Remote Electrical Neuromodulation for Acute Procedural Pain in Chronic Migraine Patients Receiving onabotulinumtoxinA
Phase: NA
Conditions: Chronic Migraine
Sponsor: Mayo Clinic

 
 
Remote Electrical Neuromodulation for Acute 
Procedural Pain in Chronic Migraine Patients 
Receiving onabotulinumtoxinA   
 
NCT05730556 
 
30November2023 

CONFIDENTIAL: This document is the intellectual property of Amaal J. Starling, MD. Acceptance of this document 
constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without prior written approval.  
 
 
 
Page 1 
RESEARCH PROTOCOL 
 
 
Remote electrical neuromodulation for acute procedural pain in chronic migraine 
patients receiving onabotulinumtoxinA 
 
 
Christopher C. Anderson, MD 
Fellow Physician 
Department of Neurology 
Mayo Clinic – Scottsdale, AZ 
 
 
Juliana H VanderPluym, MD 
Associate Professor of Neurology 
Department of Neurology 
Mayo Clinic – Scottsdale, AZ 
 
 
Amaal J. Starling, MD 
Associate Professor of Neurology 
Department of Neurology 
Mayo Clinic – Scottsdale, AZ 
starling.amaal@mayo.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version 1.7  
November 2023 
 
 

CONFIDENTIAL: This document is the intellectual property of Amaal J. Starling, MD. Acceptance of this document 
constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without prior written approval.  
 
 
 
Page 2 
SYNOPSIS 
Study Title 
Remote electrical neuromodulation for acute procedural pain in chronic migraine patients receiving 
onabotulinumtoxinA 
Objectives 
To assess the effectiveness of remote electrical neuromodulation with the Nerivio ® device at relieving acute procedural 
pain in patients receiving onabotulinumtoxinA per PREEMPT protocol for chronic migraine prevention. 
Study Period 
24 weeks 
 Subjects 
80 subjects ages 18 - 75 who meet criteria for chronic migraine receiving onabotulinumtoxinA for chronic migraine 
Study Treatment 
Nerivio ® (Remote Electrical Neuromodulation) applied to the upper extremity prior to the procedure and removed 
following procedure.  
Study Design 
Single-center, randomized, single-blind, sham-controlled, crossover study to evaluate the effectiveness of Nerivio ® for 
treatment of acute procedural pain in patients receiving onabotulinumtoxinA for the treatment of chronic migraine. During 
phase 1, 80 adults with a diagnosis of chronic migraines will be surveyed on their pain levels during routine procedure and 
then randomized to receive either intervention vs sham treatment at week 12 +/- 7 days (buffer time to accommodate 
rescheduling) for phase 2. For phase 3, subjects will then transition to receive the alternate therapy at week 24 +/- 7 days. 
Pain levels will be compared across time points 
 
Inclusion and 
Exclusion Criteria 
Inclusion Criteria 
1. 
Adults aged 18 to 75 years old 
2. 
Meet the criteria for 1.3 chronic migraine based on ICHD3 criteria 
3. 
Currently receiving onabotulinumtoxinA per PREEMPT protocol for the treatment of chronic migraine 
4. 
Patient is willing and able to comply with the protocol to the satisfaction of the investigator 
5. 
Patient has the capacity to provide written, informed consent for themselves 
 
Exclusion Criteria 
1. 
Participants with an active implanted electrical and/or neurostimulator device (e.g., cardiac pacemaker, cochlear 
implant).  
2. 
Participants with congestive heart failure (CHF), severe cardiac or cerebrovascular disease. 
3. 
Participants with uncontrolled epilepsy. 
4. 
Pregnant, trying to get pregnant or breastfeeding female participants 
5. 
Subjects participating in any other interventional clinical study. 
6. 
Participants with other significant pain, medical or psychological problems that in the opinion of the investigator may 
confound the study assessments 
7. 
Participants who have previous experience with the device 
8. 
Patients with cranial deformities, prior cranial surgeries with violation of the calvarium, or shunt placement 
9. 
Patients receiving concurrent nerve blocks or trigger point injections within the same visit 
Measurements 
Subjects will be surveyed on their pain intensity using a Visual Analog Scale pre-, intra- and post-procedure 
(approximately 0 – 5 minutes post-procedure). Additionally, patient demographic information (sex, age, race, ethnicity), 
BMI, arm circumference, depression/anxiety screen, medical comorbidities, headache qualities (location, duration, 
intensity, frequency, associated symptoms), previous rounds of onaboulinumtoxinA received, current treatment regimen 
(beyond onabotulinumtoxinA) including other preventive and abortive treatments will be recorded. Migraine-specific quality 
measures (MIDAS) will also be recorded throughout the study period. Patients will be contacted on the day following each 
treatment of onabotulinumtoxinA to follow-up on post-procedural headache.  
 
