Clinical trial NCT05102591: 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
Overall status: COMPLETED
Phase: PHASE3
Conditions: Migraine Disorders
Keywords: Migraine
Pediatric
Emergency Department
Remote Electrical Neuromodulation
Lead sponsor: University of Calgary
Sponsor class: OTHER
First posted: 2021-11-01
Enrollment: 22
Sex: ALL
Minimum age (years): 8
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
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.
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Assessment of Recruitment Rate
timeFrame: Evaluated monthly and at the end of recruitment (i.e., 2 years or once the final participant has completed the study)
Secondary outcomes:
measure: Reduction in Pain Severity
timeFrame: Difference between baseline and 1 hour, 2 hours, and 48 hours post-intervention.
measure: Number of Eligible Participants Who Are Screened, Enrolled, and Complete All Assessments
timeFrame: Evaluated monthly and at the end of recruitment (i.e., 2 years or once the final participant has completed the study)
measure: Global Impression of Change
timeFrame: Evaluated for each participant at 2-hours post-intervention, and 48-hours post-intervention
measure: Study Feedback From Participants and Staff
timeFrame: Participant feedback evaluated at 48 hours post-intervention
measure: Number of Participants Reporting Pain Freedom
timeFrame: 2 hours post-intervention
measure: Number of Participants Reporting Sustained Pain Freedom
timeFrame: 48 hours post-intervention
measure: Numbers of Participants Reporting a Change in 4-point Pain Severity Scale Between Baseline and 2 Hours Post-intervention
timeFrame: 2 hours post-intervention
measure: Number of Participants Reporting Sustained Pain Relief
timeFrame: 48 hours post-intervention
measure: Number of Participants Reporting Adverse Events
timeFrame: Evaluated from time of intervention to 2 hours and 48 hours post-intervention
measure: Number of Participants Reporting Freedom From Most Bothersome Symptom
timeFrame: 2 hours post-intervention
measure: Number of Participants Discharged From the Emergency Department With no Further Intervention
timeFrame: 2 hours post-intervention (after last intervention, following ED discharge)
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
Study officials:
affiliation: University of Calgary
name: Serena L Orr, MD, MSc, FRCPC
role: PRINCIPAL_INVESTIGATOR
References: