Migraine Disorders
Conditions
Keywords
Migraine, Pediatric, Emergency Department, Remote Electrical Neuromodulation
Brief summary
Migraine is a neurological disease characterized by severe and recurrent headaches. Children and adolescents with migraine often present to the emergency department (ED) with acute attacks, where migraine accounts for up to \ 30% of all pediatric ED visits for headache. Based on the limited evidence, many centers have adopted protocols whereby children and adolescents who visit the ED with acute attacks of migraine are treated with an IV neuroleptic (metoclopramide or prochlorperazine) and an IV non-steroidal anti-inflammatory (ketorolac). This combination of interventions is largely considered to be standard of care despite no rigorous evidence to support this practice. Side effect rates with the neuroleptics (metoclopramide or prochlorperazine) are considerable. Therefore, the current standard of care for managing children and adolescents visiting the ED with acute attacks of migraine poses concern to patients and is associated with significant pain and frequent side effects. Over the past few years, there has been a growth in research investigating the efficacy and safety of non-invasive neuromodulation for the management of acute attacks of migraine. At present, there are several commercially available, non-invasive neuromodulation devices that effectively and safely treat acute attacks of migraine in adults. Because none of these devices have a high level evidence in children, adolescents, nor in the ED setting, there is clinical equipoise as to which device would be most appropriate to study for treating children and adolescents visiting the ED with acute attacks. Throughout our patient engagement work, children and adolescents with migraine have identified that they are interested in trying remote electrical neuromodulation for treating migraine attacks in the ED. The investigators completed a pilot randomized controlled trial (RCT) to determine the feasibility and acceptability of executing a phase III RCT, in which children and adolescents visiting the ED with acute attacks of migraine were randomized to REN or standard of care IV treatment. The trial had two phases: initially the design was a parallel-group design, and after 14 months of recruitment to that design, an amendment was made to allow participants to cross over to the other treatment arm if the initial intervention was not effective, in a crossover design. This change was made in response to participant and staff feedback around the parallel-group design.
Detailed description
One in ten Canadian children and adolescents suffer from migraine, and visits to the pediatric emergency department (ED) for acute attacks are common, with over 2,500 annual visits in Alberta alone. Evidence-based acute management options for children and adolescents presenting to the ED with acute attacks of migraine are limited. The current standard of care, which comprises a combination of a neuroleptic (metoclopramide) and a non-steroidal anti-inflammatory (ketorolac), has a low level of evidence and is administered through an intravenous (IV) cannula. However, at least half of children and adolescents presenting to the ED with acute attacks of migraine would prefer to avoid an IV, and these standard of care migraine interventions have substantial side effects and costs. The Nerivio remote electrical neuromodulation (REN) device is a novel, non-invasive, wearable REN device that is applied to the arm using an armband and wirelessly controlled by a smartphone software application. REN has established efficacy and safety for the treatment of acute attacks of migraine in adults, and preliminary open-label efficacy and safety data for use in adolescents. Through user engagement efforts, the investigators have identified that children and adolescents with migraine and ED providers are interested in trying REN to treat refractory acute attacks in the ED. The investigators completed a pilot randomized controlled trial (RCT) that aimed to determine the feasibility and acceptability of implementing a phase III RCT, in which children and adolescents visiting the ED with acute attacks of migraine were randomized to REN, or to standard of care IV treatment in a double-dummy parallel group design phase, followed by a crossover design phase. During the crossover phase, participants were crossed over to the other treatment arm if the initial intervention is not effective. The objectives of the investigators were: 1. To determine the feasibility of comparing REN to the standard of care IV intervention (i.e., a combination of metoclopramide and ketorolac) for the treatment of children and adolescents visiting the ED with acute attacks of migraine. 2. To determine the acceptability of the study design and of using REN to treat children and adolescents visiting the ED with acute attacks of migraine. 