Outcomes 
Primary: Pain intensity with a Visual Analog Scale, pre- , intra-, and post-procedure 
 
Secondary: 
1.  Presence of post-procedural headache 
2.  Any adverse events.  
 
 
 
 
 

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constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without prior written approval.  
 
 
 
Page 3 
1. Background and Rationale:  
 
Migraine is a condition that impacts a large segment of the global population (~958.8 million) 
and is exceeded only by stroke with regards to its overall burden of neurological disease (GBD 
2015 Neurological Disorders Collaborator Group). It has been estimated that the prevalence 
of total migraine (episodic and chronic) is about 20.7% in women and 10.7% in men in the 
United States (Burch 2020). Of the patients with episodic migraine, it has been shown that 
around 2.5% will progress or “transform” into chronic migraine, defined as headache that occurs 
≥15 days per month with at least 8 headaches with features of migraine based on the 
International Classification of Headache Disorders 3rd Edition (ICHD-3) criteria (Buse 2012, see 
ICHD-3 criteria in supplemental material).  
 
The injection of onabotulinumtoxinA (BoNT-A) is common treatment for patients with a wide 
variety of conditions such as chronic migraine, cervical dystonia, spasticity, strabismus, 
neurogenic bladder, and hyperhidrosis. Proper implementation of this treatment modality can 
involve the injection of BoNT-A into many different sites per procedural visit and must be 
repeated to ensure continued effect. BoNT-A for the treatment of chronic migraine is 
administered per PREEMPT protocol, which involves the injection of 5U into 31 injection sites 
(total 155U) with the option for additional injections (up to 40-45U) based on a follow-the-pain 
strategy and must be administered every 10 to 12 weeks to maintain effect (Aurora, 2010; 
Diener, 2010). While levels of procedural discomfort do not appear to predict therapy 
continuation (Anderson, 2020), steps should be taken to reduce needle-related pain to 
minimize stress and anxiety surrounding the procedure.  
 
Management of acute procedural pain is an area of considerable interest, typically with relation 
to pediatric populations. Many modalities have been found to be effective at reducing procedural 
needle-related pain, including immersive virtual reality distraction, cognitive-behavioral therapy, 
hypnosis, breathing interventions, clown therapy, and ethyl chloride spray; however, the 
effective implementation of these strategies tends to require hiring additional personnel or 
dedication of time that may not be feasible in a busy, clinical setting. The utilization of devices 
for management of acute procedural pain has been investigated for needle-related procedures 
in children (Ballard, 2019), but further investigation is required to understand the potential 
benefits of using for acute needle-related procedural pain in adults. 
 
The Nerivio® device (Theranica Bio-Electronics Ltd., Israel) is a wearable, remote electrical 
neuromodulation (REN) device controlled by smartphone application that has been cleared for 
the acute treatment of migraine in adults and adolescents (Yarnitsky 2019, Tepper 2020, 
Ailani 2022). The proposed mechanism of action involves stimulation of peripheral nerves 
within the upper extremity, thereby inducing conditioned pain modulation (CPM) and reduction 
of acute pain. While this device is cleared for the treatment of paroxysmal pain in migraine, little 
is known about whether it could demonstrate effectiveness at reducing pain in the head and 
neck that occurs in response to procedural intervention. The aim of the current study is to 
compare acute procedural pain intensity among chronic migraine patients receiving Nerivio ® vs 
sham device treatment during treatment with onabotulinumtoxinA per the PREEMPT protocol.  
 
2. Objectives 
 
The goal of this research proposal is to establish remote electrical neuromodulation with Nerivio 
® as an efficacious therapy for acute procedural pain in patients receiving onabotulinumtoxinA 

CONFIDENTIAL: This document is the intellectual property of Amaal J. Starling, MD. Acceptance of this document 
constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without prior written approval.  
 
