Conditions: Migraine Disorders
Keywords: Migraine Pediatric Emergency Department Remote Electrical Neuromodulation
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 22
Healthy volunteers: no

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.

Arms:
arm 1: 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 2: 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.

Interventions: intervention 1: Ketorolac intervention 2: Metoclopramide intervention 3: Active Remote Electrical Neuromodulation Device intervention 4: Placebo intervention 5: Sham Remote Electrical Neuromodulation Device
Intervention descriptions: intervention 1: 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 2: 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 3: 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 4: 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 5: 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.

Protocol document:
Prot_SAP_000.pdf: 
Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
Page 1 of 61 
Project Title: A pilot clinical trial of a new neuromodulation device for acute attacks of 
migraine in children and adolescents visiting the emergency department 
 
Clinicaltrials.gov Registration Identifier: NCT05102591 
 
Sponsor-Investigator: 
Serena Orr, MD, MSc, FRCPC 
The Governors of the University of Calgary 
University of Calgary 
2500 University Drive NW 
Calgary, Alberta 
T2N 1N4 
 
Investigators: 
Adam Kirton, MD, FRCPC 
Pediatrics and Clinical Neurosciences Professor 
Department of Pediatrics 
Cumming School of Medicine 
University of Calgary 
2500 University Drive NW 
Calgary, Alberta 
T2N 1N4 
 
Kathryn Birnie, PhD 
Clinical Psychologist and Assistant Professor 
Department of Anesthesiology and Pain Management 
Faculty of Medicine 
University of Calgary 
2500 University Drive NW 
Calgary, Alberta 
T2N 1N4 
 
Stephen Freedman, MDCM, MSc 
Pediatrics and Emergency Medicine Professor 
Department of Pediatrics 
Cumming School of Medicine 
University of Calgary 
2500 University Drive NW 
Calgary, Alberta 
T2N 1N4 
 
Tolulope Sajobi, PhD 
Assistant Professor 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
Page 2 of 61 
Department of Community Health Sciences 
Cumming School of Medicine 
University of Calgary 
2500 University Drive NW 
Calgary, Alberta 
T2N 1N4 
 
Andrew Hershey, PhD 
Professor of Clinical-Affiliate 
Department of Neurology 
Faculty of Medicine 
University of Cincinnati 
2600 Clifton Ave 
Cincinnati, Ohio, USA 
45221 
 
Samina Ali, PhD 
Professor of Pediatrics and Adjunct Professor of Emergency Medicine 
Department of Pediatrics 
Faculty of Medicine and Dentistry 
University of Alberta 
116 Street and 85 Avenue 
Edmonton, Alberta 
T6G 2R3 
 
Prachi Khanna, BSc (Biology) Candidate 
Faculty of Science 
The University of British Columbia 
1103-6270 University Blvd 
Vancouver, British Columbia 
V6T 1Z4 
 
Eva Anderson 
Student 
Department of Physics 
Carleton University 
1125 Colonel By Drive 
Ottawa, Ontario 
K1S 5B6 
 
 
 
 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
Page 3 of 61 
Correspondence: 
Serena Orr, MD, MSc, FRCPC 
Assistant Professor 
Department of Pediatrics 
Cumming School of Medicine 
University of Calgary 
2500 University Drive NW 
Calgary, Alberta 
T2N 1N4 
Phone: (403) 955-7728 
Email: serena.orr@albertahealthservices.ca  
 
Funded by: Dr. Serena Orr’s CIHR Early Career Investigator Award in Maternal, 
Reproductive, Child, and Youth Health, and ACHRI/Department of Pediatrics Start-Up 
Funds; In-kind support provided by Theranica Bioelectrics Ltd (devices), and in-kind 
knowledge translation support provided by TREKK, SKIP, and the Alberta SPOR Support 
Unit’s (AbSPORU) KT and patient engagement platforms 
 
Date: February 10, 2023 
 
Protocol Version Number: 7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
Page 4 of 61 
Table of Contents 
 
1. 
GENERAL INFORMATION .............................................................................................................................. 7 
1.1. 
NAME AND ADDRESS OF SPONSOR ...................................................................................................................... 7 
1.2. 
NAME AND ADDRESS OF PERSON AUTHORISED TO SIGN PROTOCOL AND AMENDMENTS ............................................... 7 
1.3. 
NAME AND ADDRESS OF THE STUDY’S MEDICAL EXPERT ......................................................................................... 7 
1.4. 
NAME AND TITLE OF INVESTIGATORS RESPONSIBLE FOR THE TRIAL AND THE ADDRESS AND TELEPHONE NUMBERS FOR THE 
TRIAL SITE 7 
1.5. 
NAME AND ADDRESS OF THE QUALIFIED PHYSICIAN WHO IS RESPONSIBLE FOR TRIAL-RELATED MEDICAL DECISIONS .......... 7 
1.6. 
NAME AND ADDRESS OF THE CLINICAL LABORATORY AND RESEARCH PHARMACY INVOLVED IN THE TRIAL ......................... 8 
2. 
ABBREVIATIONS ........................................................................................................................................... 9 
3. 
STUDY SUMMARY....................................................................................................................................... 10 
4. 
BACKGROUND INFORMATION AND CLINICAL DATA ................................................................................... 11 
4.1. 
NAME AND DESCRIPTION OF INVESTIGATIONAL AGENT ......................................................................................... 15 
4.2. 
PRE-CLINICAL DATA ON KETOROLAC ................................................................................................................. 16 
4.3. 
PRE-CLINICAL DATA ON METOCLOPRAMIDE ....................................................................................................... 16 
4.4. 
PRE-CLINICAL DATA ON THE REN DEVICE .......................................................................................................... 16 
4.5. 
KNOWN RISKS AND BENEFITS OF KETOROLAC TO HUMAN PARTICIPANTS .................................................................. 16 
4.6. 
KNOWN RISKS AND BENEFITS OF METOCLOPRAMIDE TO HUMAN PARTICIPANTS ........................................................ 17 
4.7. 
KNOWN RISKS AND BENEFITS OF THE REN DEVICE TO HUMAN PARTICIPANTS ........................................................... 17 
4.8. 
DESCRIPTION AND RATIONALE FOR DOSE, ROUTE OF ADMINISTRATION, AND SINGLE ADMINISTRATION OF KETOROLAC FOR 
THIS INDICATION .......................................................................................................................................................... 17 
4.9. 
DESCRIPTION AND RATIONALE FOR DOSE, ROUTE OF ADMINISTRATION, AND SINGLE ADMINISTRATION OF 
METOCLOPRAMIDE FOR THIS INDICATION ......................................................................................................................... 18 
4.10. 
DESCRIPTION AND RATIONALE FOR USAGE AND SINGLE ADMINISTRATION OF THE REN DEVICE FOR THIS INDICATION ........ 18 
4.11. 
CONDUCT OF THE TRIAL .................................................................................................................................. 18 
5. 
TRIAL OBJECTIVES AND PURPOSE ............................................................................................................... 18 
5.1. 
OBJECTIVES .................................................................................................................................................. 18 
5.2. 
PRIMARY RESEARCH QUESTION ........................................................................................................................ 18 
5.3. 
SECONDARY RESEARCH QUESTIONS ................................................................................................................... 19 
5.3.1. 
Recruitment Rate ................................................................................................................................. 19 
5.3.2. 
Secondary Feasibility Measures ........................................................................................................... 19 
5.3.3. 
Acceptability ........................................................................................................................................ 19 
5.3.4. 
Efficacy ................................................................................................................................................. 19 
5.3.5. 
Safety ................................................................................................................................................... 20 
5.4. 
HYPOTHESIS ................................................................................................................................................. 20 
6. 
ELIGIBILITY CRITERIA................................................................................................................................... 20 
6.1. 
INCLUSION CRITERIA ....................................................................................................................................... 20 
6.2. 
EXCLUSION CRITERIA ...................................................................................................................................... 21 
7. 
STUDY DESIGN ............................................................................................................................................ 21 
7.1. 
DESCRIPTION ................................................................................................................................................ 21 
7.2. 
DESCRIPTION OF STUDY STAGES ....................................................................................................................... 22 
7.3. 
SCREENING ................................................................................................................................................... 23 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
Page 5 of 61 
7.4. 
RANDOMIZATION .......................................................................................................................................... 24 
7.5. 
BASELINE ASSESSMENT ................................................................................................................................... 25 
7.6. 
STUDY INTERVENTION ADMINISTRATION AND EFFICACY ASSESSMENTS ..................................................................... 25 
7.7. 
FOLLOW-UP ................................................................................................................................................. 26 
7.8. 
CHART REVIEW ............................................................................................................................................. 27 
7.9. 
STUDY ENDPOINTS ......................................................................................................................................... 27 
7.9.1. 
Primary Outcome ................................................................................................................................. 27 
7.9.2. 
Secondary Outcomes ........................................................................................................................... 27 
7.10. 
STUDY DESIGN AND PROTOCOL ........................................................................................................................ 28 
7.11. 
MEASURES ................................................................................................................................................... 33 
8. 
EXPECTED DURATION OF PARTICIPANT PARTICIPATION ............................................................................. 35 
9. 
STUDY MEDICATION ................................................................................................................................... 35 
9.1. 
STUDY MEDICATION DESCRIPTION .................................................................................................................... 35 
9.2. 
PLACEBO DESCRIPTION ................................................................................................................................... 35 
9.3. 
ACCOUNTABILITY PROCEDURES AND STORING ..................................................................................................... 36 
9.4. 
MONITORING FOR PARTICIPANT COMPLIANCE..................................................................................................... 38 
10. 
STATISTICAL PROCEDURES .......................................................................................................................... 39 
10.1. 
SAMPLE SIZE ................................................................................................................................................. 39 
10.2. 
OUTCOME ANALYSIS PLAN .............................................................................................................................. 39 
10.3. 
SEX AND GENDER ANALYSES ............................................................................................................................ 39 
10.4. 
RACE, INDIGENOUS, AND VISIBLE MINORITY ANALYSES ......................................................................................... 40 
10.5. 
SAMPLE SIZE ANALYSES .................................................................................................................................. 40 
11. 
SAFETY AND ADVERSE EVENTS ................................................................................................................... 40 
11.1. 
SAFETY ASSESSMENTS OF KETOROLAC ............................................................................................................... 40 
11.2. 
SAFETY ASSESSMENTS OF METOCLOPRAMIDE ..................................................................................................... 41 
11.3. 
SAFETY ASSESSMENTS OF THE REN DEVICE ........................................................................................................ 41 
11.4. 
METHODS AND TIMING OF SAFETY ASSESSMENTS AND FOLLOW-UP ........................................................................ 42 
11.5. 
DEFINITIONS PERTAINING TO ADVERSE EVENTS ................................................................................................... 43 
11.6. 
RECORDING AND REPORTING OF ADVERSE EVENTS ............................................................................................... 45 
11.7. 
TREATMENT DISCONTINUATION ....................................................................................................................... 47 
11.8. 
PREMATURE STUDY DISCONTINUATION FOR INDIVIDUAL PARTICIPANTS.................................................................... 47 
11.9. 
PROTOCOL DEVIATIONS AND VIOLATIONS ........................................................................................................... 47 
12. 
DATA HANDLING AND RECORD KEEPING .................................................................................................... 48 
12.1. 
DATA COLLECTION ......................................................................................................................................... 48 
12.2. 
CONFIDENTIALITY .......................................................................................................................................... 48 
12.3. 
RECORD RETENTION ....................................................................................................................................... 48 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE........................................................................................... 49 
13.1. 
STUDY MONITORING PLAN .............................................................................................................................. 49 
13.2. 
SAFETY MONITOR .......................................................................................................................................... 50 
13.3. 
ETHICAL CONSIDERATIONS............................................................................................................................... 50 
13.3.1. 
General Principles............................................................................................................................ 50 
13.3.2. 
Clinical Equipoise ............................................................................................................................. 51 
13.3.3. 
Informed Consent ............................................................................................................................ 51 
13.3.4. 
Privacy and Confidentiality ............................................................................................................. 52 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
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14. 
BUDGET AND FINANCE ............................................................................................................................... 52 
15. 
PUBLICATION PLAN .................................................................................................................................... 53 
16. 
KNOWLEDGE TRANSLATION PLAN .............................................................................................................. 53 
16.1. 
PATIENTS AND FAMILIES ................................................................................................................................. 53 
16.2. 
RESEARCH COMMUNITY AND HEALTH CARE PROFESSIONALS ................................................................................... 54 
17. 
REFERENCES ............................................................................................................................................... 54 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
Page 7 of 61 
1. General Information 
1.1. Name and Address of Sponsor 
University of Calgary 
2500 University Drive NW 
Calgary, Alberta 
T2N 1N4 
1.2. Name and Address of Person Authorised to Sign Protocol and 
Amendments 
Serena Orr, MD, MSc, FRCPC 
Pediatric Neurologist 
Alberta Children’s Hospital 
28 Oki Drive NW 
Calgary, Alberta 
T3B 6A8 
Phone: (403)955-7728/(403)955-7816 
1.3. Name and Address of the Study’s Medical Expert 
Serena Orr, MD, MSc, FRCPC 
Pediatric Neurologist 
Alberta Children’s Hospital 
28 Oki Drive NW 
Calgary, Alberta 
T3B 6A8 
Phone: (403)955-7728/(403)955-7816 
1.4. Name and Title of Investigators Responsible for the Trial and the Address 
and Telephone Numbers for the Trial Site 
Serena Orr, MD, MSc, FRCPC 
Primary Investigator 
Pediatric Neurologist 
Alberta Children’s Hospital 
28 Oki Drive NW 
Calgary, Alberta 
T3B 6A8 
Phone: (403)955-7728/(403)955-7816 
1.5. Name and Address of the Qualified Physician who is Responsible for 
Trial-Related Medical Decisions 
Serena Orr, MD, MSc, FRCPC 
Pediatric Neurologist 
Alberta Children’s Hospital 
28 Oki Drive NW 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
Page 8 of 61 
Calgary, Alberta 
T3B 6A8 
Phone: (403)955-7728/(403)955-7816 
1.6. Name and Address of the Clinical Laboratory and Research Pharmacy 
Involved in the Trial 
Pharmacy Research Services – Calgary Zone 
TRW Building, 5th Floor, Room 5D40 
3280 Hospital Drive NW 
Calgary, Alberta 
T2N 4Z6 
 
 
Investigator Agreement 
 
 
By signing below, I confirm that I have read this protocol and agree to conduct this study in 
accordance with the procedures described in this protocol, with Good Clinical Practice and 
Health Canada Food & Drug Act, Part C, Division 5 of the Regulations: Drugs Trials 
Involving Human participants 
 
