN device, and then crossed over to receive a single 45-minutes stimulation from the REN device (modulated frequency of 100-120 Hz and a pulse width of 400 µs) and two doses of normal saline through an IV. Two doses of saline will be used to match the dosage, route of administration, and duration to ketorolac and metoclopramide, as described above in the standard-of-care IV group. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, would be given the crossover treatment. As such, the crossover treatment was not required.	All Participants Participants from both SoC and REN treatment groups.
Numbers of Participants Reporting a Change in 4-point Pain Severity Scale Between Baseline and 2 Hours Post-intervention	6 Participants	5 Participants	2 Participants	—	—

SECONDARY outcome

Timeframe: 48 hours post-intervention

Change from baseline "moderate" to "severe pain" to "mild or "no pain", or change from baseline "mild pain" to "no pain" 2 hours post-intervention, which is sustained to 48 hours post-intervention. Measured using the 4-point pain severity scale where 0 = None, 1 = Mild, 2 = Moderate, 3 = Severe. Smaller values indicate no/less severe pain and higher values indicate more severe pain. Participants who reported they did not have a headache between 2 hours and 48 hours post-intervention were not asked to rate their pain severity and were considered to have no headache pain at 48 hours.

Outcome measures

Outcome measures
Measure	Parallel-group Design n=10 Participants A parallel-group design was used between February 22, 2022 to May 15, 2023 where participants were randomized to receive either the SoC or REN arm.	Crossover Design n=9 Participants We switched to a crossover design between May 16, 2023 and March 1, 2024 whereby participants who did not feel well enough to go home 2 hours after study intervention administration was initiated could cross over and receive the interventions of the other group.	Standard-of-Care IV (Crossover Treatment; Crossover Phase) n=2 Participants Patients who initially received stimulation from the REN device and two doses of saline, and then crossed over to receive the standard of care IV and a single, 45-minute stimulation from a sham remote electrical neuromodulation (REN) device, which will not administer the typical electrical stimulation (modulated frequency of \~ 0.083 Hz and a modulated pulse width of 40-550 µs), and will be given a single dose IV ketorolac and IV metoclopramide, at a dose of 0.5 mg/kg (for a maximum 30 mg) and 0.15 mg/kg (for a maximum 10mg), respectively. Metoclopramide will be infused over 15-30 minutes and ketorolac will be administered as a direct IV push over 1-5 minutes. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, would be given the crossover treatment. As such, the crossover treatment was not required.	REN (Crossover Treatment; Crossover Phase) Patients randomised to initially receive the Standard of Care IV and stimulation from the sham REN device, and then crossed over to receive a single 45-minutes stimulation from the REN device (modulated frequency of 100-120 Hz and a pulse width of 400 µs) and two doses of normal saline through an IV. Two doses of saline will be used to match the dosage, route of administration, and duration to ketorolac and metoclopramide, as described above in the standard-of-care IV group. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, would be given the crossover treatment. As such, the crossover treatment was not required.	All Participants Participants from both SoC and REN treatment groups.
Number of Participants Reporting Sustained Pain Relief	4 Participants	4 Participants	1 Participants	—	—

SECONDARY outcome

Timeframe: Evaluated from time of intervention to 2 hours and 48 hours post-intervention

The number of participants who reported experiencing adverse events and serious adverse events following intervention