 
 
Page 4 
for the treatment of chronic migraine. We hope to demonstrate an improvement in procedural 
pain when patients receive remote electrical neuromodulation with Nerivio ® compared to no 
treatment and sham treatment. We will record acute procedural pain utilizing a numerical 0-10 
rating scale and will compare this number across phases to determine efficacy. We will test the 
hypotheses that: 1) Patients receiving transcutaneous remote electrical neuromodulation with 
Nerivio ® will experience significantly lower levels of acute procedural pain compared to when 
they received either no treatment or sham treatment and that (2) patients receiving remote 
electrical neuromodulation with Nerivio ® will experience a reduced incidence of post-procedural 
headache compared with either no treatment or sham treatment. For the purpose of the study, 
“post-procedural headache” will be defined as a headache 24-hours post-procedure in which 
head pain lasts 4 hours or more and is at least moderate in severity or during which abortive 
medications are used to treat the patient’s head pain.  
 
We believe that enacting strategies to reduce acute procedural pain provides benefits for the 
patient experience and if results indicate that remote electrical neuromodulation provides 
significant benefits, this method of treatment may be considered for wider use where injection of 
local anesthetic is unable to be performed, contraindicated, or not feasible, e.g., 
onabotulinumtoxin for dystonia/spasticity or cosmetic use, electromyography, or acupuncture.  
 
3.  Preliminary Data 
The utilization of devices for acute procedural pain has been investigated in the past. One such 
device, the Buzzy ®, relies on a vibrating motor and cold sensation to interfere with discomfort 
related to the procedure. A meta-analysis published in 2018 compiled the results of 9 studies 
(n=1138) and found that the device significantly reduced self-reported pain levels (standardized 
mean difference [SMD]: −1.11; 95% confidence interval [CI]: −1.52 to −0.70; P < 0.0001), 
observer-reported pain levels (SMD: −1.19; 95% CI: −1.90 to −0.47; P = 0.001), and procedural 
anxiety (SMD −1.37; 95% CI: −1.77 to −0.96; P < 0.00001). The proposed mechanism of action 
of the Buzzy ® device is the Gate Control Theory, whereby non-noxious stimuli interfere with the 
transmission of painful stimuli at the level of the dorsal horn of the spinal cord (Ballard, 2018).  
The proposed mechanism of action of Nerivio ® differs from the Buzzy ® device. Per the 
device’s manufacturers, Nerivio ® produces its effects via remote electrical neuromodulation 
(REN). REN acts by stimulating peripheral nerves of the upper extremity with electrical stimulus 
that is not painful. These signals induce a conditioned pain modulation (CPM) response at the 
level of the brainstem, specifically at the periaqueductal gray and rostral ventromedial medulla 
(Yarnitsky, 2019). Nerivio ®  has been found to be effective for the acute treatment of migraine 
headache compared to sham stimulation with significant benefits in pain relief (66.7% [66/99] vs 
38.8% [40/103]; therapeutic gain of 27.9% [CI95%, 15.6-40.2]; P < .0001), pain-free (37.4% vs 
18.4%, P = .003), and most-bothersome-symptom relief (46.3% vs 22.2%, P = .0008) at 2 hours 
post-treatment. The device also has device-related adverse events (4.8% [6/126] vs 2.4% 
[3/126], P = .499) with the most common adverse events being warmth sensation (2.4% 
treatment vs 0.8% sham; redness 1.6% treatment vs 0.8% sham; and pain in the arm (1.6% 
treatment vs 0% sham) (Yarnitsky, 2019).   
While this device has been studied for acute migraine, further studies are required to determine 
its effectiveness at treating other types of pain. Of interest to this study, we will be investigating 
acute procedural pain in the cranial-cervical region.   