Name of Principal Investigator (Print):  Serena L. Orr, MD, MSc, FRCPC 
 
 
Signature of Principal Investigator ___________________________________ 
 
 
 
 
 
 
       Date:  February 10th, 2023 
 
 
Site Address 
 
Alberta Children’s Hospital 
28 Oki Drive NW 
Calgary, Alberta 
T3B 6A8 
 
 
 
 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
Page 9 of 61 
2. Abbreviations 
ACH - Alberta Children’s Hospital 
 
ADR – Adverse Drug Reaction 
 
AE - Adverse event 
 
CRF - Case report form 
 
CHREB - Conjoint Health Research Ethics Board 
 
ED - Emergency Department 
 
KT – Knowledge Translation 
 
NSAID - Non-Steroidal Anti-Inflammatory Drug 
 
RCT - Randomized Controlled Trial 
 
REDCap - Research Electronic Data Capture 
 
REN - Remote Electrical Neuromodulation 
 
RRN – Research Registered Nurse 
 
SOP - Standard Operating Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
Page 10 of 61 
3. Study Summary 
Title 
A pilot clinical trial of a new neuromodulation device for acute 
attacks of migraine in children and adolescents visiting the 
emergency department 
Short Title 
A pilot clinical trial of a new neuromodulation device for acute 
attacks of migraine in children and adolescents 
Protocol Number 
N/A 
Phase 
 
Methodology 
Randomized, double-dummy, crossover randomized controlled 
trial 
Study Duration 
2 years 
Study Center(s) 
Single center: Alberta Children’s Hospital Emergency Department 
Objectives 
To determine the feasibility, efficacy, and safety of treating 
children and adolescents reporting to the ED and suffering from an 
acute migraine attack with a remote electrical neuromodulation 
(REN) device in comparison to the standard of care emergency 
department migraine treatment (a combination of ketorolac and 
metoclopramide). The primary scientific objective is to determine 
if use of the REN device is feasible and acceptable in treating acute 
migraine attacks in the ED. If this objective is achieved, design of a 
fully-powered, phase 3 randomized controlled trial (RCT) will be 
implemented. 
Number of 
Participants 
40 
Diagnosis and 
Main Inclusion 
Criteria 
Children and adolescents suffering from an acute migraine attack 
and reporting to the emergency department at the Alberta 
Children’s Hospital (ACH) 
Study Product, 
Dose, Route, 
Regimen 
Ketorolac (0.5 mg/kg, maximum 30 mg) 
Metoclopramide (0.15 mg/kg, maximum 10mg) 
REN device (modulated symmetrical biphasic square electrical 
pulse, modulated frequency of 100-120 Hz, pulse width of 400 µs, 
maximum of 40 mA) 
Duration of 
administration 
Single dose of ketorolac and metoclopramide in the emergency 
department. 
Single, 45-minute stimulation session with REN stimulation or 
sham stimulation in the emergency department. 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
Page 11 of 61 
Reference therapy
Normal saline placebo (0.9% sodium chloride, volume matched to 
that given to participants receiving ketorolac and metoclopramide)
and sham REN stimulation 
Sham REN device (modulated symmetrical biphasic square 
electrical pulse, modulated frequency of ~0.083 Hz and a 
modulated pulse width of 40-550 µs) 
Statistical 
Methodology 
The primary outcome pertains to the recruitment rate for the 
duration of the study, which will be reported as the number of 
participants recruited/month. Our feasibility and acceptability 
outcomes will be summarized using appropriate descriptive 
statistics across both groups. For secondary efficacy outcomes, Chi 
square tests will be used to examine the association between each 
dichotomized outcome and treatment group. Adverse events will 
be presented descriptively in tabular form, with the frequency and 
percentage of each adverse event listed by the corresponding 
group. 
 
4. Background Information and Clinical Data 
Migraine in children and adolescents is a major public health problem. Migraine is a 
neurological disease characterized by severe and recurrent headaches.1 It is the second 
most prevalent and disabling disease worldwide2 affecting 1 in 10 children and adolescents 
(>800,000 in Canada).3,4 At least 1/3 of migraine cases present in childhood or 
adolescence5 and at least half persist into adulthood.6–10 Migraine is considerably more 
prevalent3 and resistant to preventive treatment in females,11 though there is no sex 
difference in acute treatment response.12 Unfortunately, migraine is one of the best 
examples of gender disparity in the allocation of research funds; it is one of the most 
underfunded chronic diseases and it is dominant in women.13 The public health 
implications of migraine across the lifespan are enormous and include massive health care 
costs, loss of productivity at school and work, and impaired social functioning.14–17 
Compared to peers, children and adolescents with migraine experience higher rates of 
school absenteeism,18–22 poorer academic performance,23,24 fewer friendships,25 and high 
disability in the home18–22 and extra-curricular spheres.18–22 Children and adolescents with 
migraine often present to the ED with acute attacks, where migraine accounts for up to 
~30% of all pediatric ED visits for headache.26 In Alberta, this translates to ~2,500 annual 
pediatric ED visits (Alberta Health Services data). Extrapolating expenditures from the US27 
to the Canadian context, the incremental cost of migraine in the pediatric ED would exceed 
CAD$ 100 million per year. Unsuccessful treatment of acute attacks of migraine in the ED 
may result in hospitalization, which costs ~USD$ 2,000 per day and has an average length 
of stay of 3.7 days.28 Acute attacks of migraine are also severely disabling, as illustrated by 
these quotes from our qualitative study,29 in which children, adolescents and their families 
were interviewed about their perspectives on recent ED visits:  


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
Page 12 of 61 
 
 
 
Children and adolescents need better treatments for refractory acute attacks of migraine. 
Patients, families, and health professionals from across Canada recently identified the need 
for better treatments to manage acute pain flares, such as acute attacks of migraine, as a 
top 10 research priority for Canadian pediatric chronic pain research30 and for Canadian 
pediatric emergency medicine research.31 Access to effective acute treatment options is of 
paramount importance; ineffective acute treatment leads to prolonged pain exposure, 
which has the biological underpinnings of central and peripheral sensitization and 
increases the risk of chronic migraine32 (i.e., >15 headache days/month).33 However, 
despite the importance of effective acute treatments, and the cost and disability associated 
with pediatric ED visits for acute attacks of migraine, evidence for how to manage migraine 
in this setting is lacking. Only three RCTs have investigated interventions in this setting, 
and all involved IV access.34–36  The remaining studies on the management of children and 
adolescents presenting to the ED with acute attacks of migraine are limited to mostly small, 
uncontrolled, retrospective, observational studies.37 The dearth of data in this area has led 
to a substantial amount of practice variation.38 The lack of evidence-based treatment 
options may also be a factor in the continued inappropriate administration of opioids for 
children and adolescents presenting to the ED with acute attacks of migraine (up to 33% of 
these visits).38–41 Given the link between adolescent chronic pain, including migraine, and 
the opioid crisis, improving treatment options in the ED has major public health 
implications.42,43  
 
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).12,44–47 This combination of interventions is largely considered to 
be standard of care,26,38 despite no rigorous evidence to support this practice.37 Moreover, 
the reliance on IV interventions contradicts the preferences of a large proportion of 
patients: in a prior study, when we questioned children and adolescents with recent ED 
visits for migraine about their intervention preferences, approximately 50% expressed 
concern about IV interventions, with most of their concerns focused on IV-related pain.29 
The insertion of an IV requires a needle poke, which is known to be the most painful non-
surgical procedure that children and adolescents experience in hospital.48,49 Additionally, 
side effect rates with the neuroleptics (metoclopramide or prochlorperazine) are 
considerable, with up to 1/3 of patients experiencing extrapyramidal side effects including 
akathisia, which is an unpleasant movement disorder associated with restlessness and 
mental distress.50–52 Furthermore, IV catheters themselves are associated with high 
“It was just really really bad and we didn’t know what else to do, because we’d already used 
Tylenol, naproxen and sleep, but it wasn’t getting any better ” – Child with migraine29 
“It was debilitating in the sense that she was crying; she couldn’t function anymore. It was just 
one of those things that, that particular moment on Monday morning, she just collapsed into 
my arms and said: Mummy, I can’t do it” – Parent of a child with migraine29 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
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adverse event and failure rates in children and adolescents.53 There are also substantial 
material and personnel costs associated with IV insertions and infusions.54 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 pain, significant and 
frequent side effects, and costs. 
 
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.55,56 Children 
and adolescents with migraine are also more interested in non-invasive neuromodulation 
devices to treat refractory acute attacks of migraine than they are in IV interventions; in an 
ongoing study where we are assessing the treatment preferences of children and 
adolescents with migraine (N=65 to date), our preliminary data suggest that more patients 
are interested in neuromodulation devices (26%) than in IV interventions (9%) for treating 
acute attacks that are refractory to swallowed pills (Orr lab; unpublished). Unfortunately, 
children continue to be excluded from acute migraine RCTs; all published RCTs evaluating 
non-invasive neuromodulation devices have excluded children and adolescents.55,56 At 
present, there are 3 commercially available, non-invasive neuromodulation devices that 
effectively and safely treat acute attacks of migraine in adults.57–59 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. Given this equipoise, and our 
commitment to integrated knowledge translation (iKT) and patient engagement, we hosted 
a virtual patient engagement session on December 12th, 2020 to solicit feedback from 
patients about their appraisal of the device options. During this session, we engaged with 
adolescents (N=9) with migraine or chronic daily headache from across Canada (see 
patient research partner letter of support). The participants included individuals with 
disabilities, with diverse sexual orientations and gender identities, as well as racialized 
individuals. We presented the 3 device options to the group, along with plain language 
explanations of how they work, and the available safety and efficacy data from the adult 
literature. The majority (6/9) of the adolescents expressed a preference for trying the non-
invasive NerivioTM remote electrical neuromodulation (REN) device to treat an acute attack 
in the ED (Orr lab; unpublished). The adolescents were enthusiastic about a study that aims 
to investigate the REN device for the treatment of acute attacks of migraine in the ED, as 
illustrated by these quotes: 
 
 
“The Nerivio seemed appealing to me because of the fact that it’s just like on your arm, like I feel I 
could move around a lot (…) as someone who is not particularly affected by needles, it still seems 
more appealing to me to have a device that just feels less invasive cuz then I can move around more” 
“For me, I would rather come in and get the Nerivio on its own… I don’t like the drug kind of stuff” 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
Page 14 of 61 
 
We also presented this protocol to a large group of emergency medicine physicians and 
researchers on February 3rd 2021, at the Pediatric Emergency Research Canada (PERC) 
annual meeting. PERC is a well-established, highly productive, and award-winning national 
network of Canadian pediatric emergency medicine researchers with a track record of 
supporting successful multicenter phase III trials.60 All meeting participants polled (N=44) 
indicated that they would use the REN device to treat children and adolescents with acute 
attacks of migraine in the ED if supportive evidence was available. 
 
REN has a scientifically established mechanism of action and promising clinical data. REN 
stimulates C and Aδ nociceptive sensory nerves below their perceived pain thresholds, but 
above their depolarization thresholds, to induce a conditioned pain modulation response in 
the brain.57 Conditioned pain modulation is a well-established endogenous analgesic 
mechanism that activates descending brain pathways that facilitate pain inhibitory 
effects.61 By activating nociceptive sensory nerves in the arm, the REN device activates 
ascending spinothalamic pain pathways with collaterals in the brainstem, which 
concurrently activate descending brainstem pain inhibitory pathways. Ultimately, the 
activation of descending pain inhibitory pathways modulates incoming pain signals in the 
trigeminal nucleus caudalis arising from the acute attack of migraine, leading to an 
analgesic effect (see Figure 1).  
 
 
Figure 1. Schematic of the mechanism of action of REN58 
 
Data from a phase III RCT have established the efficacy and safety of REN for the treatment 
of acute attacks of migraine in adults.57 In this trial (N=252), 66.7% of participants 
randomized to REN achieved pain relief at 2 hours, as compared to 38.8% of participants in 
the sham stimulation group. Adverse events did not differ between the groups (15.1% of 
REN group vs. 11.9% of sham group p=0.581), only 2.7% had device-related adverse 
events, and no serious adverse events occurred.57 In addition, comparison of data from the 
run-in phase whereby trial participants treated acute attacks with their usual care (i.e. at 
home oral medications), and data from the clinical trial period, showed that REN was more 
effective than usual care.62 REN also appears to substantially reduce medication use, with 
89.7% of the trial participants treating their attacks with REN alone in the open label 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
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extension period.63 In addition, a recently published open-label trial among 60 adolescents 
treating acute attacks of migraine in the home setting suggests that REN is safe and 
effective for use in adolescents.64 Pain relief was achieved in 71% of participants at 2 hours. 
Importantly, only one participant (2.2%) experienced a device-related adverse event 
(transient pain in the arm), and no serious adverse events were reported. Further, the cost 
of REN is very low: each NerivioTM REN device costs the equivalent of CAD$ 120 and 
provides 12 stimulation sessions (~ CAD$ 10/stimulation), making it a cost-effective 
option. While the FDA has recently approved use of the REN device for managing acute 
attacks of migraine in adolescents and adults based on this data, there is no current Health 
Canada indication for this device.  
 
Based on this promising data, we believe that a trial evaluating REN in children and 
adolescents seeking ED care for refractory acute attacks of migraine has the potential to 
dramatically improve outcomes and patient experience. We propose a pilot RCT (N=40) 
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. 
4.1. Name and Description of Investigational Agent 
This study will examine the safety and efficacy of using the REN device, as compared to 
standard of care IV treatment with ketorolac and metoclopramide, to treat acute migraine 
attacks in children and adolescents reporting to the ED. 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. Ketorolac is a non-steroidal, anti-inflammatory medication indicated 
for acute pain management. Metoclopramide is a neuroleptic, benzamide-derived 
medication indicated for a variety of uses, such as a vomiting prophylactic. 
 