Outcome measures

Outcome measures
Measure	Parallel-group Design n=10 Participants A parallel-group design was used between February 22, 2022 to May 15, 2023 where participants were randomized to receive either the SoC or REN arm.	Crossover Design n=9 Participants We switched to a crossover design between May 16, 2023 and March 1, 2024 whereby participants who did not feel well enough to go home 2 hours after study intervention administration was initiated could cross over and receive the interventions of the other group.	Standard-of-Care IV (Crossover Treatment; Crossover Phase) n=2 Participants Patients who initially received stimulation from the REN device and two doses of saline, and then crossed over to receive the standard of care IV and a single, 45-minute stimulation from a sham remote electrical neuromodulation (REN) device, which will not administer the typical electrical stimulation (modulated frequency of \~ 0.083 Hz and a modulated pulse width of 40-550 µs), and will be given a single dose IV ketorolac and IV metoclopramide, at a dose of 0.5 mg/kg (for a maximum 30 mg) and 0.15 mg/kg (for a maximum 10mg), respectively. Metoclopramide will be infused over 15-30 minutes and ketorolac will be administered as a direct IV push over 1-5 minutes. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, would be given the crossover treatment. As such, the crossover treatment was not required.	REN (Crossover Treatment; Crossover Phase) Patients randomised to initially receive the Standard of Care IV and stimulation from the sham REN device, and then crossed over to receive a single 45-minutes stimulation from the REN device (modulated frequency of 100-120 Hz and a pulse width of 400 µs) and two doses of normal saline through an IV. Two doses of saline will be used to match the dosage, route of administration, and duration to ketorolac and metoclopramide, as described above in the standard-of-care IV group. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, would be given the crossover treatment. As such, the crossover treatment was not required.	All Participants Participants from both SoC and REN treatment groups.
Number of Participants Reporting Adverse Events 2 hours post-intervention	1 Participants	0 Participants	0 Participants	0 Participants	—
Number of Participants Reporting Adverse Events 48 hours post-intervention	1 Participants	0 Participants	0 Participants	0 Participants	—

SECONDARY outcome

Timeframe: 2 hours post-intervention

The number of participants who experienced freedom from their most bothersome symptom (nausea, vomiting, sensitivity to light, or sensitivity to sound).

Outcome measures

Outcome measures
Measure	Parallel-group Design n=10 Participants A parallel-group design was used between February 22, 2022 to May 15, 2023 where participants were randomized to receive either the SoC or REN arm.	Crossover Design n=9 Participants We switched to a crossover design between May 16, 2023 and March 1, 2024 whereby participants who did not feel well enough to go home 2 hours after study intervention administration was initiated could cross over and receive the interventions of the other group.	Standard-of-Care IV (Crossover Treatment; Crossover Phase) n=2 Participants Patients who initially received stimulation from the REN device and two doses of saline, and then crossed over to receive the standard of care IV and a single, 45-minute stimulation from a sham remote electrical neuromodulation (REN) device, which will not administer the typical electrical stimulation (modulated frequency of \~ 0.083 Hz and a modulated pulse width of 40-550 µs), and will be given a single dose IV ketorolac and IV metoclopramide, at a dose of 0.5 mg/kg (for a maximum 30 mg) and 0.15 mg/kg (for a maximum 10mg), respectively. Metoclopramide will be infused over 15-30 minutes and ketorolac will be administered as a direct IV push over 1-5 minutes. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, would be given the crossover treatment. As such, the crossover treatment was not required.	REN (Crossover Treatment; Crossover Phase) Patients randomised to initially receive the Standard of Care IV and stimulation from the sham REN device, and then crossed over to receive a single 45-minutes stimulation from the REN device (modulated frequency of 100-120 Hz and a pulse width of 400 µs) and two doses of normal saline through an IV. Two doses of saline will be used to match the dosage, route of administration, and duration to ketorolac and metoclopramide, as described above in the standard-of-care IV group. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, would be given the crossover treatment. As such, the crossover treatment was not required.	All Participants Participants from both SoC and REN treatment groups.
Number of Participants Reporting Freedom From Most Bothersome Symptom	8 Participants	3 Participants	1 Participants	—	—

SECONDARY outcome

Timeframe: 2 hours post-intervention (after last intervention, following ED discharge)

The number of participants discharged from the emergency department with no further intervention other than study intervention

