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

Primary Purpose

Migraine Disorders

Status
Recruiting
Phase
Phase 3
Locations
Canada
Study Type
Interventional
Intervention
Ketorolac
Metoclopramide
Active Remote Electrical Neuromodulation Device
Placebo
Sham Remote Electrical Neuromodulation Device
Sponsored by
University of Calgary
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Migraine Disorders focused on measuring Migraine, Pediatric, Emergency Department, Remote Electrical Neuromodulation

Eligibility Criteria

8 Years - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Exclusion Criteria:

Exclusion criteria include the following: allergy or contraindication to metoclopramide, ketorolac, or non-steroidal anti-inflammatories; implanted electrical device, congestive heart failure, severe cardiac or cerebrovascular disease, uncontrolled epilepsy (2 or more unprovoked seizures per year), abnormal skin on both upper arms (e.g., cancerous lesion on both upper arms, metallic implants on both upper arms, or abnormal physical sensation in both upper arms), febrile at triage, head trauma in the past 7 days, current secondary headache, previously enrolled in the study, pregnant or lactating.

Sites / Locations

  • Alberta Children's HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Other

Arm Label

Standard-of-Care IV Group

REN Group

Arm Description

Patients 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 (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.

Patients 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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Proportion of eligible participants who are screened, enrolled, and complete all assessments
These secondary feasibility outcomes will involve the following: The proportion 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). The proportion of screened eligible participants who are subsequently enrolled in the study. The proportion of approached potential participants who subsequently decide to enroll in the study.
Global impression of change
This acceptability outcome will involve the following: -The proportion of participants who report a global impression of change as "very much improved" or "much improved".
Study feedback from participants and staff
This acceptability outcome will involve the following: Participant feedback regarding study acceptability. Emergency department staff feedback provided
Pain freedom
Pain freedom post-intervention
Sustained pain freedom
Pain freedom 2-hours post-intervention and maintaining pain freedom to 48 hours post-intervention
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
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
Adverse events
Experiencing adverse events and serious adverse events following intervention
Freedom from most bothersome symptom
Experienced freedom from most bothersome symptom (nausea, vomiting, sensitivity to light, or sensitivity to sound)
Discharged from the emergency department with no further intervention
Discharged from the emergency department with no further intervention other than study intervention

Full Information

First Posted
September 28, 2021
Last Updated
May 4, 2023
Sponsor
University of Calgary
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1. Study Identification

Unique Protocol Identification Number
NCT05102591
Brief Title
A Pilot Clinical Trial of a New Neuromodulation Device for Acute Attacks of Migraine in Children and Adolescents
Official Title
A Pilot Clinical Trial of a New Neuromodulation Device for Acute Attacks of Migraine in Children and Adolescents Visiting the Emergency Department
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 22, 2022 (Actual)
Primary Completion Date
February 2025 (Anticipated)
Study Completion Date
February 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Calgary

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
Yes
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
No