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constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
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Page 5 
 
4. Patient Selection 
 
Subjects will be recruited from the patient population at the Headache Medicine clinic at the Mayo 
Clinic Scottsdale, Arizona location. Subjects will initially be approached in the clinic in person or 
by phone. Prior to study initiation, written informed consent or electronic consent will be obtained 
from the subject. Goal enrollment is 80 adults (18 - 75 years old) who meet the criteria for a 
diagnosis of chronic migraine that have been stable on their current headache medication for a 
minimum of 8 weeks. Definition of chronic migraines will be defined per the International 
Classification of Headache Disorders (ICHD3) as a headache occurring on 15 or more 
days/month for more than 3 months, which have the features of migraine headache on at least 8 
days/month. Subjects should be approved and scheduled to received onabotulinumtoxinA for the 
treatment of chronic migraine for recruitment.  
 
4.1. Inclusion Criteria 
 
4.1.1 Adults aged 18 to 75 years old 
4.1.2 Meet the criteria for 1.3 chronic migraine based on ICHD3 criteria 
4.1.3 Currently receiving onabotulinumtoxinA per PREEMPT protocol for the treatment of 
chronic migraine 
4.1.4 Patient is willing and able to comply with the protocol to the satisfaction of the investigator 
4.1.5 Patient has the capacity to provide written, informed consent for themselves 
 
4.2. Exclusion Criteria 
 
4.2.1 Participants with an active implanted electrical and/or neurostimulator device (e.g., cardiac 
pacemaker, cochlear implant).  
4.2.2 Participants with congestive heart failure (CHF), severe cardiac or cerebrovascular 
disease. 
4.2.3 Participants with uncontrolled epilepsy. 
4.2.4 Pregnant, trying to get pregnant or breastfeeding female participants 
4.2.5 Subjects participating in any other interventional clinical study. 
4.2.6 Participants with other significant pain, medical or psychological problems that in the 
opinion of the investigator may confound the study assessments 
4.2.7 Participants who have previous experience with the device 
4.2.8 Patients with cranial deformities, prior cranial surgeries with violation of the calvarium, or 
shunt placement 
4.2.9 Patients receiving concurrent nerve blocks or trigger point injections within the same visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. Methods:  

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constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without prior written approval.  
 
 
 
Page 6 
5.1. Study design: Single-center, randomized, single-blind, sham-controlled crossover trial 
 
 
 
5.2. Pretreatment phase 
Informed consent in English will be obtained prior to enrollment into the study.  
 
5.3. Treatment Phase 
Upon receipt of informed consent, the patient will enter phase 1 of the study. This phase is used 
to determine baseline experience with the PREEMPT protocol and will involve obtaining pre-, 
intra-, and post-procedural pain intensity levels based on a standard visual analog scale. 
Subjects will then be contacted the following day to inquire about the presence of post-
procedural headache. Following their initial treatment of BoNT-A, subjects will then be 
randomized to receive either remote electrical neuromodulation with Nerivio ® or stimulation 
with a sham device for their next BoNT-A treatment and enter phase 2. During phase 2, patients 
will again receive BoNT-A treatment via PREEMPT protocol at week 12 +/- 7 days (buffer period 
to accommodate rescheduling) and will also be treated with either Nerivio ® or receive 
stimulation with a sham device supplied by Theranica Bio-electronics, Ltd. Patients will have 
the device applied 20 minutes prior to starting the Botox procedure with an estimated total time 
of wearing the device around 40 to 45 minutes. Again, patients will be surveyed regarding their 
pre-, intra-, and post-procedural pain intensity and will be contacted on the following day re: 
post-procedural headache. Finally, patients will receive their final treatment of BoNT-A at week 
24 +/- 7 days and will receive concurrent treatment with the alternative stimulation setting (either 
Nerivio ® treatment stimulation or sham stimulation). Pre-, intra-, and post-procedural pain 
levels and post-procedural headache will be recorded in an identical fashion.  

CONFIDENTIAL: This document is the intellectual property of Amaal J. Starling, MD. Acceptance of this document 
constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
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Page 7 
 
5.4. Conclusion of study 
The study ends 24 weeks after consent was obtained (excluding potential buffer time to 
accommodate rescheduling).  
 
6.  Data Collection and Monitoring 
6.1. Clinical Assessments 
Patients will have received a focused neurological exam at their prior clinic visit and will be 
surveyed regarding their pre-procedural, intra-procedural, and post-procedural pain, before, 
during, and after receipt of onabotulinumtoxinA with PREEMPT protocol. Per routine clinical 
practice, patients will be monitored for 5 minutes post-procedure to ensure lack of acute 
adverse effects to the procedure. 
 