3. To gather preliminary efficacy and safety data on the use of REN to treat children and adolescents visiting the ED with acute attacks of migraine (for both the initial assigned intervention and the crossover intervention where applicable). The investigators employed a pilot RCT to determine the feasibility and acceptability of implementing a double-dummy, parallel and crossover RCT protocol. The controlled trial was completed with two design phases: 1) a parallel-group phase from February 22, 2022 to May 15, 2023, and 2) a crossover design phase from May 16, 2023 to March 1, 2024. The design was switched to a crossover design mid-way through the trial based on feedback from participants and clinical staff around concerns with not being able to receive typical care in a timely manner if randomized to the REN arm in the parallel-group design. In this pilot study, children and adolescents visiting the ED with acute attacks of migraine were randomized to initially receive either REN or standard of care IV treatment (i.e. a combination of metoclopramide and ketorolac). Each group also received a blinded control (either normal saline through the IV for the REN group, or sham stimulation for the standard of care IV group). Consenting participants were randomized at a 1:1 ratio to either REN or standard of care IV treatment. The allocation sequence was sent to the research pharmacy and was not accessible to anyone involved in the study or patient care. The REN group received active stimulation and normal saline placebo that appeared identical in appearance and volume to the medications given to the comparison group. The comparison group received a combination of pharmaceutical interventions considered to be the standard of care for treating children and adolescents visiting the ED with migraine: IV metoclopramide and IV ketorolac. The comparison group also received sham stimulation that was low enough that it did not induce conditioned pain modulation, the mechanism of action of REN, but it was perceptible and similar to the sensation induced by the REN device. Stimulation for both groups occurred over 45 minutes. In the crossover design phase, participants were assessed 120 minutes following the initial intervention and were crossed over to the other treatment arm if the initial intervention was not effective. Efficacy and safety outcomes were measured at baseline, 60 minutes, and 120 minutes (for both the initial and crossover study interventions as applicable), as well as 48 hours post-intervention.
Interventions
DRUGKetorolac
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
DRUGMetoclopramide
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
DEVICEActive 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.
DRUGPlacebo
0.9% NaCl will be administered to participants through IV in identical dosages, methods, and duration as the ketorolac and metoclopramide interventions described above.
DEVICESham 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.
Sponsors
University of Calgary
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Participants, research staff, and clinical staff, including the investigator, research assistant, research nurse, and attending physician, will remain blind to the study interventions.
Intervention model description
The investigators will carry out a pilot randomized controlled trial (RCT) to determine the feasibility and acceptability of implementing a double-dummy, parallel and crossover RCT protocol. The parallel-group phase was completed from February 22, 2022 to May 15, 2023, and the crossover design phase was completed from May 16, 2023 to March 1, 2024.
Eligibility
Sex/Gender
ALL
Age
8 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
Patients aged 8-18 years visiting the Alberta Children's Hospital Emergency Department (ED) with an acute attack of migraine as per criteria B-E of the International Classification of Headache Disorders-3 criteria (ICHD-3): B. Headache attacks lasting at least 2 hours (untreated or unsuccessfully treated) C. Headache has at least two of the following four characteristics: * unilateral location * pulsating quality * moderate or severe pain intensity * aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs) D. Also has least one of the following: * nausea and/or vomiting * photophobia and phonophobia E. Not better accounted for by another diagnosis in the opinion of the treating physician Criterion A (at least 5 attacks) is not being used in this study because prior research has shown that removing criterion A increases the sensitivity of these criteria in the ED. The patient and their caregiver will also be required to understand spoken and written English. In addition, potential participants will be required to have an upper arm circumference of at least 20 cm to ensure optimal device fit and safety.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of Recruitment Rate | Evaluated monthly and at the end of recruitment (i.e., 2 years or once the final participant has completed the study) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Reduction in Pain Severity | Difference between baseline and 1 hour, 2 hours, and 48 hours post-intervention. | 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. |
| Number of Eligible Participants Who Are Screened, Enrolled, and Complete All Assessments | 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). |
| Study Feedback From Participants and Staff | 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. |
| Number of Participants Reporting Pain Freedom | 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. |
| Number of Participants Reporting Sustained Pain Freedom | 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. |
| Global Impression of Change | 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. |
| Number of Participants Reporting Sustained Pain Relief | 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. |
| Number of Participants Reporting Adverse Events | 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 |
| Number of Participants Reporting Freedom From Most Bothersome Symptom | 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). |
| Number of Participants Discharged From the Emergency Department With no Further Intervention | 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 |
| Numbers of Participants Reporting a Change in 4-point Pain Severity Scale Between Baseline and 2 Hours Post-intervention | 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. |
Countries
Canada
Participant flow
Recruitment details
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.