Patients randomised to the REN group will receive 45 minutes of stimulation from the REN 
device (modulated frequency of 100-120 Hz and a pulse width of 400 µs) and will also 
receive normal saline though an IV. Patients randomised to the standard of care IV group 
will receive stimulation from a sham 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 an 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. 
Should participants not achieve enough pain relief to feel ready for discharge without 
further intervention at 2-hours post-intervention, then they will be crossed over to the 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
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other treatment arm. This change to the protocol is being made after feedback from 
participants and potential participants about being concerned that should they be 
randomized to one arm, then they would not be eligible to receive the alternate treatment 
during their ED visit. Specifically, patients have expressed concerns they will not be able to 
receive the first-line standard of care treatment (ketorolac and metoclopramide) during 
their ED visit should they initially receive the active REN device and placebo IV 
medications. 
4.2. Pre-Clinical Data on Ketorolac 
Ketorolac is a cyclooxygenase-1 and cyclooxygenase-2 (COX-1/COX-2) inhibitor, a sub-class 
of NSAIDs designed to inhibit production of prostanoids, prostaglandins, and 
thromboxanes, which play key roles in inflammatory cascades in the body and in 
nociception. Limiting the release of these chemicals thereby limits activation of nociceptive 
neurons.65 Ketorolac selectively inhibits COX-2 to limit pain and inflammation, as inhibition 
of COX-1 can result in gastrointestinal ulcers and bleeding. However, cardiovascular-
related adverse event may be more common due to selective inhibition of COX-2.66 
4.3. Pre-Clinical Data on Metoclopramide 
Metoclopramide is a neuroleptic which acts as a dopamine antagonist; it is believed to 
block dopaminergic D-2 receptors, and can help to treat nausea and vomiting, and increase 
the absorption rate of other medications.67 According to the product monograph, 
metoclopramide has been shown to induce catalepsy, elevate levels of plasma renin, 
prolactin, and aldosterone, increase dopamine turnover in the mesolimbic and striatal 
structures, and to antagonise apomorphine-induced stereotyped behaviours in rat models. 
Parenteral administration of metoclopramide has also been shown to decrease striatal 
acetylcholine levels in rat models. In other animal models, metoclopramide has been 
shown to modulate gastrointestinal motility by magnifying resting muscle tension and 
increasing the intensity of peristaltic movements. In vitro, metoclopramide influences the 
release of 3H-acetylcholine in striatal structures. 
4.4. Pre-Clinical Data on the REN Device 
The REN device modulates the pain response in the brain using conditioned pain 
modulation to trigger an analgesic effect. This mechanism is achieved by electrically 
stimulating the C and Aδ nociceptive sensory nerves in the upper arm, just below the 
perceived pain threshold and above the depolarization threshold. Precise activation of 
these sensory nerves further triggers ascending pain pathways within the spinothalamic 
tract and brain stem. These pathways further activate descending pain inhibitory pathways 
within the brain stem to modulate incoming pain signals and produce an analgesic 
effect.57,68 
4.5. Known Risks and Benefits of Ketorolac to Human Participants 
Many of the established side effects for ketorolac are related to chronic use rather than 
single doses. The product monograph for ketorolac provides a comprehensive list of 
possible side effects, including sweating, dizziness, nausea, vomiting, or pain at the 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
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injection site. Rare and serious side effects that are possible include the development of 
stomach ulcers, bladder inflammation, a decrease in red or white blood cells, or allergic 
reactions (see product monograph in Appendix A). These rare and serious side effects 
typically only occur after prolonged usage and are exceptionally uncommon after receiving 
a single dose; we found no cases of any of these rare and serious adverse events after single 
use doses in children and adolescents with migraine.12,44–47 
4.6. Known Risks and Benefits of Metoclopramide to Human Participants 
The common side effects associated with metoclopramide may include drowsiness, 
dizziness, difficulty sleeping, bowel and stomach issues, and akathisia (physical and mental 
restlessness). Rare and serious side effects that are possible include Parkinsonian-like 
symptoms involving involuntary muscle and limb movements, and neuroleptic malignant 
syndrome which involves muscle rigidity, altered consciousness, and instability in 
heartbeat and blood pressure (see product monograph in Appendix B). Cardiac-related 
adverse events in healthy individuals are uncommon after a single dose or intermittent 
doses.66  
4.7. Known Risks and Benefits of the REN device to Human Participants 
The most common side effects associated with the REN device include feelings of warmth, 
redness, or pain in the arm. The less common side effects include numbness, itching, or 
tingling in the arm or hand, neck and shoulder pain, or muscle spasms. None of the current 
studies examining the REN device reported any serious device-related adverse events, and 
they reported very low (<5%) rates of moderate and less severe device-related adverse 
events. In addition, in the published studies using REN, there were very low rates of study 
withdrawal due to device-related adverse events.57,62,64,68,69  
4.8. Description and Rationale for Dose, Route of Administration, and Single 
Administration of Ketorolac for this Indication 
The dose of ketorolac that we have chosen (0.5mg/kg, maximum 30mg) is based on 
previous adult and pediatric migraine literature, where a dose of 0.5 mg/kg, up to a 
maximum of 10 mg to 40 mg, has been most commonly used.35,44,47,51,70–74 Our chosen 
dosage is also in line with the Alberta Children’s Hospital (ACH) emergency department 
protocol for treating acute attacks of migraine, which is considered to be local standard of 
care since it was released in 2021 (developed by Dr. Orr and emergency physician Dr. Joe 
MacLellan; Appendix C). Using IV as the route of administration was chosen to be 
consistent with procedures typically followed in the ED as per published studies47,70,71 and 
as per the current ACH ED protocol. The pharmacokinetic properties of ketorolac support 
administration of a single dose to treat an acute migraine attack. Ketorolac is rapidly 
absorbed (maximum absorption in less than 1 hour) with a typical half-life of 
approximately 5 hours.66 Single dose use is also safer; frequent administration of ketorolac 
(over 5-7 days) is also considered unsafe due to an increased risk of adverse events.66 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
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4.9. Description and Rationale for Dose, Route of Administration, and Single 
Administration of Metoclopramide for this Indication 
We chose our dose of metoclopramide (0.15 mg/kg, maximum 10mg) based on prior adult 
and pediatric migraine research44,70,73,74 which typically administered 0.1-0.2 mg/kg, up to 
a maximum of between 10 mg and 20 mg. The dosage we are proposing is also identical to 
the dosage used in the ACH emergency department migraine protocol. Administration of 
metoclopramide through an IV was chosen to be consistent with procedures followed in 
the ED.44,70,73,74 Single doses of metoclopramide have been shown to help relieve nausea 
and vomiting associated with acute attacks of migraine, and can also improve the 
absorption rate of other medications when administered concurrently.66 
4.10. Description and Rationale for Usage and Single Administration of the 
REN device for this Indication 
Using the REN device for a single, 45-minute session of electrical stimulation (modulated 
symmetrical biphasic square electrical pulse, modulated frequency of 100-120 Hz, pulse 
width of 400 µs, maximum of 40 mA) administered to the sensory nerves of the upper arm 
was chosen to comply with the manufacturers recommended usage, and in accordance 
with other REN device studies for the treatment of migraine.57,62,64,68,69 
4.11. Conduct of the Trial 
The trial will be conducted in compliance with the protocol submitted to the Conjoint 
Health Research Ethics Board (CHREB). It will follow the International Conference on 
Harmonization Good Clinical Practice standards75 as described in the protocol. Any 
protocol deviation will only be implemented after approval from the CHREB, except for 
situations where immediate implementation of a protocol deviation is necessary to protect 
the trial participants from hazards or where the protocol deviation is logistic or 
administrative in nature, in which case the CHREB will be notified as soon as possible.  
5. Trial Objectives and Purpose 
5.1. Objectives 
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. 
5.2. Primary Research Question 
1) Will a pilot double-dummy crossover RCT that compares remote electrical 
neuromodulation (REN) to standard of care IV interventions (metoclopramide + 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
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ketorolac) for the treatment of acute attacks of migraine in children and 
adolescents (N=40) presenting to the ED be feasible and acceptable? 
5.3. Secondary Research Questions 
5.3.1. Recruitment Rate 
The recruitment rate will be determined by taking a count of the number of participants 
recruited per month. Our target average is to recruit 1.5 participants per month. 
 
5.3.2. Secondary Feasibility Measures 
1) We will determine the proportion of participants who complete all measures for 
all follow-up time points. Our goal is to have 80% of participants complete all 
measures at each time point. 
2) We will determine the proportion of eligible participants who are enrolled in the 
primary study (i.e., the study pertaining to ED treatment), relative to the total 
number of eligible participants who are approached in the ED. We aim to recruit 
50% of the total number of eligible participants that are approached in the ED.  
3) We will determine the proportion of participants who are enrolled in the study, 
relative to the total number of participants that are approached about the study in 
the ED. We aim to recruit 10% of individuals who are approached about the study. 
5.3.3. Acceptability 
1) We will determine the proportion of participants who report a “good” or “very 
good” global impression of change. This will be measured using a 7-point Likert 
scale, as recommended by the International Headache Society guidelines.76 Our 
goal is to have 70% of participants reporting a “very much improved” or “much 
improved” global evaluation of treatment. 
2) We will record feedback provided by participants on study acceptability for both 
the primary and secondary study. Our goal is to have most participants report that 
the study protocol is acceptable, as measured through specific questions at the 48-
hour follow-up. 
3) We will assess qualitative feedback provided by the ED staff, which will be 
collected by RRNs after completion of the 120-minute follow-up assessment. This 
feedback will be collected from the treating ED nurse and physician. Our goal is to 
have ED staff feedback centered on finding the study protocol acceptable. 
5.3.4. Efficacy 
1) We will determine the proportion of participants who are pain free at: 1) 60 and 
120 minutes (or at discharge if before 120 minutes) post-treatment in the ED (for 
both the initial assigned intervention and the crossover intervention where 
applicable). 
2) We will determine the proportion of participants with sustained pain freedom 
after ED treatment. This will be measured according to which participants achieve 
pain freedom by the 120-minute time point (or at discharge if before 120 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
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minutes) and maintain pain freedom until the 48-hour follow-up (for both the 
initial assigned intervention and the crossover intervention where applicable). 
3) We will determine the proportion of participants who achieve headache relief at 
each time point in the ED (60 and 120 minutes post-treatment, or at discharge if 
before 120 minutes). We will examine these outcomes for both the initial assigned 
intervention and the crossover intervention where applicable. This outcome will 
be defined as those participants who experience a pain reduction from “severe” or 
“moderate” severity down to a “mild” or “no pain” severity, or those participants 
who experience a pain reduction from “mild” to “no pain” severity. This will be 
assessed using the 4-point pain severity scale. 
4) We will determine the proportion of participants who are discharged from the ED 
and require no further intervention after both the initial assigned intervention 
and the crossover intervention where applicable. 
5.3.5. Safety 
1) We will determine the proportion of participants who report any adverse events. 
Adverse events will be assessed both in the ED as well as at the 48-hour follow-up.  
2) We will determine the proportion of participants who report any serious adverse 
events. Serious adverse events will be assessed both in the ED as well as at the 48-
hour follow-up.  
5.4. Hypothesis 
Based on the goals and research questions described above, we hypothesize that: 
 
1) The study design will be feasible, achieving a recruitment rate similar to previous 
studies (~20 participants per year). This will allow for the pilot study to be scaled 
up to a fully powered, multicenter, phase III RCT where larger recruitment rates 
will be achievable and comparable to previous migraine treatment device trials 
(~120-250 participants, based on the non-inferiority margin and primary 
outcome). 
2) The study design and the use of the REN device will be acceptable, as evidenced by 
quantitative and qualitative feedback from both participants and ED stakeholders. 
3) We will not have the power to fully assess the safety and efficacy of the REN 
device, but preliminary data will be used to inform appropriate sample size and 
study design for a fully powered RCT. 
6. Eligibility Criteria 
6.1. Inclusion Criteria 
Patients aged 8-18 years visiting the Alberta Children’s Hospital (ACH) ED with an acute 
attack of migraine as per criteria B-E of the International Classification of Headache 
Disorders-3 criteria (ICHD-3):33  


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and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
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A. Headache attacks lasting at least 2 hours (untreated or unsuccessfully treated)2;3 
B. Headache has at least two of the following four characteristics: 
a. Unilateral, bilateral, or frontotemporal location 
b. pulsating quality 
c. moderate or severe pain intensity 
d. aggravation by or causing avoidance of routine physical activity (eg, walking 
or climbing stairs) 
C. Also has least one of the following: 
a. nausea and/or vomiting 
b. photophobia and phonophobia 
D. 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.77,78 
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. 
6.2. 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. 
 
For the pregnancy question, the screening research nurse will ask potential participants if 
they have reached menarche (had their first menstrual period). If they answer yes, then the 
parent(s)/guardian(s) will be asked to leave the room, and the potential participant will be 
directly asked if there is any potential that they are pregnant or lactating.  
7. Study Design 
7.1. Description 
The proposed primary study will be a pilot RCT and will be designed as a randomized, 
double-dummy crossover study. Blinding will be maintained for the participant and the 
investigators throughout the study. The initial study design was a pilot parallel-group 
double-dummy study. However, as of February 10th, 2023, we have recruited at a rate of 1.0 
participants/month vs. our target of 1.5 participants/month and we are below our 50% 
target for the proportion of eligible who enroll, at ~32%. Following feedback from 
participants and potential participants, we are proposing a study design change from a 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
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parallel-group randomized controlled trial to a crossover trial; this change is being made to 
address participant/potential participant concerns expressed around the initial parallel-
group design that precludes participants from receiving the non-assigned active 
intervention should the initial assigned intervention be ineffective. Specifically, patients 
have expressed concerns they will not be able to receive the first-line standard of care 
treatment (ketorolac and metoclopramide) during their ED visit should they initially 
receive the active REN device and placebo IV medications. Transitioning to a crossover trial 
will help to address these concerns and reflect a more patient-centered design. 
 
7.2. Description of Study Stages 
Forty children and adolescents will be recruited into the study from the ACH ED. 
Outpatients in Dr. Orr's neurology clinic may also receive information about the study in 
clinic in anticipation of possible future ED visits. Patients in clinic who verbally consent to 
receiving information about the study would have the study verbally described to them by 
either Dr. Orr or her RA, and the participant would have the option of taking a copy of the 
study brochure and study treatment summary documents home if they are interested. 
Upon arrival to the ED, potential participants (whether they are known to Dr. Orr as 
outpatients or not) will be triaged as per standard of care.  Potential participants (i.e., those 
with a triage complaint of headache or migraine) will be asked by an agent of Alberta 
Health Services if they are willing to be approached regarding a research study. Potential 
participants who agree to hear about the study will then be approached by an ED-based 
research nurse who will seek verbal consent from the participant to be screened for the 
study. Demographic information will be recorded from each patient who provides verbal 
consent for screening, and this data will include sex, age, CTAS score, and date and time of 
triage). Written consent for the study will then be obtained by the research nurse after the 
patient has been screened for eligibility. Each participant will be enrolled in the study for 
approximately 48 hours, although each participant will only be assessed during their ED 
visit (duration is expected to be no more than 5 hours), and during a 48-hour follow-up 
after they have been discharged from the ED. The smartphone application used to control 
the REN device does collect de-identified data from the user, including treatment and 
symptom descriptions, actions performed within the application, and device information. 
This information is collected by the smartphone application and sent to the device 
manufacturer, Theranica Bio-Electronics Ltd. Instructions on how to use the device, the full 
End User License Agreement (EULA), and questions asked by the application can be found 
in Appendices D-H.  
 