Outcome measures

Outcome measures
Measure	Parallel-group Design n=10 Participants A parallel-group design was used between February 22, 2022 to May 15, 2023 where participants were randomized to receive either the SoC or REN arm.	Crossover Design n=9 Participants We switched to a crossover design between May 16, 2023 and March 1, 2024 whereby participants who did not feel well enough to go home 2 hours after study intervention administration was initiated could cross over and receive the interventions of the other group.	Standard-of-Care IV (Crossover Treatment; Crossover Phase) n=2 Participants Patients who initially received stimulation from the REN device and two doses of saline, and then crossed over to receive the standard of care IV and a single, 45-minute stimulation from a sham remote electrical neuromodulation (REN) device, which will not administer the typical electrical stimulation (modulated frequency of \~ 0.083 Hz and a modulated pulse width of 40-550 µs), and will be given a single dose IV ketorolac and IV metoclopramide, at a dose of 0.5 mg/kg (for a maximum 30 mg) and 0.15 mg/kg (for a maximum 10mg), respectively. Metoclopramide will be infused over 15-30 minutes and ketorolac will be administered as a direct IV push over 1-5 minutes. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, would be given the crossover treatment. As such, the crossover treatment was not required.	REN (Crossover Treatment; Crossover Phase) Patients randomised to initially receive the Standard of Care IV and stimulation from the sham REN device, and then crossed over to receive a single 45-minutes stimulation from the REN device (modulated frequency of 100-120 Hz and a pulse width of 400 µs) and two doses of normal saline through an IV. Two doses of saline will be used to match the dosage, route of administration, and duration to ketorolac and metoclopramide, as described above in the standard-of-care IV group. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, would be given the crossover treatment. As such, the crossover treatment was not required.	All Participants Participants from both SoC and REN treatment groups.
Number of Participants Discharged From the Emergency Department With no Further Intervention	6 Participants	4 Participants	1 Participants	—	—

Adverse Events

Standard-of-Care IV (Initial Treatment; Parallel and Crossover Phases)

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

REN (Initial Treatment; Parallel and Crossover Phases)

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Standard-of-Care IV (Crossover Treatment; Crossover Phase)

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

REN (Crossover Treatment; Crossover Phase)