6.2. Post-procedural headache 
Subjects will be contacted on the day following each administration of onabotulinumtoxinA to 
inquire about the presence of post-procedural headache, defined as a headache that lasts for 4 
hours or more and is at least moderate in severity or during which abortive medications are 
used to treat the patient’s head pain. 
 
6.3. Patient History 
Patient history will be collected to ensure accurate diagnosis of chronic migraines as well as to 
document currently prescribed abortive and prophylactic migraine medications. Patient medical 
history and device history will also be reviewed to ensure no contraindications to device 
administration. 
 
6.4. Lab Work 
None required 
 
7. Outcome Measures 
 
7.1. Primary Outcome Measure  
The primary outcome is the reduction in pain intensity measured via Visual Analog Scale (VAS) 
among patients at the baseline or sham treatment compared to treatment with remote electrical 
neuromodulation using Nerivio ®.  
 
7.2. Secondary Outcome Measures 
 
7.2.1. Subjects will be contacted on the day following each administration of onabotulinumtoxinA 
to inquire about the presence of post-procedural headache, defined as a headache that lasts for 
4 hours or more and is at least moderate in severity or during which abortive medications are 
used to treat the patient’s head pain. 
 
7.2.5. Any adverse events. 
 
7.3. Statistical Analysis 
 
Subjects will be randomized to treatment vs sham treatment groups utilizing the REDCap. Study 
data will be collected and managed using REDCap electronic data capture tools hosted at the 
Mayo Clinic – Arizona. REDCap (Research Electronic Data Capture) is a secure, web-based 

CONFIDENTIAL: This document is the intellectual property of Amaal J. Starling, MD. Acceptance of this document 
constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without prior written approval.  
 
 
 
Page 8 
software platform designed to support data capture for research studies, providing 1) an intuitive 
interface for validated data capture; 2) audit trails for tracking data manipulation and export 
procedures; 3) automated export procedures for seamless data downloads to common statistical 
packages; and 4) procedures for data integration and interoperability with external sources 
(Harris, 2009; Harris 2019). 
7.3.1 Sample Size Consideration 
Primary endpoint: Pain level change from pre-treatment/pre-sham, intra-treatment/intra-sham, 
and post-treatment/post-sham 
A two-sided t-test achieves 80% to infer that the mean difference (between treatment and sham) 
is not 0 when the total sample size of a 2x2 cross-over design is 80 with an equal number in 
each sequence (n=40/sequence) when the actual effect size is 0.45 (standardized difference, 
medium effect size) and the significance level is 0.05. 
7.3.2 Statistical Analysis Plan 
Summary statistics will be used to describe the patient population’s demographics and clinical 
characteristics. Patients’ pain level change and post-procedure headache after each 
treatment/sham as well as patients’ any adverse events will be summarized in descriptive 
statistics. 
Linear mixed model will be used to analyze the primary outcome for 2 by 2 cross-over study 
design. Treatment group will be the primary predictor in the model while sequence and period 
will be adjusted in the model. 
Generalized linear mixed model will be used to analyze the effect of treatment on the secondary 
endpoint presence of post-procedural headache. Similarly, treatment group will be used as the 
primary predictor while sequence and period will be adjusted in the model. 
7.3.3 Interim Analysis Plan 
Interim analyses: One interim analysis will be conducted after 50% of patients have completed 
the 24 weeks study period.  The interim analysis will include the below stopping rule for efficacy 
and futility based on Lan-DeMets spending function with O’Brien-Fleming boundaries.  
Occurrence of adverse events will also be evaluated at the interim analysis.  
Accrual  
Total Number 
Efficacy 
boundary    
(Z scale) 
Alpha 
spent 
Futility 
boundary    
(Z scale) 
Beta 
spent 
50% 
40 
  +/- 2.96 
0.003   +/- 0.35 
0.04 
100% 
80 
  +/- 1.95 
0.05 
  +/- 1.95 
0.2 
 
 

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constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
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Page 9 
8.  Potential Risks 
8.1. Breach of confidentiality 
There is minimal risk associated with the collection and recording of patient medical record 
numbers to permit review of the patient’s medical record. 
 