Pre-assignment details
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).
Participants by arm
| Arm | Count |
|---|---|
| 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. | 7 |
| 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. | 7 |
| 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). | 3 |
| 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). | 2 |
| Total | 19 |
Baseline characteristics
| Characteristic | REN Group (Parallel Design Phase) | Standard-of-Care IV Group First, Then REN Group if Applicable (Crossover Design Phase) | REN Group First, Then Standard-of-Care IV Group First if Applicable (Crossover Design Phase) | Total | Standard-of-Care IV Group (Parallel Design Phase) |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 7 Participants | 3 Participants | 2 Participants | 19 Participants | 7 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 15 years STANDARD_DEVIATION 1.2 | 15.3 years STANDARD_DEVIATION 2.1 | 13 years STANDARD_DEVIATION 0 | 14.4 years STANDARD_DEVIATION 1.8 | 13.7 years STANDARD_DEVIATION 2.1 |
| Current attack baseline pain severity | 5 units on a scale | 7 units on a scale | 8 units on a scale | 7 units on a scale | 7 units on a scale |
| Current attack duration in hours | 168 Hours | 72 Hours | 168 Hours | 96 Hours | 96 Hours |
| Current attack with aura | 1 Participants | 1 Participants | 0 Participants | 6 Participants | 4 Participants |
| Duration of time with headaches in months | 3 Months | 72 Months | 2.5 Months | 24 Months | 48 Months |
| Headache frequency in days/month | 7 Days per Month | 4 Days per Month | 5 Days per Month | 6 Days per Month | 6 Days per Month |
| History of prior attacks with aura | 3 Participants | 1 Participants | 0 Participants | 9 Participants | 5 Participants |
| Number of participants with continuous headache at baseline | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Number of past headache-related ED visits 1 | 0 Counts | 0 Counts | 1 Counts | 1 Counts | 0 Counts |
| Number of past headache-related ED visits 2 | 0 Counts | 0 Counts | 0 Counts | 1 Counts | 1 Counts |
| Number of past headache-related ED visits 3 | 3 Counts | 1 Counts | 1 Counts | 5 Counts | 0 Counts |
| Number of past headache-related ED visits 4 | 1 Counts | 1 Counts | 0 Counts | 2 Counts | 0 Counts |
| Number of past headache-related ED visits 5 | 0 Counts | 0 Counts | 0 Counts | 2 Counts | 2 Counts |
| Number of past headache-related ED visits >=6 | 2 Counts | 0 Counts | 0 Counts | 3 Counts | 1 Counts |
| Number of past headache-related ED visits None | 1 Counts | 1 Counts | 0 Counts | 5 Counts | 3 Counts |
| On a migraine preventive intervention at home | 4 Participants | 2 Participants | 0 Participants | 10 Participants | 4 Participants |
| PedMIDAS Score | 39 units on a scale | 61 units on a scale | 49.5 units on a scale | 49 units on a scale | 80 units on a scale |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 2 Participants | 2 Participants | 17 Participants | 7 Participants |
| Region of Enrollment Canada | 7 participants | 3 participants | 2 participants | 19 participants | 7 participants |
| Sex: Female, Male Female | 5 Participants | 2 Participants | 1 Participants | 10 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 1 Participants | 9 Participants | 5 Participants |
| Took acute intervention at home prior to ED visit | 7 Participants | 3 Participants | 2 Participants | 19 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 9 | 0 / 2 | 0 / 0 |
| other Total, other adverse events | 1 / 10 | 0 / 9 | 0 / 2 | 0 / 0 |
| serious Total, serious adverse events | 0 / 10 | 0 / 9 | 0 / 2 | 0 / 0 |
Outcome results
Primary
Assessment of Recruitment Rate
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Parallel-group Design | Assessment of Recruitment Rate | 1.1 participants per month | Standard Deviation 1.5 |
| Crossover Design | Assessment of Recruitment Rate | 0.6 participants per month | Standard Deviation 1 |
Secondary
Global Impression of Change
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.