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Standard-of-Care IV (Initial Treatment; Parallel and Crossover Phases) n=10 participants at risk Patients randomised to initially receive the standard of care IV group will receive a single, 45-minute stimulation from a sham remote electrical neuromodulation (REN) device, which will not administer the typical electrical stimulation (modulated frequency of \~ 0.083 Hz and a modulated pulse width of 40-550 µs), and will be given a single dose IV ketorolac and IV metoclopramide, at a dose of 0.5 mg/kg (for a maximum 30 mg) and 0.15 mg/kg (for a maximum 10mg), respectively. Metoclopramide will be infused over 15-30 minutes and ketorolac will be administered as a direct IV push over 1-5 minutes. Ketorolac: Intervention in syringe for target dose of 0.5 mg/kg, maximum 30 mg of ketorolac (1 mL), and administer as a direct IV push over 1-5 minutes Metoclopramide: Intervention in 50 mL mini bag of normal saline (0.9% NaCl) for target dose of 0.15 mg/kg, maximum 10 mg of metoclopramide (2 mL), and administer as infusion over 15-30 minutes Sham Remote Electrical Neuromodulation Device: The sham REN device is identical to the active REN device but the stimulation parameters are different, administering a modulated symmetrical biphasic square electrical pulse, modulated frequency of \~0.083 Hz and a modulated pulse width of 40-550 µ. These sham parameters are designed to induce a sensation that will be perceptible to participants, similar to stimulation from the active REN device, but at a frequency that is low enough so as to not modulate the nociceptive sensory nerves.	REN (Initial Treatment; Parallel and Crossover Phases) n=9 participants at risk Patients randomised to initially receive the REN group will receive a single 45-minutes stimulation from the REN device (modulated frequency of 100-120 Hz and a pulse width of 400 µs) and will also receive two doses of normal saline though an IV. Two doses of saline will be used to match the dosage, route of administration, and duration to ketorolac and metoclopramide, as described above in the standard-of-care IV group. Active Remote Electrical Neuromodulation Device: The REN device is a battery-powered, wirelessly controlled neuromodulation device that attaches via armband to the upper arm. The REN device is controlled by a smartphone application and administers electrical stimulation to the local C and Aδ nociceptive sensory nerves of the upper arm. This stimulation is achieved using a symmetrical, biphasic, square pulse, modulated at a frequency between 100-120 Hz. Each pulse has a width of 400 µs and the user, via the smartphone application, can adjust the output current to apply a maximum of 40 mA. Each stimulation session occurs over 45 minutes and each device can administer up to 12 stimulation sessions. Placebo: 0.9% NaCl will be administered to participants through IV in identical dosages, methods, and duration as the ketorolac and metoclopramide interventions described above.	Standard-of-Care IV (Crossover Treatment; Crossover Phase) n=2 participants at risk Patients who initially received stimulation from the REN device and two doses of saline, and then crossed over to receive the standard of care IV and a single, 45-minute stimulation from a sham remote electrical neuromodulation (REN) device, which will not administer the typical electrical stimulation (modulated frequency of \~ 0.083 Hz and a modulated pulse width of 40-550 µs), and will be given a single dose IV ketorolac and IV metoclopramide, at a dose of 0.5 mg/kg (for a maximum 30 mg) and 0.15 mg/kg (for a maximum 10mg), respectively. Metoclopramide will be infused over 15-30 minutes and ketorolac will be administered as a direct IV push over 1-5 minutes. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, they are given the crossover treatment. When participants indicate that they feel well enough to go home after initial study treatments, they are not given the crossover treatment.	REN (Crossover Treatment; Crossover Phase) Patients randomised to initially receive the Standard of Care IV and stimulation from the sham REN device, and then crossed over to receive a single 45-minutes stimulation from the REN device (modulated frequency of 100-120 Hz and a pulse width of 400 µs) and two doses of normal saline through an IV. Two doses of saline will be used to match the dosage, route of administration, and duration to ketorolac and metoclopramide, as described above in the standard-of-care IV group. Participants are assessed 2-hours after the initial study treatment and, if they indicate they are not well enough to go home, they are given the crossover treatment. When participants indicate that they feel well enough to go home after initial study treatments, they are not given the crossover treatment. Because all participants randomized to the standard of care IV group for initial treatment felt well enough to go home after initial treatment, no participants received the REN crossover treatment and no participants in this group were at risk for adverse events during this phase of the study.
Nervous system disorders Akathisia	10.0% 1/10 • Number of events 1 • Adverse events were monitored and recorded from the start of study treatment administration until completion of the 48-hour follow-up. Any symptom, sign, illness or experience that develops or worsens in severity during the study, including intercurrent illnesses or injuries. Abnormal results of diagnostic tests are considered if it: * results in study withdrawal * is associated with a serious adverse event, or with clinical signs or symptoms * leads to additional treatment/tests * is considered by the PI to be of clinical significance No participants received REN as the crossover treatment during the crossover phase.	0.00% 0/9 • Adverse events were monitored and recorded from the start of study treatment administration until completion of the 48-hour follow-up. Any symptom, sign, illness or experience that develops or worsens in severity during the study, including intercurrent illnesses or injuries. Abnormal results of diagnostic tests are considered if it: * results in study withdrawal * is associated with a serious adverse event, or with clinical signs or symptoms * leads to additional treatment/tests * is considered by the PI to be of clinical significance No participants received REN as the crossover treatment during the crossover phase.	0.00% 0/2 • Adverse events were monitored and recorded from the start of study treatment administration until completion of the 48-hour follow-up. Any symptom, sign, illness or experience that develops or worsens in severity during the study, including intercurrent illnesses or injuries. Abnormal results of diagnostic tests are considered if it: * results in study withdrawal * is associated with a serious adverse event, or with clinical signs or symptoms * leads to additional treatment/tests * is considered by the PI to be of clinical significance No participants received REN as the crossover treatment during the crossover phase.	— 0/0 • Adverse events were monitored and recorded from the start of study treatment administration until completion of the 48-hour follow-up. Any symptom, sign, illness or experience that develops or worsens in severity during the study, including intercurrent illnesses or injuries. Abnormal results of diagnostic tests are considered if it: * results in study withdrawal * is associated with a serious adverse event, or with clinical signs or symptoms * leads to additional treatment/tests * is considered by the PI to be of clinical significance No participants received REN as the crossover treatment during the crossover phase.

Additional Information

Dr. Serena Orr

University of Calgary/Alberta Health Services

Phone: 403-955-7728

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place