8.3 Remote Electrical Neuromodulation with Nerivio ® 
Nerivo® is a wearable, remote electrical neuromodulation (REN) device controlled by smartphone 
application that has been cleared for the acute treatment of migraine in adults and adolescents. 
Thus, the device is non-invasive and non-pharmaceutical. The device is contraindicated in 
patients with congestive heart failure, severe cardiac or cerebrovascular disease, or poorly 
controlled epilepsy and should not be used in patients with active implantable disease such as 
vagus nerve stimulator (VNS), cardiac pacemaker, deep brain stimulator, or cochlear implant due 
to theoretical ability to disrupt regular function of the device. It should only be applied to healthy 
skin that is free if cuts, abrasions, burns, infection, or malignancy. It should not be used near 
metallic implants. Potential adverse reactions include skin rash or redness under the electrodes 
of the device.  
 
Patients’ skin will be examined for integrity prior to placement of the device. Patients who 
develop skin rash or redness in response to the study or sham device will be excluded from 
further investigation.  
 
There is no known risk of Nerivio ® interfering with onabotulinumtoxinA efficacy or 
administration. 
 
Nerivio ® User Manual will be included in supplemental information separate from this protocol. 
 
8.2. OnabotulinumtoxinA administration 
OnabotulinumtoxinA is a product of Allergan Pharmaceuticals (BOTOX ®, Abbvie, North 
Chicago, IL). Botulinum toxin is a neurotoxin produced the bacterium Clostridium botulinum. The 
mechanism of action of botulinum toxin is the inhibition of acetylcholine release at the 
neuromuscular junction by binding to SNARE (SNAP Receptor) proteins at the synaptic bouton. 
The pharmacologic mechanism of botulinum toxin prevents the build-up of intracellular sodium 
ions and subsequent generation of the endplate potential required for calcium channel activation 
that induces muscle contraction. Botulinum toxin is potentially fatal when absorbed systemically, 
typically via infection with Clostridium botulinum spores (i.e., botulism) or exposure to large 
amounts of foodborne toxin.  
 
While the mechanism of action of botulinum toxin through inhibition of acetylcholine release at 
the neuromuscular junction is a sufficient explanation for its effects at reducing spasticity, it is a 
matter of debate how local, intramuscular injection of the toxin reduces headache frequency and 
intensity in patients with chronic migraine. Proposed mechanisms involve local uptake and 
inhibition of proteins known to be involved in migraine pathophysiology such as calcitonin gene-
related peptide (Burstein, 2020). While further research is required to elucidate its mechanism, 
onabotulinumtoxinA has been found to be effective at reducing headache burden when applied 
via the PREEMPT protocol, which involves the injection of 5U into 31 injection sites (total 155U) 
with the option for additional injections (up to 40U) based on a follow-the-pain strategy and must 
be administered every 10 to 12 weeks to maintain effect (Aurora, 2010; Diener, 2010). In usual 
clinical practice, patients will receive between 150 and 200U based on vial size made available 

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constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without prior written approval.  
 
 
 
Page 10 
by the pharmaceutical company with most patients receiving between 155 and 200U every 10 to 
12 weeks.  
 
The risks involved with local onabotulinumtoxinA for the treatment of chronic migraine include 
temporary increased neck pain, headache, bruising, bleeding, and infection at the injection site. 
There is a low risk of brow ptosis following administration of onabotulinumtoxinA to the forehead 
that is temporary. Patients are also informed that there is a Boxed Warning applied to 
onabotulinumtoxinA regarding the Distant Spread of Toxin Effect that can be life-threatening 
and involve symptoms similar to systemic absorption of the toxin, namely swallowing and 
breathing difficulties. Generally, the risk of life-threatening adverse effect is exceedingly rare 
and is highest in patients receiving the toxin for treatment of spasticity (higher unit amount 
injected) and in children (BOTOX full prescribing information). 
 
8.3 Steps Taken to Mitigate Risk 
Studies are conducted under the supervision of the investigating physicians who are trained and 
experienced in performing research in human subjects. 
 
Inclusion and exclusion criteria, monitoring, and the clinical protocol are designed to ensure that 
risks are minimal. Subjects are informed that participation is voluntary, and they may refuse to 
participate and may withdraw from the study at any time without penalty.  
 