5. Study Description

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, and IV catheters are associated with high adverse event and failure rates in children and adolescents. 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. Emerging neuromodulation devices show promise for expanding acute treatment options. Over the past few years, there has been a growth in research investigating the efficacy and safety of non-invasive neuromodulation, which delivers electrical or magnetic stimulation to nerves or neural tissue, for the management of acute attacks of migraine. At present, there are 3 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 propose a pilot randomized controlled trial (RCT) that will determine the feasibility and acceptability of executing a phase III RCT, in which children and adolescents visiting the ED with acute attacks of migraine will be randomized to REN or standard of care IV treatment, and then crossed over to the other treatment arm if the initial intervention is not effective.
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 are proposing a pilot randomized controlled trial (RCT) that will aim 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 will be randomized to REN, or to standard of care IV treatment in a double-dummy crossover design. Participants will be crossed over to the other treatment arm if the initial intervention is not effective. The objectives of the investigators are: 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. 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. 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 propose to carry out a pilot RCT to determine the feasibility and acceptability of implementing a double-dummy, crossover RCT protocol. In this pilot study, children and adolescents visiting the ED with acute attacks of migraine will be randomized to initially receive either REN or standard of care IV treatment (i.e. a combination of metoclopramide and ketorolac). Each group will also receive 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 will be randomized at a 1:1 ratio to either REN or standard of care IV treatment. The allocation sequence will be sent to the research pharmacy and will not be accessible to anyone involved in the study or patient care. The REN group will receive active stimulation and normal saline placebo that will appear identical in appearance and volume to the medications given to the comparison group. The comparison group will receive a combination of pharmaceutical interventions that are 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 will also receive sham stimulation that will be low enough that it cannot induce conditioned pain modulation, the mechanism of action of REN, but it will be perceptible and similar to the sensation induced by the REN device. Stimulation for both groups occurs over 45 minutes. Participants will be assessed 120 minutes following the initial intervention and will be crossed over to the other treatment arm if the initial intervention is not effective. Efficacy and safety outcomes will be 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Migraine Disorders
Keywords
Migraine, Pediatric, Emergency Department, Remote Electrical Neuromodulation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Crossover Assignment
Model Description
The investigators will carry out a pilot randomized controlled trial (RCT) to determine the feasibility and acceptability of implementing a double-dummy, crossover RCT protocol.
Masking
ParticipantCare ProviderInvestigator
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.
Allocation
Randomized
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Standard-of-Care IV Group
Arm Type
Other
Arm Description
Patients 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 (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.
Arm Title
REN Group
Arm Type
Other
Arm Description
Patients 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.
Intervention Type
Drug
Intervention Name(s)
Ketorolac
Other Intervention Name(s)
Toradol
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Metoclopramide
Other Intervention Name(s)
Maxeran
Intervention Description
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
Intervention Type
Device
Intervention Name(s)
Active Remote Electrical Neuromodulation Device
Other Intervention Name(s)
Active REN (Nerivio)
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Saline
Intervention Description
0.9% NaCl will be administered to participants through IV in identical dosages, methods, and duration as the ketorolac and metoclopramide interventions described above.
Intervention Type
Device
Intervention Name(s)
Sham Remote Electrical Neuromodulation Device
Other Intervention Name(s)
Sham REN (Sham Nerivio)
Intervention Description
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.
Primary Outcome Measure Information:
Title
Assessment of recruitment rate
Description
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.
Time Frame
Evaluated monthly and at the end of recruitment (i.e., 2 years or once the final participant has completed the study)
Secondary Outcome Measure Information:
Title
Proportion of eligible participants who are screened, enrolled, and complete all assessments
Description
These secondary feasibility outcomes will involve the following: The proportion 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). The proportion of screened eligible participants who are subsequently enrolled in the study. The proportion of approached potential participants who subsequently decide to enroll in the study.
Time Frame
Evaluated monthly and at the end of recruitment (i.e., 2 years or once the final participant has completed the study)
Title
Global impression of change
Description
This acceptability outcome will involve the following: -The proportion of participants who report a global impression of change as "very much improved" or "much improved".
Time Frame
Evaluated for each participant at 2-hours post-intervention, and 48-hours post-intervention
Title
Study feedback from participants and staff
Description
This acceptability outcome will involve the following: Participant feedback regarding study acceptability. Emergency department staff feedback provided
Time Frame
Clinical staff feedback evaluated after each participant's enrollment; participant feedback evaluated at 48 hours post-intervention
Title
Pain freedom
Description
Pain freedom post-intervention
Time Frame
2 hours post-intervention
Title
Sustained pain freedom
Description
Pain freedom 2-hours post-intervention and maintaining pain freedom to 48 hours post-intervention
Time Frame
48 hours post-intervention
Title
Pain relief
Description
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
Time Frame
2 hours post-intervention
Title
Sustained pain relief
Description
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
Time Frame
48 hours post-intervention
Title
Adverse events
Description
Experiencing adverse events and serious adverse events following intervention
Time Frame
Evaluated from time of intervention to 48 hours post-intervention
Title
Freedom from most bothersome symptom
Description
Experienced freedom from most bothersome symptom (nausea, vomiting, sensitivity to light, or sensitivity to sound)
Time Frame
2 hours post-intervention
Title
Discharged from the emergency department with no further intervention
Description
Discharged from the emergency department with no further intervention other than study intervention
Time Frame
2 hours post-intervention

10. Eligibility

Sex
All
Minimum Age & Unit of Time
8 Years
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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. Exclusion Criteria: Exclusion criteria include the following: allergy or contraindication to metoclopramide, ketorolac, or non-steroidal anti-inflammatories; implanted electrical device, congestive heart failure, severe cardiac or cerebrovascular disease, uncontrolled epilepsy (2 or more unprovoked seizures per year), abnormal skin on both upper arms (e.g., cancerous lesion on both upper arms, metallic implants on both upper arms, or abnormal physical sensation in both upper arms), febrile at triage, head trauma in the past 7 days, current secondary headache, previously enrolled in the study, pregnant or lactating.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Serena L Orr, MD, MSc, FRCPC
Phone
403-955-7816
Email
serena.orr@albertahealthservices.ca
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Serena L Orr, MD, MSc, FRCPC
Organizational Affiliation
University of Calgary
Official's Role
Principal Investigator
Facility Information:
Facility Name
Alberta Children's Hospital
City
Calgary
State/Province
Alberta
ZIP/Postal Code
T3B 6A8
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Serena L Orr, MD
Phone
403-955-7816
Email
serena.orr@albertahealthservices.ca

12. IPD Sharing Statement

Plan to Share IPD
No

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

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