We expect each participant to be actively involved in the study for 2 to 5 hours in the ED 
(depending on whether or not they cross over), and for 48 hours post-intervention. Should 
they enter the crossover phase, their engagement time in the ED will be 4 to 5 hours. 
Assessments in the ED will either be completed electronically by the participant (with or 
without assistance from their parent and/or guardian if needed) or by the ED Research 


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Nurse, and the 48-hour follow-up will either be completed electronically or through a 
telephone call, whatever is most convenient for the participant.  
 
Figure 2.  Study Flow Diagram 
7.3. Screening 
Patients presenting to the ACH ED with a triage complaint of migraine, headache, head 
pain, or symptoms in keeping with migraine aura will first be approached by an agent of 
Alberta Health Services who is not associated with the research study. This individual will 
request permission for the research team member to approach regarding the proposed 
study. If the potential participant agrees to learn more about the study, they will be 
approached by an ED-based research nurse who will seek verbal consent from the 
participant to be screened for the study, as per the procedure outlined above (in 7.2). The 
research nurse will be a member of the established ACH Pediatric Emergency Research 
Team (PERT), with study recruitment happening between the hours of 08:00 and 22:00. 
Specific recruitment times will vary based on the PERT nurse schedule for any given week, 


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and adolescents visiting the emergency department 
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but generally 4 PERT nurses, at 0.5 FTE each, are available 7 days per week to cover the 
hours between 08:00 and 22:00. Eligibility assessment will occur once the patient has been 
approached by an agent of Alberta Health Services and has verbally consented to screening. 
Demographic data will be recorded from each screened potential participant including age, 
sex, Canadian Triage and Acuity Scale (CTAS) scores, date and time of triage, and reason for 
non-enrollment (if applicable). If eligible, the study procedures will be explained to the 
patient and their family, and a responsible physician will review and confirm study 
eligibility. All ED physicians will receive training on the study protocol prior to 
involvement. In addition to the process above, at enrollment, the research nurse will ask 
the participant if they would like assistance with adjusting their environment for comfort 
purposes. These accommodations are being included in the protocol because many patients 
with migraine experience sensory sensitivities such as photophobia and phonophobia. The 
participant will be asked if they would like a pair of ear plugs to help with phonosensitivity, 
and they will be asked if they would like help to adjust the lights (i.e., turn off lights in the 
room) to help with photosensitivity. For those interested in ear plugs, the research nurse 
will provide the participant with a pair of basic ear plugs that will be purchased for the 
study. Finally, a study brochure will be available for participants to review electronically 
using their smartphones or using the ED research iPads, or physically by an ED-based 
research nurse while they are in the ED (after approach as described above). This brochure 
will be made available to participants through a QR code on the consent form, by showing 
them the brochure on an ED research iPad, or they will be provided with a physical copy 
while in the ED(see Appendix I) along with  a one-page summary explaining the study 
treatments (Appendix J). 
7.4. Randomization 
Eligible and consenting participants will be randomized at a 1:1 ratio to initially receive: 
 
1) the standard of care IV treatment for migraine in the ED (a combination of 
ketorolac and metoclopramide) and a sham REN device that will not administer 
therapeutic electrical stimulation 
 
or 
 
2) the standard REN device that will administer the therapeutic electrical stimulation 
and IV fluid containing normal saline (i.e. placebo). 
 
At 120-minutes post-intervention, and if not already discharged, participants will be asked 
if they feel ready to go home without further intervention. Should they respond “yes” to 
this question at either the 60-minute or 120-minute time point, they will be discharged 
from the ED in consultation with their treating physician. Should they respond “no” to this 
question at both the 60-minute and 120-minute time points, they will be crossed over at 2 
hours to the alternate treatment arm. The randomization sequence will be prepared by a 
statistician who will have no role in the recruitment or clinical care of the participants. The 


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and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
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sequence will be sent to the pharmacy and will not be accessible to anyone involved in the 
study or care of the participant. 
 
The pharmacy will maintain a list with the randomization code and the corresponding 
treatment allocation order. Only the pharmacy will be able to link the randomization to the 
treatment allocation order. Where necessary, the ED clinical staff and study investigators 
will also be given access to this information to ensure the health and safety of the 
participant, should any adverse events requiring intervention and/or treatment 
discontinuation occur (i.e., in these cases, the clinical personnel will ask the pharmacy for 
the treatment allocation order associated with the given randomization code, which will 
allow them to unblind clinical and/or research personnel to what intervention(s) the 
participant received for participant safety and/or clinical treatment purposes). 
7.5. Baseline Assessment 
A baseline assessment will comprise additional demographics (beyond those in the 
screening questions), a headache history, and a past medical history (see Appendix K-N). 
Efficacy and safety measures will also be recorded at baseline (see Appendix L and M for 
baseline measures).  
7.6. Study Intervention Administration and Efficacy Assessments 
Following consent, screening, and baseline assessment, the initial study intervention will 
be administered. A fluid bolus, to help alleviate potential dehydration, may also be 
administered at the discretion of the attending ED physician if it is felt to be clinically 
indicated (i.e., if the patient is clinically dehydrated). Study medications will be stored in 
the access restricted ED research fridge, and one study package at a time will be stored in 
the ED research office (i.e., each package will contain an “Initial Treatment” part and a 
“Crossover Treatment” part; the “Initial Treatment” part will comprise two vials containing 
either metoclopramide and ketorolac, or normal saline and normal saline, which will be 
stored in the ED research fridge, and one device, either sham or active, which will be stored 
in the ED research office in a locked cupboard. The “Crossover Treatment” part will contain 
the alternate vials and device for crossover should it be necessary. For each package, the 
medication vials and the corresponding device will be labeled with “Initial Treatment” vs. 
“Crossover Treatment” and the given randomization code. The study intervention(s) will 
be administered by the ED research nurse. Once the study package is used, another study 
package will be ordered from research pharmacy so that the ED supply is replenished. For 
participants not requiring crossover, the “Crossover Treatment” part of the study kits will 
be sent back to Pharmacy for handling and possible reuse in the next kit if not expired. 
 
Efficacy and safety assessments will be completed by participants and administered by the 
ED research nurse at 60 and 120 minutes (or at discharge if before 120 minutes) following 
each treatment (Appendix N). We will allow for a 30-minute time window around each of 
the timed assessments in the ED to account for any small deviations regarding when the 
assessments are completed. Pain severity will be measured using the 11-point pain 
numerical rating scale, which is a well-established self-reported pain scale that has a strong 


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recommendation to use in children aged 6-18 years with acute pain based on a recent 
systematic review.79 To align with International Headache Society (IHS)76,80  and FDA 
guidelines for migraine trials,81 we will also use the 4-point pain severity scale (0=none, 
1=mild, 2=moderate, 3=severe),  and participants will be asked about their most 
bothersome migraine associated symptom for the current attack, and whether it is present 
or not. For safety, participants will be asked about adverse events, and these will be defined 
according to the Good Clinical Practice of the International Conference on Harmonization. 
Using these measures, secondary efficacy and safety outcomes will be reported, in 
accordance with the IHS76,80 and FDA guidelines.81 If participants experience nausea or 
vomiting following the study intervention, the treating physician will manage the nausea or 
vomiting at their discretion. If participants experience adverse events at any time point in 
the ED, the treating physician will manage the adverse events. If participants are 
experiencing ongoing pain that they are requesting intervention for after the initial 120-
minute assessment (following the first assigned intervention), then they will be crossed 
over to the alternate treatment arm. If participants are experiencing ongoing pain that they 
are requesting intervention for after the 60-minute post-crossover assessment, the ED 
physician will determine ongoing management at their discretion, and may administer 
additional interventions to manage the pain before the 120-minute post-crossover 
assessment. In cases where participants do receive additional pain interventions before the 
120-minute post-crossover assessment, the intervention and the timing of its delivery will 
be recorded. If participants are not feeling well enough to be discharged home after the 60-
minute post-crossover assessment, the treating physician will determine ongoing 
management at their discretion.  
7.7. Follow-Up 
Participants will be offered the option of completing their follow-up via a self-administered 
electronic questionnaire sent through Research Electronic Data Capture (REDCap), or over 
the phone with a research assistant. If they choose the option of the self-administered 
electronic questionnaire, they will receive an email with a link to the REDCap-administered 
questionnaire at 48 hours post-intervention. Should they not complete the given 
questionnaire within 12 hours, a reminder email will be sent. Should they fail to complete 
the given questionnaire within 24 hours of the reminder, the research assistant will contact 
them over the telephone for the follow-up. We will allow for 36-hour time window for data 
collection around the 48-hour outcome time point to ensure feasibility and ease of 
participation in the study. 
 
For participants selecting the option of telephone follow-up, the research assistant will call 
the patient for a follow-up telephone-administered questionnaire approximately 48 hours 
post-interventions (see Appendix O and P). In the event where it is not possible to contact a 
patient for follow-up over the telephone after several attempts, follow-up questionnaires 
will be emailed to the participant through REDCap, with 12-hour reminders as described 
above. Because some questions posed in the 48-hour follow-up pertain to participants 
rating their experience of the study and study personnel, part of the 48-hour assessment 


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and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
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will be completed electronically even where participants select the option of telephone 
follow-up. In these instances, the study research assistant who calls participants will 
complete the telephone questions, then ask participants how they would like to receive the 
remaining questions electronically (i.e., over email or via text message). 
 
When an adverse event is reported during follow-up on one of the electronic 
questionnaires, the participant may be contacted over the telephone to clarify details 
pertaining to the adverse event, where needed to clarify the nature and severity of the 
adverse event. 
 
Where clinically relevant information is reported at follow-up (e.g., occurrence of new 
concerning neurological symptoms), the research assistant will contact Dr. Orr to discuss 
the information. Dr. Orr will then decide how to proceed in handling the information and 
making a management plan for the participant where applicable. 
 
Participants who complete the 48-hour follow-up questionnaires will be sent a $20 
electronic gift card of their choice via email.  
7.8. Chart Review 
The research assistant will review the participants’ charts 7 days or later after discharge to 
record any return visits to the ED and hospital admissions. Return visits will be coded as 
either headache-related or unrelated (see Appendix Q). Charts will also be reviewed for a 
period encompassing up to 6 months after the 48-hour follow-up to record any return 
visits to the ED and hospital admissions. 
7.9. Study Endpoints 
7.9.1. Primary Outcome 
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. 
7.9.2. Secondary Outcomes 
Secondary outcomes will relate to the feasibility, acceptability, efficacy, and safety of using 
the REN device. 
 
Secondary feasibility outcomes will involve: 
 
The proportion of participants who complete all assessments at each time point 
(baseline, 60, 120 minutes or at discharge if before 120 minutes, 60 and 120 
minutes post-crossover, where applicable, and 48-hours). 


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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. 
 
The acceptability outcomes involve: 
 
The proportion of participants who report a global impression of change as “very 
much improved” or “much improved”. 
 
Participant feedback regarding study acceptability 
 
ED staff feedback provided  
 
Efficacy and safety outcomes will assess the proportion of participants who: 
 
are pain-free following the 60 and 120-minute assessments (or at discharge if 
before 120 minutes), and 60 and 120-minute post-crossover assessments after 
treatment. 
 
maintain pain-freedom following the 120-minute assessment (or at discharge if 
before 120 minutes) or the 120-minute post-crossover assessment and up to the 
48-hour follow-up after treatment. 
 
experience headache relief after treatment. 
 
are free of their most bothersome migraine-associated symptom after treatment. 
 
Receive additional interventions for pain prior to the 120-minute post-crossover 
assessment 
 
are discharged from the ED and require no further intervention after the initial 
assigned treatment or after the crossover treatment. 
 
experience adverse events. 
 
experience serious adverse events. 
7.10. Study Design and Protocol 
We propose to carry out a pilot RCT to determine the feasibility and acceptability of 
implementing a double-dummy, crossover RCT protocol. Though treatment carry-over 
effects can occur in cross-over design,76 it is standard in the literature to expect both REN 
and the IV medications (metoclopramide and ketorolac) to have had effect by 2 hours (this 
is the standard time point at which acute interventions are assessed as per international 
trial guidelines)76, and we feel that there will be adequate washout with this design without 
significant contamination from treatment carry over effects, while balancing the need for 
timely further intervention should the first intervention not provide adequate pain relief. 
We also considered the possibility of a futility design, however the lack of adequate 
historical control data82 preclude a futility design. 
 
In this pilot study, 40 children and adolescents (N=40) visiting the ED with acute attacks of 
migraine will be randomized to REN, or to standard of care IV treatment (i.e. a combination 
of metoclopramide and ketorolac), and crossed over to the alternate treatment arm if they 
have not had adequate pain relief at 2-hours post-intervention. Each group will also receive 


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and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
Page 29 of 61 
a blinded control in each phase of the trial (either normal saline through the IV for the REN 
group, or sham stimulation for the standard of care IV group). Design will adhere to 
International Headache Society76 and CONSORT83 trial guidelines. A trained ED-based 
research nurse from the established ACH Pediatric Emergency Research team (PERT) will 
assess eligibility of identified patients who are present during PERT research nursing 
hours, from 8:00 to 22:00, 7 days per week. This will occur following placement in a 
treatment room and prior to, or just following ED physician assessment. If potentially 
eligible, the study procedures will be explained to the family and the responsible physician 
will review and confirm all eligibility criteria and their support for participant recruitment. 
All ED physicians potentially enrolling patients into the study will be trained on the study 
protocol. 
 
Consenting participants will be randomized at a 1:1 ratio to either REN or standard of care 
IV treatment as their initial treatment allocation, with the option to cross over to the 
alternate treatment arm at 2-hours post-initial treatment should they not feel that they 
have had adequate pain relief. The allocation sequence will be prepared by a statistician 
with no role in recruitment or clinical care. The allocation sequence will be sent to the 
pharmacy and will not be accessible to anyone involved in the study or care. The 
pharmacist will prepare study intervention kits with two parts for each participant: the 
“Initial Treatment” part will contain either IV metoclopramide (0.15 mg/kg, maximum 10 
mg), ketorolac (0.5 mg/kg, maximum 30 mg), and a sham stimulation device, or normal 
saline placebo and REN with the NerivioTM device, and the “Crossover Treatment” part will 
contain the alternate components. Regarding preparation of study kits, each kit will contain 
six elements: four medication vials, and two devices. The pharmacist will direct transfer 
either a metoclopramide solution and a ketorolac solution into two separate vials, and will 
direct transfer normal saline into two separate vials. The pharmacist will label these vials 
with the randomization code and which part of the kit they belong to (“Initial Treatment” 
or “Crossover Treatment”). Two devices (active and sham) will also be sent with the study 
kit, labelled as to which part of the kit they correspond to (“Initial Treatment” or 
“Crossover Treatment”) and labelled with the randomization code.  
 