With regard to confidentiality: (1) all subjects will be assigned a study ID number, (2) the link to 
identifiers will be deleted at the end of the study, (3) data will be stored in REDcap. If data are 
published, there will be no link to identifiers. Study data will not be revealed to any organization, 
individuals other than the subjects, or the subjects themselves, (4) study data will not be entered 
in subjects' medical records.  
 
9. Management of Intercurrent Events 
9.1. Adverse Experiences 
The investigator will closely monitor subjects for evidence of adverse events.  All adverse events 
will be reported and followed until satisfactory resolution.  The description of the adverse 
experience will include the time of onset, duration, intensity, etiology, relationship to the study 
drug (none, unlikely, possible, probable, highly probable), and any treatment required. 
 
9.2. Premature Discontinuation 
If a subject withdraws from the study, the subject will be replaced to provide the required number 
of subjects. Subjects will be withdrawn if the investigator decides that discontinuation is in the 
best interest of the subject, or the subject requests withdrawal from the study. Data collected from 
patients who withdraw will be kept for analysis however they will not be included in the primary or 
secondary outcome measures.  
 
10.  Data and Safety Monitoring Plan 
Studies conducted in the Department of Neurology follow the Mayo Clinic Institutional Review 
Board Policies and Procedures. All individuals working on the study are required to read and be 
familiar with and compliant with the IRB Policies and Procedures. The specific monitoring plan for 
this investigation is commensurate with the risks and the size and complexity of the investigations 
planned. The potential risks are attributable to the use of onabotulinumtoxinA for the treatment of 
chronic migraine. Based on the small size and relatively low risk nature of the protocol, the 
investigating physicians are involved in the monitoring plan. These individuals will review the 

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constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without prior written approval.  
 
 
 
Page 11 
annual summary of adverse events. In addition, they will review all reports of a Serious Adverse 
Event, or an Unexpected Adverse Event.  
 
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Anderson, C. C., Ray, C. A., Butler, M. R., & Darken, R. S. (2020). Effects of Procedural 
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constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without prior written approval.  
 
 
 
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https://doi.org/10.1111/head.13551 
 
 
Supplemental Material – ICHD-3 Criteria for episodic and chronic migraine 
 
1.1 Migraine without aura 
Previously used terms: 
Common migraine; hemicrania simplex. 
Description: 
Recurrent headache disorder manifesting in attacks lasting 4-72 hours. Typical characteristics of the 
headache are unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine 
physical activity and association with nausea and/or photophobia and phonophobia. 
Diagnostic criteria: 
A. At least five attacks1 fulfilling criteria B-D 
B. Headache attacks lasting 4-72 hr (untreated or unsuccessfully treated)2;3 
C. Headache has at least two of the following four characteristics: 
1. unilateral location 
2. pulsating quality 
3. moderate or severe pain intensity 
4. aggravation by or causing avoidance of routine physical activity (eg, walking or climbing 
stairs) 
D. During headache at least one of the following: 
1. nausea and/or vomiting 
2. photophobia and phonophobia 
E. Not better accounted for by another ICHD-3 diagnosis. 

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constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without prior written approval.  
 
 
 
Page 13 
Notes: 
1. One or a few migraine attacks may be difficult to distinguish from symptomatic migraine-like 
attacks. Furthermore, the nature of a single or a few attacks may be difficult to understand. 
Therefore, at least five attacks are required. Individuals who otherwise meet criteria for 1.1 
Migraine without aura but have had fewer than five attacks should be coded 1.5.1 Probable 
migraine without aura. 
2. When the patient falls asleep during migraine and wakes up without it, duration of the attack is 
reckoned until the time of awakening. 
3. In children and adolescents (aged under 18 years), attacks may last 2-72 hours (the evidence for 
untreated durations of less than two hours in children has not been substantiated). 
1.2 Migraine with aura 
Previously used terms: 
Classic or classical migraine; ophthalmic, hemiparaesthetic, hemiplegic or aphasic migraine; migraine 
accompagnée; complicated migraine. 
Description: 
Recurrent attacks, lasting minutes, of unilateral fully-reversible visual, sensory or other central nervous 
system symptoms that usually develop gradually and are usually followed by headache and associated 
migraine symptoms. 
Diagnostic criteria: 
A. At least two attacks fulfilling criteria B and C 
B. One or more of the following fully reversible aura symptoms: 
1. visual 
2. sensory 
3. speech and/or language 
4. motor 
5. brainstem 
6. retinal 
C. At least three of the following six characteristics: 
1. at least one aura symptom spreads gradually over ≥5 minutes 
2. two or more aura symptoms occur in succession 
3. each individual aura symptom lasts 5-60 minutes1 
4. at least one aura symptom is unilateral2 
5. at least one aura symptom is positive3 
6. the aura is accompanied, or followed within 60 minutes, by headache 
D. Not better accounted for by another ICHD-3 diagnosis. 