Time frame: Evaluated for each participant at 2-hours post-intervention, 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).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Parallel-group Design | Global Impression of Change | 2 Hours | 5 participants |
| Parallel-group Design | Global Impression of Change | 48 Hours | 5 participants |
| Crossover Design | Global Impression of Change | 2 Hours | 3 participants |
| Crossover Design | Global Impression of Change | 48 Hours | 3 participants |
| Standard-of-Care IV (Crossover Treatment; Crossover Phase) | Global Impression of Change | 2 Hours | 1 participants |
| Standard-of-Care IV (Crossover Treatment; Crossover Phase) | Global Impression of Change | 48 Hours | 1 participants |
Secondary
Number of Eligible Participants Who Are Screened, Enrolled, and Complete All Assessments
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).
Time frame: Evaluated monthly and at the end of recruitment (i.e., 2 years or once the final participant has completed the study)
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).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Parallel-group Design | Number of Eligible Participants Who Are Screened, Enrolled, and Complete All Assessments | 10 Participants |
| Crossover Design | Number of Eligible Participants Who Are Screened, Enrolled, and Complete All Assessments | 9 Participants |
| Standard-of-Care IV (Crossover Treatment; Crossover Phase) | Number of Eligible Participants Who Are Screened, Enrolled, and Complete All Assessments | 2 Participants |
Secondary
Number of Participants Discharged From the Emergency Department With no Further Intervention
The number of participants discharged from the emergency department with no further intervention other than study intervention
Time frame: 2 hours post-intervention (after last intervention, following ED discharge)
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).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Parallel-group Design | Number of Participants Discharged From the Emergency Department With no Further Intervention | 6 Participants |
| Crossover Design | Number of Participants Discharged From the Emergency Department With no Further Intervention | 4 Participants |
| Standard-of-Care IV (Crossover Treatment; Crossover Phase) | Number of Participants Discharged From the Emergency Department With no Further Intervention | 1 Participants |
Secondary
Number of Participants Reporting Adverse Events
The number of participants who reported experiencing adverse events and serious adverse events following intervention
Time frame: Evaluated from time of intervention to 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).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Parallel-group Design | Number of Participants Reporting Adverse Events | 2 hours post-intervention | 1 Participants |
| Parallel-group Design | Number of Participants Reporting Adverse Events | 48 hours post-intervention | 1 Participants |
| Crossover Design | Number of Participants Reporting Adverse Events | 48 hours post-intervention | 0 Participants |
| Crossover Design | Number of Participants Reporting Adverse Events | 2 hours post-intervention | 0 Participants |
| Standard-of-Care IV (Crossover Treatment; Crossover Phase) | Number of Participants Reporting Adverse Events | 2 hours post-intervention | 0 Participants |
| Standard-of-Care IV (Crossover Treatment; Crossover Phase) | Number of Participants Reporting Adverse Events | 48 hours post-intervention | 0 Participants |
| REN (Crossover Treatment; Crossover Phase) | Number of Participants Reporting Adverse Events | 2 hours post-intervention | 0 Participants |
| REN (Crossover Treatment; Crossover Phase) | Number of Participants Reporting Adverse Events | 48 hours post-intervention | 0 Participants |
Secondary
Number of Participants Reporting Freedom From Most Bothersome Symptom
The number of participants who experienced freedom from their most bothersome symptom (nausea, vomiting, sensitivity to light, or sensitivity to sound).
Time frame: 2 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).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Parallel-group Design | Number of Participants Reporting Freedom From Most Bothersome Symptom | 8 Participants |
| Crossover Design | Number of Participants Reporting Freedom From Most Bothersome Symptom | 3 Participants |
| Standard-of-Care IV (Crossover Treatment; Crossover Phase) | Number of Participants Reporting Freedom From Most Bothersome Symptom | 1 Participants |
Secondary
Number of Participants Reporting Pain Freedom
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.