The REN device (Figure 3) is a wearable, battery-operated neuromodulation device that is 
applied to the arm using an armband and wirelessly controlled by a smartphone software 
application. The REN device delivers electrical stimulation to local C and Aδ nociceptive 
sensory nerves using a modulated symmetrical biphasic square pulse, with a modulated 
frequency of 100-120 Hz, a pulse width of 400 µs, and with participant-adjusted output 
current to a maximum of 40 mA. Stimulation occurs over 45 minutes.57 During stimulation, 
participants will also have the option of watching a video consisting of guided imagery, 
education about migraine, and guided relaxation, which is embedded into the device’s 
smartphone application. The REN assignment will comprise active stimulation and normal 
saline (0.9% sodium chloride solution) placebo that will appear identical in appearance 
and volume to the medications given to the comparison group. The normal saline solution 
will be transferred to vials by the research pharmacy in the same volumes as those planned 


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and adolescents visiting the emergency department 
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for the active metoclopramide and ketorolac solutions (i.e., for ketorolac 1.4 mL of normal 
saline, and for metoclopramide 2.4 mL of normal saline). The placebo ketorolac solution 
(i.e., 1.4 mL of normal saline) will be transferred from the vial to a syringe and will be 
administered to participants, in the appropriate volume to mimic the weight-based dosing 
of ketorolac (30 mg/mL solution concentration, with target dose of 0.5 mg/kg, maximum 
30 mg or 1 mL maximum), using a direct IV push. The placebo metoclopramide solution 
(i.e., 2.4 mL of normal saline) will be transferred from the vial to a 50 mL mini bag of 
normal saline and will be administered to participants, in the appropriate volume to mimic 
the weight-based dosing of metoclopramide (5 mg/mL solution concentration, with target 
dose of 0.15 mg/kg, maximum 10 mg or 2 mL maximum), over 15-30 minutes. Please see 
Table 1 for details on the interventions administered to each group. 
 
 
 
The comparison assignment will comprise 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 ketorolac (0.5 mg/kg, maximum 30 mg) and IV metoclopramide 
(0.15 mg/kg, maximum 10 mg).26,38 As per ACH ED protocols, ketorolac solution 
(concentration = 30 mg/mL) will be transferred from the vial provided by the pharmacy to 
a syringe and will be administered to participants, at the appropriate weight-based dose 
(0.5 mg/kg, maximum 30 mg or 1 mL), using a direct IV push. The ketorolac solution will 
thus be undiluted and administered over 1-5 minutes, averaging 2-3 minutes. 
Metoclopramide solution (5 mg/mL) will be transferred from the vial provided by the 
pharmacy to a 50 mL mini bag of normal saline (0.9% sodium chloride), and will be 
administered to participants, at the appropriate weight-based dose (0.15 mg/kg, maximum 
10 mg or 2 mL) over 15-30 minutes (see Table 1). IV fluid boluses are often co-
administered with these interventions,36,38 but there is no evidence that this approach is 
effective in children and adolescents, and there is evidence that IV fluid boluses are 
ineffective for the treatment of adults visiting the ED with acute attacks of migraine.84 
Therefore, we will not co-administer an IV fluid bolus in this trial, unless the treating 
physician feels that it is clinically indicated for dehydration. In this case, the treating ED 
Figure 2. The REN Device* 
*Image from: www.theranica.com


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physician will order the IV fluid bolus at their discretion. In addition, though there have 
been more data reported on the use of prochlorperazine for treating migraine in children 
and adolescents,12,44,45 it is no longer available in Canada, and metoclopramide, which is a 
neuroleptic with a similar mechanism of action, has replaced its use. The comparison 
assignment will also comprise 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 active REN device. As with the 
active stimulation assignment, during stimulation, participants in the sham stimulation 
group will also have the option of watching a video consisting of guided imagery, education 
about migraine, and guided relaxation, which is embedded into the device’s smartphone 
application. The sham stimulation parameters will mirror those from the published trial in 
adults (modulated frequency of ~ 0.083 Hz and a modulated pulse width of 40-550 µs), 
where the validity of this sham protocol was established.57 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. 
 
Table 1. Interventions Administered During Each Assignment 
 
Intervention 
Standard of Care Assignment 
REN Assignment 
Vial #1 
Metoclopramide: 
 Concentration of solution in 
vials kept in fridge: 5 mg/mL 
 Volume of solution in vials 
kept in fridge: 2.4 mL 
 Administration: Transfer 
appropriate volume of 
solution to 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 
Normal saline (0.9% NaCl): 
 Concentration of solution in 
vials kept in fridge: N/A 
 Volume of solution in vials kept 
in fridge: 2.4 mL 
 Administration: Transfer 
appropriate volume of solution 
to 50 mL mini bag of normal 
saline (0.9% NaCl) for target 
dose of 0.15 mg/kg, maximum 
10mg of metoclopramide 
(2mL), and administer as 
infusion over 15-30 minutes 
Vial #2 
Ketorolac: 
 Concentration of solution in 
vials kept in fridge: 30 mg/mL 
 Volume of solution in vials 
kept in fridge: 1.4 mL 
 Administration: Transfer 
appropriate volume of 
solution to syringe for target 
dose of 0.5 mg/kg, maximum 
Normal saline (0.9% NaCl): 
 Concentration solution in vials 
kept in fridge: N/A 
 Volume of solution in vials kept 
in fridge: 1.4 mL 
 Administration: Transfer 
appropriate volume of solution 
to syringe for target dose of 0.5 
mg/kg, maximum 30 mg of 


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30 mg of ketorolac (1 mL), and 
administer as a direct IV push 
over 1-5 minutes 
ketorolac (1 mL), and 
administer as a direct IV push 
over 1-5 minutes 
Device 
Sham device: 
 Parameters: Modulated 
frequency of ~ 0.083 Hz and a 
modulated pulse width of 40-
550 µs 
 Duration: 45 minutes of 
stimulation 
Active device: 
 Parameters: Modulated 
frequency of 100-120 Hz, a 
pulse width of 400 µs, with 
participant-adjusted output 
current to a maximum of 40 
mA 
 Duration: 45 minutes of 
stimulation 
 
The study kits will be stored in the ED (with medications in fridge) and labelled as per 
Health Canada regulations. The study interventions will not be labeled with intervention 
information, so that the research and clinical staff can remain blinded to the interventions. 
The PERT research nurse will administer the assigned interventions to participants. 
Efficacy and safety outcomes will be measured at baseline, 60, and 120 minutes, and 48 
hours post-intervention. For participants who cross over, additional 60-minute and 120-
minute post-crossover assessments will occur. Participants, the ED research nurse, and the 
clinical team will remain blinded to the interventions. 
 
Participants with significant relief prior to the initial or post-crossover 120-minute 
assessment may be discharged from the ED, rather than being asked to remain in the ED 
until the next assessment. For such participants, an additional time point for data collection 
will occur at discharge. Additionally, the ED research nurse will electronically schedule the 
next assessment questions to be sent to the participant through REDCap at 120 minutes 
after the last intervention via text message or email, contingent on the participant’s 
preferred method of contact. Reminders for the 120-minute assessment will also be 
scheduled in REDCap and will be sent every 30 minutes (up to 3 times) after the 
assessment was initially sent to the participant. Where the participant does not complete 
these questions post-discharge, the discharge questions will be used in lieu of the 120-
minute questions to measure the 120-minute outcomes (after initial or post-crossover 
assessment). 
 
The smartphone application used to control the REN device does collect data from the user, 
including treatment and symptom descriptions, actions performed within the application, 
and device information. This information is collected by the smartphone application and 
sent to the device manufacturer. The full End User License Agreement (EULA) that 
describes this data collection can be found in Appendix G. The application will be accessed 
on a study device (e.g., iPad), using a study account, and participants will not be asked to 
enter data directly into the device, as all outcome data will be collected through REDCap. 


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Therefore, participants will not have to use their own device to participate, and will only 
enter data into the application if they choose to. 
7.11. Measures 
In order to compare enrolled to non-enrolled individuals, we will record basic 
demographic data on all individuals approached for the study, including: age, sex, Canadian 
Triage and Acuity Scale (CTAS) score, date and time of triage, and where, applicable, reason 
for non-enrollment. The primary outcome for this pilot trial will pertain to feasibility. All 
feasibility and acceptability outcomes are described in previous sections, along with 
targets, that were established using data from prior similar trials.34–36,85  
 
Participants will be asked to report on the main efficacy and safety measures at each 
outcome measurement time point (baseline, 60, and 120 minutes, 60 minutes and 120 
minutes post-crossover where applicable, or at discharge if before 120 minutes after the 
last intervention, and 48 hours). Pain severity will be measured using the 11-point pain 
numerical rating scale, which is a well-established self-reported pain scale that has a strong 
recommendation to use in children aged 6-18 years with acute pain based on a recent 
systematic review.79 To align with International Headache Society (IHS)76,80 and FDA 
guidelines for migraine trials,81 we will also use the 4-point pain severity scale (0=none, 
1=mild, 2=moderate, 3=severe),  and participants will be asked about their most 
bothersome migraine associated symptom for the current attack, and whether it is present 
or not (see Appendix L, N, and O). For safety, participants will be asked about adverse 
events, and these will be defined according to the Good Clinical Practice of the International 
Conference on Harmonization. Using these measures, secondary efficacy and safety 
outcomes will be reported, in accordance with the IHS76,80 and FDA guidelines.81 
 
In addition to these efficacy and safety measures, we will measure: 
 
1. Treatment expectancy: We will measure treatment expectancy in both the 
participant and the parent at baseline using two questions, one referring to 
expectancy in relation to the study device, and one referring to expectancy in 
relation to the standard of care IV medications (see Appendix L and M). These 
questions have been designed specifically for this study and have not been 
previously piloted or validated. 
2. Expected magnitude of pain relief: At baseline, we will ask both the participant 
and their parent about what level of pain they would deem acceptable prior to 
discharge. We have designed two questions for this purpose (see Appendix L and 
M). These have been designed specifically for this study and have not been 
previously piloted or validated. 
3. State pain catastrophizing: Both the participant and an accompanying parent or 
guardian will be asked to complete the 3-item State Pain Catastrophizing Scale for 
Children (SPCS-C) at baseline. The State Pain Catastrophizing Scale for Children 
(SPCS-C) is a shorter derivative of the Pain Catastrophizing Scale for Children (PCS-


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
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C) and has been found to be reliable and valid in the pediatric chronic pain 
population (see Appendix L and M).86 Questions in the PCS-C will refer to the 
child/participant’s pain (ie. Participants will answer question about their own pain 
and the parent/guardian will answer questions about their child’s pain).  
4. State anxiety: Both the participants and a parent/guardian will also be asked to 
complete the short-form, 6-item State-Trait Anxiety Inventory (STAI-6) at baseline. 
The STAI-6 contains six items from the 20 state-related items of the State-Trait 
Anxiety Inventory (STAI), and has been validated in both adult87,88 and pediatric 
clinical populations.89–92 The STAI was developed to assess both current (state) and 
general (trait) levels of anxiety, with the state and trait measures each containing 20 
items.93 The STAI-6 is based on the state-related items and was developed for 
settings that are time sensitive, making such a scale ideal for the emergency 
department.87 Appendix L and M shows the items used in the STAI-6. 
5. Participant global impression of change: At the 120-minute (or at discharge if 
before 120 minutes) and 48-hour time points, the participants will be asked to 
report their global impression of change using a single item question, rated on a 7-
point Likert scale that ranges from “very much improved” to “very much worse” 
(see Appendix N and O). 
6. Data on baseline demographics, headache history, and medical history: At 
baseline or any time during the participant’s stay in the ED, the research nurse will 
ask participants a series of questions aimed at ascertaining their demographics, 
headache history, and medical history. These questions are listed on the baseline 
data collection form that will be completed by the research nurse (see Appendix K). 
7. Disposition outcomes: The research nurse will also enter data into REDCap with 
regards to the participants’ disposition outcomes (e.g., whether the patient was 
discharged from the ED without further intervention, what other interventions were 
administered according to the ED physician between the 60- and 120-minute post-
crossover assessments and after study interventions, etc). These questions are 
listed on the baseline data collection form that will be completed by the research 
nurse (see Appendix K). 
8. Additional questions at 48-hour follow-up: In addition to the main efficacy and 
safety measures as outline above, at the 48-hour follow-up questionnaire, 
participants will be asked about headache recurrence, medication use at home, 
migraine-related disability, impressions of the study interventions received, and to 
provide feedback on their study experience. The study feedback questions were 
mostly derived from a prior published survey.94 All of these questions are listed on 
the 48-hour feedback data collection form (see Appendix P). 
 
Based on feedback from our patient engagement, we will offer each participant the option 
of selecting their preferred reporting method for initial outcomes in the ED (i.e., electronic 
surveys completed by the participant, or data collected from the research nurse and 
entered into REDCap on behalf of the participant). For the 48-hour outcomes, participants 
will choose between electronic or telephone follow-up, as per our prior study.85 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
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Qualitative feedback will also be collected from the nurses and physicians who are treating 
the participants in the ED (see Appendix R). The PERT nurse will approach the treating 
clinicians towards or at the end of each participant’s involvement in the primary study to 
solicit verbal or written feedback from them. These clinical staff will be asked: 1. “Did you 
have any concerns with the study?”, and 2) “Do you have any suggestions for improvement 
of the study?”. For those providing verbal feedback, the PERT nurse will transcribe the 
feedback and place it into REDCap. For those providing written feedback, they will have the 
option of writing it down on a paper form, or being sent an emailed or text messaged 
REDCap link. 
8. Expected Duration of Participant Participation 
Participants will remain in the ED for variable lengths of time, which will largely be 
dependent on the time needed to effectively treat and manage their acute migraine attack. 
Further interventions will be administered at the discretion of the attending ED physician if 
participants do not experience a significant reduction in pain 60-120 minutes after 
receiving the crossover study intervention. We expected participants will remain in the ED 
on an average of 2-5 hours, depending on whether they cross over or not. 
 