CONFIDENTIAL: This document is the intellectual property of Amaal J. Starling, MD. Acceptance of this document 
constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without prior written approval.  
 
 
 
Page 14 
Notes: 
1. When for example three symptoms occur during an aura, the acceptable maximal duration is 
3×60 minutes. Motor symptoms may last up to 72 hours. 
2. Aphasia is always regarded as a unilateral symptom; dysarthria may or may not be. 
3. Scintillations and pins and needles are positive symptoms of aura. 
1.3 Chronic migraine 
Description: 
Headache occurring on 15 or more days/month for more than 3 months, which, on at least 8 days/month, 
has the features of migraine headache. 
Diagnostic criteria: 
A. Headache (migraine-like or tension-type-like1) on ≥15 days/month for >3 months, and fulfilling 
criteria B and C 
B. Occurring in a patient who has had at least five attacks fulfilling criteria B-D for 1.1 Migraine 
without aura and/or criteria B and C for 1.2 Migraine with aura 
C. On ≥8 days/month for >3 months, fulfilling any of the following2: 
1. criteria C and D for 1.1 Migraine without aura 
2. criteria B and C for 1.2 Migraine with aura 
3. believed by the patient to be migraine at onset and relieved by a triptan or ergot 
derivative 
D. Not better accounted for by another ICHD-3 diagnosis3;4;5. 
Notes: 
1. The reason for singling out 1.3 Chronic migraine from types of episodic migraine is that it is 
impossible to distinguish the individual episodes of headache in patients with such frequent or 
continuous headaches. In fact, the characteristics of the headache may change not only from day 
to day but even within the same day. Such patients are extremely difficult to keep medication-free 
in order to observe the natural history of the headache. In this situation, attacks with and those 
without aura are both counted, as are both migraine-like and tension-type-like headaches (but not 
secondary headaches). 
2. Characterization of frequently recurring headache generally requires a headache diary to record 
information on pain and associated symptoms day-by-day for at least one month. 
3. Because tension-type-like headache is within the diagnostic criteria for 1.3 Chronic migraine, this 
diagnosis excludes the diagnosis of 2. Tension-type headache or its types. 
4. 4.10 New daily persistent headache may have features suggestive of 1.3 Chronic migraine. The 
latter disorder evolves over time from 1.1 Migraine without aura and/or 1.2 Migraine with aura; 
therefore, when these criteria A-C are fulfilled by headache that, unambiguously, is daily and 
unremitting from <24 hours after its first onset, code as 4.10 New daily persistent headache. 
When the manner of onset is not remembered or is otherwise uncertain, code as 1.3 Chronic 
migraine. 
5. The most common cause of symptoms suggestive of chronic migraine is medication overuse, as 
defined under 8.2 Medication-overuse headache. Around 50% of patients apparently with 
1.3 Chronic migraine revert to an episodic migraine type after drug withdrawal; such patients are 
in a sense wrongly diagnosed as 1.3 Chronic migraine. Equally, many patients apparently 
overusing medication do not improve after drug withdrawal; the diagnosis of 8.2 Medication-

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constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed 
without prior written approval.  
 
 
 
Page 15 
overuse headache may be inappropriate for these (assuming that chronicity induced by drug 
overuse is always reversible). For these reasons, and because of the general rule to apply all 
relevant diagnoses, patients meeting criteria for 1.3 Chronic migraine and for 8.2 Medication-
overuse headache should be coded for both. After drug withdrawal, migraine will either revert to 
an episodic type or remain chronic, and should be re-diagnosed accordingly; in the latter case, 
the diagnosis of 8.2 Medication-overuse headache may be rescinded. 
Supplemental Material – MIDAS