Time frame: 2 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).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Parallel-group Design | Number of Participants Reporting Pain Freedom | 4 Participants |
| Crossover Design | Number of Participants Reporting Pain Freedom | 1 Participants |
| Standard-of-Care IV (Crossover Treatment; Crossover Phase) | Number of Participants Reporting Pain Freedom | 0 Participants |
Secondary
Number of Participants Reporting Sustained Pain Freedom
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.
Time frame: 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).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Parallel-group Design | Number of Participants Reporting Sustained Pain Freedom | 1 Participants |
| Crossover Design | Number of Participants Reporting Sustained Pain Freedom | 1 Participants |
| Standard-of-Care IV (Crossover Treatment; Crossover Phase) | Number of Participants Reporting Sustained Pain Freedom | 0 Participants |
Secondary
Number of Participants Reporting Sustained Pain Relief
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.
Time frame: 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).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Parallel-group Design | Number of Participants Reporting Sustained Pain Relief | 4 Participants |
| Crossover Design | Number of Participants Reporting Sustained Pain Relief | 4 Participants |
| Standard-of-Care IV (Crossover Treatment; Crossover Phase) | Number of Participants Reporting Sustained Pain Relief | 1 Participants |
Secondary
Numbers of Participants Reporting a Change in 4-point Pain Severity Scale Between Baseline and 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.
Time frame: 2 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).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Parallel-group Design | Numbers of Participants Reporting a Change in 4-point Pain Severity Scale Between Baseline and 2 Hours Post-intervention | 6 Participants |
| Crossover Design | Numbers of Participants Reporting a Change in 4-point Pain Severity Scale Between Baseline and 2 Hours Post-intervention | 5 Participants |
| Standard-of-Care IV (Crossover Treatment; Crossover Phase) | Numbers of Participants Reporting a Change in 4-point Pain Severity Scale Between Baseline and 2 Hours Post-intervention | 2 Participants |
Secondary
Reduction in Pain Severity
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.
Time frame: 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).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Parallel-group Design | Reduction in Pain Severity | 2 hours post-intervention | 4 units on a scale | Standard Deviation 3.5 |
| Parallel-group Design | Reduction in Pain Severity | 1 hour post-intervention | 2.9 units on a scale | Standard Deviation 2.9 |
| Parallel-group Design | Reduction in Pain Severity | 48 hours post-intervention | 3.3 units on a scale | Standard Deviation 2.7 |
| Crossover Design | Reduction in Pain Severity | 48 hours post-intervention | 2.6 units on a scale | Standard Deviation 1.5 |
| Crossover Design | Reduction in Pain Severity | 1 hour post-intervention | 2.1 units on a scale | Standard Deviation 1.3 |
| Crossover Design | Reduction in Pain Severity | 2 hours post-intervention | 2.4 units on a scale | Standard Deviation 1.6 |
| Standard-of-Care IV (Crossover Treatment; Crossover Phase) | Reduction in Pain Severity | 2 hours post-intervention | 3.5 units on a scale | Standard Deviation 0.7 |
| Standard-of-Care IV (Crossover Treatment; Crossover Phase) | Reduction in Pain Severity | 1 hour post-intervention | 3 units on a scale | Standard Deviation 0 |
Secondary
Study Feedback From Participants and Staff
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.