Following discharge from the ED, participants will then complete an electronic or 
telephone follow-up 48 hours post-intervention. We expect this follow-up to take between 
15-30 minutes. Participation in the study will end once this 48-hour follow-up has been 
completed.  
9. Study Medication 
9.1. Study Medication Description 
The study interventions will consist of either a one-time dose of the standard of care IV 
medications: a combination of ketorolac and metoclopramide, or electrical stimulation 
from the REN device. Ketorolac will be administered at a dose of 0.5 mg/kg, up to a 
maximum of 30 mg, and metoclopramide will be administered at a dose of 0.15 mg/kg, up 
to a maximum of 10 mg. The standard of care medications will be prepared at the ACH 
research pharmacy and sent down in vials to the ED research office, to be kept in the ED 
research fridge. The REN device will administer electrical stimulation to the upper arm 
over 45 minutes, using a modulated frequency of 100-120 Hz, a pulse width of 400 µs, and 
a maximum output current of 40 mA. The REN device is manufactured by Theranica Bio-
Electronics, Ltd. 
9.2. Placebo Description 
The placebo IV medication consists of normal saline that is matched in volume to the 
weight-based volume that would be given if the participant were received the standard of 
care IV medications. The sham REN device uses a pulse frequency of about 0.083 Hz, and a 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
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modulated 40-550μs pulse width. These settings differ from the active REN device but are 
designed to create a sensation similar to the active REN device without stimulating the 
nociceptive sensory nerves in the arm. These parameters were chosen based on previous 
RCT studies using the active and sham REN devices.57 
9.3. Accountability Procedures and Storing 
The ketorolac and metoclopramide suspensions will be stored in vials within the AHS-
maintained research fridge of the ACH ED. This fridge is wirelessly monitored and 
maintained at a range of 2-8°C as per the recommended pharmacy guidelines for storage of 
the investigational products. The fridge is locked, along with the research office containing 
the fridge, and only relevant and trained study staff have access. The saline placebo 
suspensions (one for ketorolac and metoclopramide) will also be stored in the research 
fridge, in vials identical to those used to store ketorolac and metoclopramide.   Ketorolac 
and metoclopramide vials will remain stable for 9 days while in the fridge and both 
medications will be labelled with their respective expiration dates. The saline placebos will 
also be labelled with expiration dates matched to the expiration dates of ketorolac or 
metoclopramide (see Appendix S-U for label templates). After the expiration date, 
remaining vials will be destroyed in compliance with the research pharmacy’s standard 
operating procedures (SOP) for the destruction of investigational drugs, which are 
compliant with the guidelines as set out in ICH.75  
 
The ketorolac, metoclopramide, and placebo vial labeling will be compliant with Health 
Canada Division 5 Food and Drug Regulation clinical trial labeling guidelines (see Appendix 
S-U for labels). 
 
The active and sham REN devices will be stored in the pharmacy, and devices (a sham and 
an active device) will be sent down with the kits (i.e., medication vials and devices, divided 
into “Initial Treatment” and “Crossover Treatment” parts to reflect the crossover design), 
to be stored in a locked access-controlled cupboard in the ED research office. The devices 
will not be labelled as active or sham; they will only be identified with randomization codes 
and the part of the kit they correspond to (“Initial Treatment” or “Crossover Treatment” 
that corresponds to their paired medication vials in the kits) so that blinding of both 
research personnel and staff is maintained. This office is locked and compliant with Health 
Canada regulations.  
 
Throughout the study recruitment period, pre-printed orders will be sent to the pharmacy 
to ensure that a consistent stock of study treatments is maintained in the ED fridge. One-
two study kits will be maintained in the fridge at a time. When the pharmacist receives an 
order for a study kit, they will then check the randomization scheme and prepare the 
appropriate kit, with “Initial Treatment” being either a ketorolac, metoclopramide, and a 
sham REN device, or a normal saline and an active REN device, according to the 
randomization code, and “Crossover Treatment” being the alternate intervention. When a 
participant is randomized to the study, the current study treatment in the ED research 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
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office will be used and a new kit will be ordered by Dr. Orr’s research team following kit 
use. If the kit expires before use, then the expired kit will be sent to pharmacy for disposal, 
and a new kit will be ordered and delivered to the ED research office. For kits where only 
the “Initial Treatment” part was used (i.e., the participant did not require crossover), then 
the unused part of the kit (“Crossover Treatment”) will be sent to pharmacy for handling 
(either disposal or reuse in the next kit depending on expiry date). The pharmacy will 
maintain a list documenting kit preparation with the information as follows: randomization 
number associated with kit, date of kit preparation, person who prepared the kit, person 
who checked the kit. The pharmacy will also maintain a copy of the randomization scheme. 
The research nurse will document the randomization number on their baseline case report 
form, which will include participant identifying information, and which will be linked in 
REDCap to the participant’s record ID form that will include contact information (see 
Appendix V). Thus, in the case where unblinding is required for participant safety reasons, 
the research team will reach out to the Alberta Children’s Hospital inpatient pharmacy with 
the randomization code assigned to the participant and the pharmacy personnel will be 
able to report which study intervention(s) were administered to that participant. 
 
Study packages will be kept in the ED research office: each device (sham vs. active) and 
each medication package (placebo vs. active) will be labelled with “Initial Treatment” or 
“Crossover Treatment”, a randomization code, and a label. Medication packages (placebo 
and active) will be kept in the ED research office fridge and will comprise vials of 
metoclopramide, ketorolac, and normal saline placebo. Devices will be stored in the ED 
research office, outside of the fridge. Each medication package will have the same 
randomization code and “Initial Treatment” or “Crossover Treatment” labels as one of the 
devices, so that the appropriate device can be linked to the appropriate medication package 
during each phase of the study. When a participant consents and is randomized, a PERT 
nurse will prepare the “Initial Treatment” study interventions for the participant according 
to their randomization code and the kit part. The PERT nurse will draw the study 
interventions from the vials in the corresponding medication packages, which will be 
labeled in compliance with Health Canada Division 5 Food and Drug Regulation clinical trial 
labeling guidelines, into either a syringe or a normal saline mini bag. The corresponding 
appropriate REN device for the “Initial Treatment” part (either active or sham, depending 
on the randomization code) will also be obtained from the research office by the PERT 
nurse. The PERT nurse will then bring both the prepared IV interventions and the 
corresponding device to the participant for administration, along with an iPad that will 
contain the application that is required to connect with the device and allow the user to 
initiate treatment and control the stimulation intensity. Where an IV catheter has not 
already been put in place by the clinical team, an IV catheter will be placed by either the 
clinical team or the research nurse into the participant at this time. The IV interventions 
(metoclopramide and ketorolac or normal saline, depending on group assignment), will be 
administered to the participants through the IV catheter as is detailed in 7.10 and Table 1 
above. The device (active or sham, depending on group assignment) will be placed on the 
participant’s chosen arm by the PERT nurse, and connected to either the participant’s (or 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
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their parent or guardian’s) smartphone (after downloading the REN application): 
https://play.google.com/store/apps/details?id=app.theranica.neriviomigra&hl=en_CA&gl=
US), or to an iPad from the ED. The PERT nurse will teach the participant how to control the 
intensity of electrical stimulation, and participants will be offered the option of controlling 
the stimulation intensity themselves using their chosen smart device (i.e., their own vs. the 
study iPad), or having either a parent/guardian or the PERT nurse control the stimulation 
intensity. 
 
At 120-minutes post-“Initial Treatment” intervention, participants will be asked if they feel 
ready to go home without further intervention. If they answer “yes”, they will be 
discharged home. If they answer “no”, they will be crossed over to the “Crossover 
Treatment” intervention. 
 
Medications that are not administered to patients will be sent back to the research 
pharmacy for destruction according to the research pharmacy’s SOPs for destruction of 
investigational products. REN devices that are not used, and not worn, by participants will 
be returned to the research office. REN devices that have been unused will be sent back to 
the manufacturer. 
 
Drug accountability forms will be completed and stored in the pharmacy and records will 
be maintained in accordance with Health Canada Division 5 Food and Drug Regulation 
guidelines. An accountability log will also be maintained in the ED research office to 
document dispensation of the study kits to the participants. 
9.4. Monitoring for Participant Compliance 
We expect few compliance issues once participants are fully informed and have consented 
to participate in the study. The combination IV treatment of ketorolac and metoclopramide, 
or saline, will only be administered as a one-time dose, and both the active and sham REN 
devices will only administer a single, 45-minute session in the study. The study treatments 
will also be administered by the attending ED research nurse. Should participants wish to 
discontinue their participation in the study (e.g., due to adverse events, no meaningful 
reduction in pain, spending too much time in the ED), the treating ED research nurse and 
physician will withdraw the participant from the study and administer further treatment, 
as needed and at their discretion. Compliance issues are expected to be more likely 
between ED discharge and the 48-hour follow-up. Completion and withdrawal rates will be 
carefully monitored and recorded to properly determine the feasibility and acceptability of 
the study design. 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
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10. Statistical Procedures 
10.1. Sample Size 
We expect to recruit 40 participants over two years to the study, averaging 1.5 participants 
per month. Given that this is a pilot study, data regarding recruitment rates will be used to 
help inform and design a fully-powered, multi-center phase III RCT study in the future.  
10.2. Outcome Analysis Plan 
Demographic data for each screened participant will be collected and will include: age, sex, 
Canadian Triage and Acuity Scale (CTAS) scores, date and time of triage, and reasons for 
non-enrollment (if applicable). This demographic data will be summarised and described in 
tabular form. The primary outcome measures of this pilot study pertain to feasibility while 
the secondary outcomes measures relate to feasibility, acceptability, efficacy, and safety of 
using the REN device to treat child and adolescent acute migraine attacks in the ED. 
 
Our feasibility and acceptability outcomes will be summarized using appropriate 
descriptive statistics across both groups. Participant global evaluations of treatment from 
the 7-point Likert scale will be dichotomized into good (i.e., “good” or “very good” global 
impression of change) and poor (“minimally improved”, “no change”, “minimally worse”, 
“much worse”, and “very much worse”), and Likert scale-based responses to the questions 
on the “Participant Protocol Feedback Form” will be dichotomized into agree (“strongly 
agree” or “agree), and disagree (“neutral”, “disagree”, “strongly disagree”). These responses 
will be reported as proportions. Chi square tests will be used to examine the association 
between each (dichotomized) outcome and treatment group. Qualitative feedback from the 
“Participant Protocol Feedback Form” and feedback from treating physicians and nurses 
will be coded independently by two researchers using a content-driven immersion process, 
whereby concept and theme elements will be extracted as content units. Open coding will 
be used, with inductive and logical reasoning applied to identify rival means of categorizing 
the data. A codebook will be kept and updated iteratively.95–97  
 
Secondary outcomes will pertain to efficacy and safety. We will calculate the proportion of 
patients in each group who achieve each dichotomous efficacy outcome. We will also 
calculate adverse event rates and serious adverse event rates in each group. All planned 
analyses comparing treatment groups will be exploratory, and this data will be used to 
guide our sample size calculations for a phase III trial. 
10.3. Sex and Gender Analyses 
We will measure and report sex and gender. We will assess sex with the question: “What 
sex was assigned at birth?” and options will be “male”, “female” or “other (please 
describe)”. Gender will be assessed with the question: “What gender do you currently 
identify with?” and options will be “male”, “female”, “unknown”, “I prefer not to disclose”, 
“not listed, I identify as (please describe)”. These sex and gender questions are derived 
from the NIH core common data elements for headache. We expect that approximately 


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and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
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75% of the sample will be female, based on the sex distribution of prior similar 
studies.34,36,85 We have no a priori expectation regarding the gender distribution, as this has 
not been measured in prior studies. We hypothesize that there will be no significant 
differences in trial acceptability by sex or gender, but we will compare our acceptability 
outcome results by sex and gender using chi square tests.  
10.4. Race, Indigenous, and Visible Minority Analyses 
We will measure race, Indigenous, and visible minority status with questions derived from 
the Canadian Community Health Survey, and from CIHR’s Equity, Diversity, and Inclusion 
Questionnaire, respectively (see form to be completed by research nurse in Appendix K). 
We hypothesize that there will be no significant differences in trial acceptability by race, 
Indigenous, or visible minority status, but we will compare the groups’ acceptability results 
using chi square tests. 
10.5. Sample Size Analyses 
We are planning a sample of size of 40 participants, to acquire adequate data on feasibility 
and acceptability, and preliminary efficacy and safety data to help inform the sample size 
and design of a future fully powered RCT. Determining if we can recruit at the rate of ~1.5 
participants/month will also help to determine the feasibility of scaling to a fully powered, 
multicenter phase III RCT.  
11. Safety and Adverse Events 
11.1. Safety Assessments of Ketorolac 
Below is a list of the most commonly reported adverse events in the pediatric and adult 
research involving single-dose ketorolac. Because ketorolac will be administered in the ED 
under the supervision of a treating ED physician, treatment of these possible adverse 
events will be at the discretion of the treating ED physician: 
 
Dizziness: One study examining the treatment of adult migraine using ketorolac found that 
7% of patients reported feelings of dizziness.73 Several other studies examining single-dose 
ketorolac have also reported dizziness as a common adverse event with rates at 
approximately 10%, 17%, and 10% respectively.98–100  
 
Nausea: A common adverse event among many single-dose ketorolac studies, whether 
migraine-related or not, is nausea, with rates varying between less than 1% to 67%47,98–104 
 
Vomiting: Several studies using ketorolac for non-migraine related pain treatment have 
reported instances of vomiting, varying from 8% to 42%.98–100,103 
 
Drowsiness: Several studies of adult and pediatric migraine treatment have reported 
drowsiness in less than 1% to as much as 38% of participants.47,73,98–102,105 
 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
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Injection-site Pain: Between 2% and 21% of participants reported pain at the injection site 
after receiving IV ketorolac.99,104,105 
 
Gastrointestinal: Gastrointestinal issues, including bloating, dyspepsia, and heartburn, have 
been reported in a couple studies, with 2% to 7% of participants reporting gastrointestinal-
related adverse events.73,104 
 
Increased Risk of Bleeding: Rarely, events of bleeding have been reported after a single 
dose of intravenous ketorolac, though these reports have come predominantly from studies 
of ketorolac given perioperatively in surgical patients.98,106,107 
11.2. Safety Assessments of Metoclopramide 
Below is a list of the possible adverse events that may occur when using a single dose of 
metoclopramide, as described in several studies using a single dose of metoclopramide as 
treatment in adult and pediatric populations. Because metoclopramide will be 
administered in the ED under the supervision of a treating ED physician, treatment of these 
possible adverse events will be at the discretion of the treating ED physician: 
 