Time frame: Participant feedback evaluated at 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).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Parallel-group Design | 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 |
| Parallel-group Design | 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 |
| Parallel-group Design | 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 |
| Parallel-group Design | 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 |
| Parallel-group Design | 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 |
| Parallel-group Design | 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 |
| Parallel-group Design | 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 |
| Crossover Design | Study Feedback From Participants and Staff | I would only use my usual treatment instead of the device to treat future migraine attacks at home. | 2.8 units on a scale | Standard Deviation 1.1 |
| Crossover Design | Study Feedback From Participants and Staff | I would use the device to treat future migraine attacks at home instead of my usual treatment. | 3.3 units on a scale | Standard Deviation 1.1 |
| Crossover Design | 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 |
| Crossover Design | Study Feedback From Participants and Staff | I would use the device to treat future migraine attacks at home with my usual treatment. | 3.7 units on a scale | Standard Deviation 0.9 |
| Crossover Design | Study Feedback From Participants and Staff | If I could, I would bring the device home with me to treat future migraine attacks at home. | 3.7 units on a scale | Standard Deviation 1 |
| Crossover Design | Study Feedback From Participants and Staff | I would be interested in using device instead of IV to treat future migraine attacks in the ED. | 3.6 units on a scale | Standard Deviation 1 |
| Crossover Design | 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 |
| Standard-of-Care IV (Crossover Treatment; Crossover Phase) | Study Feedback From Participants and Staff | I would prefer to only use IV to treat future migraine attacks in the ED. | 3 units on a scale | Standard Deviation 0 |
| Standard-of-Care IV (Crossover Treatment; Crossover Phase) | Study Feedback From Participants and Staff | I would be interested in using device instead of IV to treat future migraine attacks in the ED. | 3.5 units on a scale | Standard Deviation 0.7 |
| Standard-of-Care IV (Crossover Treatment; Crossover Phase) | Study Feedback From Participants and Staff | I would be interested in using device with IV to treat future migraine attacks in the ED. | 3.5 units on a scale | Standard Deviation 0.7 |
| Standard-of-Care IV (Crossover Treatment; Crossover Phase) | Study Feedback From Participants and Staff | I would use the device to treat future migraine attacks at home instead of my usual treatment. | 3 units on a scale | Standard Deviation 1.4 |
| Standard-of-Care IV (Crossover Treatment; Crossover Phase) | Study Feedback From Participants and Staff | I would use the device to treat future migraine attacks at home with my usual treatment. | 3.5 units on a scale | Standard Deviation 0.7 |
| Standard-of-Care IV (Crossover Treatment; Crossover Phase) | Study Feedback From Participants and Staff | I would only use my usual treatment instead of the device to treat future migraine attacks at home. | 3 units on a scale | Standard Deviation 1.4 |
| Standard-of-Care IV (Crossover Treatment; Crossover Phase) | 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 units on a scale | Standard Deviation 0 |
| All Participants | 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 |
| All Participants | 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 |
| All Participants | Study Feedback From Participants and Staff | I would only use my usual treatment instead of the device to treat future migraine attacks at home. | 2.6 units on a scale | Standard Deviation 0.8 |
| All Participants | 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 |
| All Participants | Study Feedback From Participants and Staff | I would be interested in using device instead of IV to treat future migraine attacks in the ED. | 3.7 units on a scale | Standard Deviation 1 |
| All Participants | 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 |
| All Participants | Study Feedback From Participants and Staff | If I could, I would bring the device home with me to treat future migraine attacks at home. | 4.1 units on a scale | Standard Deviation 0.8 |
| All Participants | 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 |
| All Participants | 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 |
| All Participants | Study Feedback From Participants and Staff | I understood that participation was voluntary. | 4.9 units on a scale | Standard Deviation 0.3 |
| All Participants | 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 |
| All Participants | 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 |
| All Participants | 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 |
| All Participants | 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 |
| All Participants | 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 |
| All Participants | Study Feedback From Participants and Staff | I felt the research staff were professional. | 4.7 units on a scale | Standard Deviation 0.5 |
| All Participants | Study Feedback From Participants and Staff | I felt the research staff were knowledgeable. | 4.6 units on a scale | Standard Deviation 0.5 |
| All Participants | Study Feedback From Participants and Staff | I felt the research staff were courteous. | 4.7 units on a scale | Standard Deviation 0.5 |
| All Participants | 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 |
| All Participants | Study Feedback From Participants and Staff | The study went smoothly. | 4.6 units on a scale | Standard Deviation 0.6 |
| All Participants | Study Feedback From Participants and Staff | My overall experience was positive. | 4.6 units on a scale | Standard Deviation 0.6 |
| All Participants | Study Feedback From Participants and Staff | I would use the device to treat future migraine attacks at home with my usual treatment. | 3.8 units on a scale | Standard Deviation 1 |
| All Participants | Study Feedback From Participants and Staff | I would use the device to treat future migraine attacks at home instead of my usual treatment. | 3.8 units on a scale | Standard Deviation 1 |