Akathisia: Movement disorders such as akathisia have been commonly reported by several 
adult and pediatric migraine studies, with rates varying from 5% to 32%.73,108–112 
 
Dizziness: Feelings of dizziness were also commonly reported in many adult and pediatric 
migraine studies. Between approximately 1% and 13% of participants reported feeling 
dizzy after receiving a single dose of metoclopramide.66,73,74,109,110  
 
Drowsiness: Along with dizziness, drowsiness was reported in 13% and 38% of adult and 
pediatric headache participants.73,74,109,110,113 
 
Nausea: Several studies reported nausea following a single dose of metoclopramide, with 
rates between less then 1% to 15%.74,111,114 
 
Gastrointestinal: Several gastrointestinal issues, including vomiting and dyspepsia, were 
reported by about 1% of participants in some studies.73,74,111 
 
Dystonic Reactions: Very rarely (< 0.1%) after a single dose of metoclopramide, a dystonic 
reaction can occur (a sustained muscle contraction).115,116  
11.3. Safety Assessments of the REN Device 
The current literature exploring the use of the REN device in treating adult and pediatric 
migraine has reported either no or very low (< 5%) device-related adverse events. All 
adverse events resolved within 48 hours and none were considered serious. Below is a list 
of the reported adverse events from the literature. If any of these adverse events occur in 
the ED and are considered intolerable to the participant, the participant will have the 
option of stopping stimulation or notifying their treating ED physician who can decide on 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
Version: 7 | Date: February 10, 2023 
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treatment at their discretion. For adverse events occurring at home, participants will have 
the option of presenting back to the ED or consulting with their family physician if these 
adverse events are intolerable or serious: 
 
Warmth Sensation: Two studies with adult migraine participants indicated that about 2.4% 
of participants reported feeling a warm sensation when using the REN device.57,62 
 
Arm/Hand Numbness: A single study examining adult migraine had 0.8% of participants 
report numbness in the arm or hand when using the REN device to treat their migraines.57 
 
Arm/Hand Redness: Two adult migraine studies indicated that 1.6% of participants 
reported redness in their hand or upper arm when using the REN device.57,62 
 
Arm/Hand Pain: One adult migraine study and one pediatric migraine study reported that 
approximately 2% of participants reported pain in their hand or arm when using the REN 
device.57,64 However, both studies indicate that this pain was temporary, considered to be 
mild, and resolved within 24 hours without the need for medical intervention. 
 
Itching: One adult migraine study had a single participant (0.8%) report an itching feeling 
when using the REN device.57 
 
Muscle Spasms: The same study as described above also had a single participant (0.8%) 
experience muscle spasms when using the REN device.57  
11.4. Methods and Timing of Safety Assessments and Follow-Up 
For the study, assessment of adverse events will occur at each time point while the 
participant is in the ED (60 and 120 minutes, 60 and 120 minutes post-crossover 
intervention, or at discharge if before the initial or post-crossover 120 minute time point). 
The participant will also be asked to indicate if they have experienced any adverse events 
when they are contacted for the 48-hour follow-up assessment. Participants who indicate 
they have experienced adverse events will be asked to describe the adverse events, either 
in writing if completing the electronic assessment or verbally if completing the assessment 
over the phone. Participants who complete the assessment electronically, and indicate they 
have experienced adverse events of concern (i.e., that require more information or follow-
up), will be contacted by phone to obtain more information about the adverse events. The 
Qualified Investigator or co-investigator will determine if each adverse event is related to 
the investigational product. 
 
Any participants that report experiencing adverse events prior to being discharged from 
the ED will only have the option of completing the 48-hour follow-up over the phone, 
rather than electronically. This will be done to ensure that all reported adverse events are 
thoroughly described during the 48-hour follow-up. Further follow-ups beyond the initial 
48-hours will occur as needed should any adverse events not stabilize or resolve prior to 


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the 48-hour follow-up. How and when further follow-ups occur will be at the discretion of 
the Qualified Investigator. If deemed necessary by the Qualified Investigator, in-person 
follow-ups may be required to ensure the health and safety of participants. 
11.5. Definitions Pertaining to Adverse Events 
Starting from the time participants provide informed consent until the conclusion of the 
48-hour follow-up, adverse events will be monitored and recorded. Adverse events will be 
described according to the definitions provided by the International Conference on 
Harmonization (ICH E2A topic): 
 
Adverse event: Any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries will be regarded as adverse 
events. Abnormal results of diagnostic procedures are considered adverse events if the 
abnormality: 
 
 
results in study withdrawal 
 
is associated with a serious adverse event 
 
is associated with clinical signs or symptoms 
 
leads to additional treatment or to further diagnostic tests 
 
is considered by the investigator to be of clinical significance 
 
Adverse drug reaction: Any response to a drug, biologic, or natural health product which is 
noxious and unintended, which occurs at doses normally used or tested for the diagnosis, 
treatment or prevention of a disease or the modification of an organic function. A reaction, 
as opposed to an adverse event, is characterized by the fact that a causal relationship 
between the product and the occurrence is suspected (i.e. judged to be at least a reasonably 
possibility). 
 
Important medical events are those that may not be immediately life-threatening, but are 
clearly of major clinical significance. They may jeopardize the subject, and may require 
intervention to prevent a serious outcomes.  For example, drug overdose or abuse, a seizure 
that did not result in in-patient hospitalization, or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious.  
 
Unexpected adverse drug reaction: An adverse reaction, the nature or severity of which is 
not consistent with the applicable product information (e.g. the Investigator’s Brochure for 
an unapproved investigational product or package insert/summary of product 
characteristics for an approved product). 
 
Unanticipated problem: Any incident, experience, or that meets all the following criteria:  
 
 
Unexpected (in terms of nature, severity, or frequency) given: 


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○ 
the research procedures that are described in the protocol-related 
documents, such as the CHREB-approved research protocol and informed 
consent document, or the Investigator Brochure 
○ 
the characteristics of the research participant population being studied 
 
Related or possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the [investigational product(s)] or procedures involved in the 
research) 
 
Suggests that the research places research participants or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than was 
previously known or recognized.  
 
Serious adverse event: Adverse events will be classified as serious or non-serious.  A serious 
adverse event is defined as any adverse event that is:  
 
 
fatal 
 
life-threatening 
 
requires or prolongs hospital stay 
 
results in persistent or significant disability or incapacity 
 
a congenital anomaly or birth defect 
 
an important medical event 
 
The severity of an adverse event will be determined by the investigator, who should use 
the following definitions when assessing the intensity of an adverse event: 
 
 
MILD: Participant is aware of symptoms or has minor findings but tolerates them 
well and no or minimal intervention required 
 
MODERATE: Participant experiences enough symptoms or findings to require 
intervention 
 
SEVERE: Participant experiences symptoms or findings that require significant 
intervention 
 
An event will be qualified as unexpected when the specificity or severity of the event is not 
consistent with the package inserts or investigational brochure for the drugs under study. 
 
Causality will be determined by the following question, where an affirmative answer 
designates the event as a suspected adverse reaction: Is there a reasonable possibility that 
the drug caused the event? ‘‘Reasonable possibility’’ means there is evidence to suggest a 
causal relationship between the drug and the specific adverse event being assessed. 
 
In relation to the identification of adverse events, some participants in this study will 
have pre-existing medical conditions and those pre-existing conditions will not be 
considered as adverse events. New events that occur or the worsening in frequency or 


Ethics ID: REB21-0408 
PROTOCOL – A pilot clinical trial of a new neuromodulation device for acute attacks of migraine in children 
and adolescents visiting the emergency department 
PI: Dr. Serena Orr 
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intensity of pre-existing conditions will be reported as adverse events (Schedule of Events). 
All reportable events as defined above, determined to be an adverse event based on 
physical examination, laboratory findings, or other means will be recorded in the source 
documents and entered in the CRF. Each event will be recorded on an adverse event CRF 
starting after first dose of study drug has been delivered. The investigator will provide date 
of onset and resolution, severity, action(s) taken, changes in study drug dosing, causality to 
study drug, and outcome. 
 
For follow-up of adverse events, any safety event that is identified at the last assessment 
(or an early termination) will be recorded on the CRF with the status of the safety event 
noted. All serious suspected adverse reactions and serious adverse reactions will be 
followed until resolution or until the patient is medically stable.  
11.6. Recording and Reporting of Adverse Events 
All adverse events, adverse drug reactions and unanticipated problems will be recorded on 
the electronic adverse event data collection form (see Appendix W), which will be stored in 
REDCap. Only adverse drug reactions that are both serious and unexpected are subject to 
expedited reporting to Health Canada. 
 
Expedited reporting of reactions which are serious but expected is not required. Expedited 
reporting is also inappropriate for serious events from clinical investigations that are 
considered unrelated to the study product, whether or not the event is expected. 
 
During this trial, the sponsor (University of Calgary) will inform Health Canada of any 
serious, unexpected adverse drug reaction that has occurred inside or outside Canada: 
 
 
where it is neither fatal nor life-threatening, within 15 days after becoming aware 
of the information 
 
where it is fatal or life-threatening, immediately where possible and, in any event, 
within 7 days after becoming aware of the information 
 
within 8 days after having informed Health Canada of the adverse drug reaction 
(ADR), submit as complete a report as possible which includes an assessment of the 
importance and implication of any findings 
Each ADR which is subject to expedited reporting will be reported individually in 
accordance with the data element(s) specified in the Health Canada / ICH Guidance 
Document E2A: Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting. The Council for International Organization of Medical Sciences (CIOMS) form 1 
will be used for reported serious and unexpected adverse events (see Appendix X). 
In situations when causality assessment and determination of expectedness is not 
straightforward, the report will be submitted in the expedited manner and the relevant 
issues will be outlined in a cover letter. Final reports of fatal or life-threatening reactions 


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will include an assessment of the importance and implication of the findings, including 
relevant previous experience with the same or similar drugs. 
 
In addition to the above, if any additional situations arise, appropriate scientific and 
medical judgment will be applied to determine if rapid communication to Health Canada is 
required. For example, information that might influence the risk-benefit assessment of a 
drug, or that would be sufficient to consider changes in drug administration, or in the 
overall conduct of a clinical trial, represent such situations where rapid communication to 
Health Canada will occur; including: 
 
 
for an "expected" serious ADR, an increase in the rate of occurrence which is judged 
clinically important. 
 
a significant hazard to the patient population, such as lack of efficacy with a drug 
used in treating a life-threatening disease. 
 
a major safety finding from a newly completed animal study. 
 
As per the ICH Good Clinical Practice Guidelines stipulations, the Conjoint Health Research 
Ethics Board will establish, document in writing and follow procedures for: 
 
 
Determining the frequency of continuing review as appropriate (including adverse 
drug reactions and adverse events). 
 
Requiring that the Investigator should promptly report to the CHREB. 
○ 
Changes increasing the risk to participants and/or significantly affecting 
the conduct of the trial. 
○ 
All adverse drug reactions that are both serious and unexpected. 
○ 
New information may adversely affect the safety of the participant or the 
conduct of the trial. 
 
In additions to the reporting to Health Canada as described above, all serious adverse 
events that occur at the Alberta Children’s Hospital along with any adverse events that are 
both serious and unexpected, will be reported to the CHREB. 
 
With regards to device-related adverse events, serious adverse events related to the REN 
(NerivioTM) device will be reported to Health Canada, the CHREB, and the manufacturer 
and importer within 72 hours of discovery. This includes cases in which the incident: 
 
a. is related to a failure of the device or a deterioration in its effectiveness, or 
any inadequacy in its labelling or in its directions for use, and 
 
b. has led to the death or a serious deterioration in the state of health of a 
patient, user or other person, or could do so were it to recur. 


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In these cases, a preliminary and a final report in respect of the incident will be submitted: 
 
a. within 10 days after the manufacturer or importer of a medical device becomes 
aware of an incident, if the incident has led to the death or a serious deterioration in 
the state of health of a patient, user or other person, or 
 
b. within 30 days after the manufacturer or importer of a medical device becomes 
aware of an incident, if the incident has not led to the death or a serious 
deterioration in the state of health of a patient, user or other person, but could do so 
were it to recur. 
11.7. Treatment Discontinuation 
In the study, participants will receive either a one-time dose of a combination of 
metoclopramide and ketorolac, or a single 45-minute electrical stimulation session from 
the REN device, or each intervention should they enter the crossover phase, and placebo 
treatment/sham device. However, participants will be able to withdraw from the study at 
any point. At the discretion of the attending ED research nurse and physician, further 
treatments will be administered to participants who withdraw from the study to ensure 
proper treatment and management of pain and symptoms associated with an acute 
migraine attack. 
11.8. Premature Study Discontinuation for Individual Participants 
A participant will be permanently discontinued from the study when: 
 
 
Consent is withdrawn by the participant (ie. the participant requests to discontinue 
their participation) 
 
The investigator believes that ongoing participation in the trial will either pose a 
significant risk to the participant, invalidate the results of the study or involve a 
high risk of self-harm 
 
Loss to follow-up involving absence of all feasibility, acceptability, efficacy, and 
safety assessments, and follow-up assessments, for any reason 
11.9. Protocol Deviations and Violations 
A protocol deviation is defined as any modification or alteration of the CHREB approved 
protocol. A major deviation is defined as a modification or alteration of the REB approved 
protocol involving a potential impact on the participants’ safety, rights, welfare, or a 
potential impact on the integrity of the data. A minor deviation is defined as a modification 
or alteration of the CHREB approved protocol involving no significant impact on the study.  
 
No deviations from the protocol will occur prior to having received written permission 
from CHREB, except where required to protect participants from hazards or where the 
deviation is limited to a logistical or administrative aspect of the trial. In such instances, 
CHREB will be notified as soon as possible about the deviation. 


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12. Data Handling and Record Keeping 
12.1. Data Collection 
For the study, data collected for participants in the ED will either be collected electronically 
or by the ED research nurse, depending on how the participants wants to complete the 
assessments. Depending on the participant’s preference, data from the 48-hour follow-up 
will either be collected electronically or will be collected during a telephone call by the 
research assistant. Participants, the research nurse, and the research assistant will be blind 
to the randomized treatment group and will be asked to report and assess all outcomes. All 
data, whether collected electronically or otherwise, will be transferred into a dedicated, 
validated REDCap database. 
 
REDCap is a secure, web-based application hosted by the Clinical Research Unit in the 
Faculty of Medicine at the University of Calgary that is compliant with ICH Good Clinical 
Practice Guidelines section 5.5.3. REDCap is designed for the purposes of capturing data for 
research studies. REDCap provides: 
 
 
an intuitive interface for data entry (with data validation) 
 
128-bit encryption between the data entry client and the server (https) 
 
audit trails for tracking data manipulation and export procedures 
 
automated export procedures for seamless data downloads to common statistical 
packages (SPSS, SAS, Stata, R) 
 
procedures for importing data from external sources 
 
advanced features, such as branching logic and calculated fields 
12.2. Confidentiality 
All participant information will be kept strictly confidential. Study data will be entered into 
an electronic data capture system, REDCap, as described above. All data entered into 
REDCap will be de-identified and coded using a numeric code only. Access to REDCap is 
password-encrypted and only granted to research staff. 
 
Upon request, participant records will be made available to the sponsor (University of 
Calgary), Health Canada or other applicable regulatory agencies. 
12.3. Record Retention 
Study records will be retained for 15 years in accordance with Division 5 of Health 
Canada’s Food and Drug Regulations. 


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13. Quality Control and Quality Assurance 
13.1. Study Monitoring Plan 
The study will comply with the ICH Good Clinical Practice Guidelines, the requirements of 
the CHREB and Division 5 of Health Canada’s Food and Drug Regulations. 
 
A study binder detailing all standard operating procedures and including a copy of the 
protocol will be kept on site and accessible to all research personnel. Prior to trial 
commencement, the site investigators will give a presentation to the research personnel 
outlining the study protocol, documentation, and reporting procedures.  
 
Research personnel will maintain study records that are complete, legible, and accurate so 
as to allow for appropriate interpretation, reporting and verification of study records. 
 
Monitoring for this protocol will be coordinated by the sponsor-investigator. A study 
monitor will monitor the study regularly. The plan will consist of monitoring for CHREB 
and regulatory compliance on-site and remotely, to ensure that the rights and well-being of 
participants are protected and reported data are accurate, complete, and verifiable from 
source documents, along with the trial being conducted in compliance with the currently 
approved protocol and other applicable regulatory requirements. The peer monitoring 
activities will consist of, but not be limited to verification of:  
 
 
the investigator has adequate qualifications and resources. 
 
the investigational product(s) are stored, supplied, returned/disposed as per 
protocol and applicable regulatory requirement(s). 
 
the investigator follows the approved protocol and all protocol amendments. 
 
the written informed consent was obtained before each participant’s participation 
and was re-consented when amendments were made in the trial. 
 
the investigator receives current protocol amendments, all documents, and all trial 
supplies needed to conduct the trial properly. 
 
the investigator and the investigator’s trial staff are adequately informed about the 
trial. 
 
the investigator and the investigator’s trial staff are performing the specified trial 
functions in accordance with the protocol and written agreements. 
 
the investigator is enrolling only eligible participants. 
 
the participant recruitment rate. 
 
the source documents and the other trial records are accurate, complete, and kept 
up-to-date and maintained. 
 
the investigator provides all the required reports, notification, applications, and 
submissions, and that these documents are accurate, complete, timely, legible, 
dated and identify the trial. 


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checking the accuracy and completeness of the electronic CRF entries, source 
documents and other trial-related material. 
 
informing the investigator of any electronic CRF entry error, omission, or illegibility 
in writing. 
 
determining whether all adverse events are appropriately reported within the time 
periods required by GCP, the protocol, the CHREB, the sponsor, and applicable 
regulatory requirements. 
 
determining whether the investigator is maintaining the essential documents. 
 
communicating deviations from the protocol, SOPs, GCP, and the applicable 
regulatory requirements to the investigator and taking appropriate action designed 
to prevent recurrence of the detected deviations. 
13.2. Safety Monitor 
The study’s safety monitor will be a neurologist with extensive clinical trial experience 
from the Hotchkiss Brain Institute at the University of Calgary (or someone with 
comparable experience with clinical trials who practices within Canada, should the 
identified individual have to cease their duties for personal or other reasons). This 
individual will review the protocol prior to initiation of recruitment. Should this individual 
have concerns about the protocol, they will bring those concerns up to the study team and 
suggest appropriate actions. After this individual has approved the protocol and 
recruitment has begun, they will review study progress and data as necessary thereafter, if 
safety issues arise. 
 
Any safety concerns raised by clinical or research staff will be reported to the safety 
monitor by the investigators in a written report as soon as possible. All serious adverse 
events will be brought to the attention of the safety monitor immediately by the Qualified 
Investigator, who will also send a report to Health Canada (see section 11.4), as applicable. 
Once safety issues have been brought to the attention of the safety monitor, should the 
safety monitor review the data and identify concerning trends in adverse events or should 
a serious adverse event requiring unblinding occur, they will contact the research 
pharmacists and the research team, at their discretion, to access participant information if 
required for safety reasons. The safety monitor will make recommendations regarding 
early trial termination. Should the safety monitor decide for early trial termination or 
should they identify major concerns relating to safety in relation to the trial, the safety 
monitor will prepare a written report and communicate the plans or findings both verbally 
and in written form to the study investigators. 
13.3. Ethical Considerations 
13.3.1. General Principles 
This trial will be carried out according to the principles outlined in the Declaration of 
Helsinki,117  the ICH Good Clinical Practice Guidelines75 and the Division 5 of Health 
Canada’s Food and Drug Regulations. The institutional policies of the CHREB will also be 
followed. 


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Prior to initiating the study, written approval from the CHREB will be sought. Protocol 
deviations will only be implemented following approval from the CHREB, except where the 
investigators are concerned about potential hazards to the participants or where the 
deviations are logistical or administrative in nature. 
13.3.2. Clinical Equipoise 
While most of the research determining the effectiveness of the REN device to treat acute 
migraine attacks has been done in adult populations,57,62,68,69,118 there is more recent work 
suggesting the REN device can effectively treat acute migraine attacks in children and 
adolescents at home.64 However, there is a lack of evidence demonstrating the effectiveness 
of the REN device in treating acute migraine attacks in children and adolescents who are 
reporting to the ED. Recent research has focused on participants who were trained to treat 
their migraine attacks with the REN device at home, often using the device to treat multiple 
attacks across several weeks. Given that the nature of an acute migraine attack in the ED 
likely differs from acute attacks in non-ED settings38,50 it is unclear how the migraine 
attack, and participants themselves, will respond to the REN device as ED treatment. As 
such, there is much uncertainty in how feasible, acceptable, effective, and safe the REN 
device will be when treating a pediatric population suffering from acute migraine attacks in 
an ED setting. The use of a placebo treatment and a sham device is crucial for comparing 
the REN device to standard of care treatments. (i.e., ketorolac and metoclopramide). 
13.3.3. Informed Consent 
Informed consent will be sought from all participants who are deemed to be capable of 
consenting (i.e., mature minors 14 years of age of over who want to and are capable of 
consenting on their own behalf). Additionally, informed assent will be sought from 
participants who are not deemed to be capable of consenting. Where participants are not 
deemed to be capable of consenting, the parent or guardian will carry out informed consent 
in their place. All elements pertinent to consent and assent will be explained verbally to the 
parents and participants by the PERT research nurse. Parents and participants will also be 
provided with a written informed consent form, and in applicable cases, with a written 
assent form. The consent and assent forms comply with the Tri-Council Policy Statement: 
Ethical Conduct for Research Involving Humans119 (see Appendix Y-AC). The consent and 
assent discussions and forms use simple language, written and expressed at grade levels 
recommended by the CHREB. Participants and their parents will receive a detailed 
explanation about potential harms incurred by the study, namely about potential side 
effects of metoclopramide, ketorolac, and the REN device, and delayed treatment of the 
acute migraine attack should the study interventions be ineffective. Anticipated benefits 
will also be discussed:  
 
1) Direct benefits: Participants may potentially avoid side effects associated with a 
single-dose, IV administration of ketorolac and metoclopramide. They will also 
receive a $20 e-gift card of their choice upon completion of the 48-hour follow-up.  
 


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2) Indirect benefits: Participants will be involved in research to explore a non-IV, 
non-medication treatment to manage acute migraine attacks in children and 
adolescents reporting to the ED, potentially allowing for future patients to avoid 
the side effects associated with a single-dose, IV administration of ketorolac and 
metoclopramide. 
13.3.4. Privacy and Confidentiality 
Participant information will be coded using study identification numbers. Participant data 
will be entered into the REDCap study database using the study identification numbers. 
The Record ID form in REDCap will contain participants’ names, dates of birth, and contact 
information. The purpose of this will be to identify participants for follow-up and to have 
adequate identifying and contact information available for the purposes of following up on 
adverse events as needed. The password-protected access to REDCap is granted to 
research staff only and is monitored by the Clinical Research Unit in the Faculty of Medicine 
at the University of Calgary. REDCap is housed in servers located in Canada and is firewall 
protected. Only the pharmacists carrying out randomization will have access to the 
participants’ group assignments in case there are adverse reactions that require 
unblinding. The allocation list maintained by pharmacy will not contain identifiable 
information, but will contain the participant randomization code. This code will be used to 
identify participants for unblinding if needed for safety reasons (i.e., the randomization 
code assigned to the participant will be entered into REDCap, where identifying and contact 
information will also be stored, and this code will be linked to the assignment information 
provided by pharmacy). 
14. Budget and Finance 
 
This study is funded by a Canadian Institutes of Health Research Early Career Investigator 
Grant in Maternal, Reproductive, Child & Youth Health (funding reference number = 
177445), and through Dr. Orr’s start-up funds from the University of Calgary Department 
of Pediatrics and the Alberta Children’s Hospital Research Institute. We have partnered 
with Theranica Bioelectrics Ltd for this study, who will also be offering 5,000$ of in-kind 
contributions towards to study in the form of active and sham REN devices for the trial. For 
knowledge translation, we have also partnered with SKIP, TREKK and the Alberta SPOR 
Support Unit’s (AbSPORU) KT and patient engagement platforms, each of whom have 
contributed to design of our KT plan and who are providing in-kind support for our KT 
plans. The total estimated cost for this study will be 35,000$ of in-kind support, and 
236,603.60$ of cash costs, over the planned 3 year study period (2 years of recruitment, 
and 1 year of preparation and study completion). Details regarding our budget are 
available in Appendix AD. 


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15. Publication Plan 
A manuscript will be submitted for publication to a peer-reviewed medical journal and at 
least one conference abstract will be submitted for presentation. The listed investigators 
will participate in the drafting, review and dissemination of the manuscript and abstracts. 
Authors will be required to meet authorship criteria as laid out in the International 
Committee of Medical Journal Editors Guidelines (ICMJE).  
16. Knowledge Translation Plan 
16.1. Patients and Families 
We will engage with patients throughout all study phases as part of our knowledge 
translation (KT) plan. We have already engaged with patients through our preliminary 
treatment preferences survey and our virtual patient engagement session, as previously 
described. During these endeavours, we received feedback from patient knowledge users 
that has directly informed the proposed project regarding device preferences and 
optimizing study design. We evaluated our patient engagement session using the Public 
and Patient Engagement Evaluation Tool (PPEET),120 and found that this tool was easy to 
implement, and that it demonstrated clearly that the participants felt engaged and 
supported (Orr lab; unpublished). 
 
To facilitate our ongoing patient engagement strategy and implementation, we have 
partnered with Solutions for Kids in Pain (SKIP), a knowledge mobilization network for 
which co-investigator Dr. Birnie is Assistant Scientific Director. SKIP has offered an in-kind 
contribution of 15,000$ and we will have engaged with a knowledge broker and patient 
engagement coordinator from SKIP to further develop and carry out our patient 
engagement strategy. We are also working with the Alberta SPOR Support Unit’s 
(AbSPORU) KT and patient engagement platforms to optimize our KT and patient 
engagement strategies. We have identified two patient partners to engage with us regularly 
throughout the study to inform study design, execution, and translation for greater impact 
(e.g. recruitment, readability/understandability of materials, sharing of study findings). 
The patient partners will receive payment for their collaboration in accordance with SKIP’s 
guidelines on patient partner reimbursement (i.e., 500$/year for each year of involvement 
with the study). The patient partners will also help to co-facilitate another patient 
engagement session once the pilot trial is complete to plan next steps (i.e., planning a 
multicenter trial and how to disseminate the pilot trial results in a patient-centered 
manner). We will again use the PPEET120 to evaluate patient engagement at this stage. 
 
For end-of-grant KT, our goal is to inform patients and families about our preliminary 
results and plans for future research. To achieve this, we will continue to work with SKIP 
and the AbSPORU, and we will also be working with Translating Emergency Knowledge for 
Kids (TREKK; www.trekk.com), a knowledge mobilization network focused on pediatric 


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emergency medicine that will be providing us with 5,000$ of in-kind support. We will 
leverage the SKIP, the AbSPORU, and the TREKK networks of partners and knowledge 
users (patients, caregivers, health professionals, decision-makers, and policymakers) to 
mobilize our study findings (e.g., webinars, media articles). 
16.2. Research community and health care professionals 
We are engaging with pediatric emergency researchers regularly through Pediatric 
Emergency Research Canada (PERC).60 At the recent PERC annual meeting (February 3rd 
2021), we presented our pilot protocol and engaged with pediatric ED researchers for 
feedback, which we have integrated into the proposal. We also presented to pediatric ED 
nurses and physicians at ACH to solicit their feedback. These engagements occurred during 
the May 6, 2021 Research Steering Committee meeting and the June 8, 2021 Quality 
Improvement Committee meeting. Feedback obtained from these meetings has been 
incorporated into the current protocol. 
 
For our end-of-grant KT plan, we aim to disseminate the results of our pilot trial to the 
research community and to health care professionals, and to engage them in future plans 
arising from this pilot trial (i.e., if feasibility and acceptability are demonstrated, we will 
engage these knowledge users in multicenter RCT design and execution). To achieve these 
goals, we will publish the results of this pilot trial in an open access journal to disseminate 
our key findings and messages. We will present these results at local, national, and 
international clinical rounds and research conferences, including the PERC annual meeting 
and the American Headache Society annual meeting. We will engage clinicians and 
researchers through the SKIP and TREKK networks. National and international 
engagement will also occur through consultation with the Pediatric Canadian Headache 
Network (PeCaHN: https://headachesociety.ca/pecahn/), a national group of pediatric 
headache experts led by Dr. Orr, and the American Headache Society, of which NPA Dr. Orr 
is an emerging leader. 
17. References 
 
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James SL, Abate D, Abate KH, et al. Global, regional, and national incidence, 
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Orr SL, Potter BK, Ma J, Colman I. Migraine and mental health in a population-based 


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Pain 2010;14(9):951–8.  
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Rocha-Filho PA, Santos P V. Headaches, quality of life, and academic performance in 
schoolchildren and adolescents. Headache 2014;54(7):1194–202.  
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