Imaging the Migraine Brain Pre- and Post-Erenumab: an MRI Study to Identify Functional and Structural Changes That Correlate With Patient Improvement
Phase: PHASE4
Conditions: Migraine
Sponsor: Mayo Clinic

 
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Imaging the migraine brain pre-and post-erenumab:  
an MRI study to identify functional and structural changes that 
correlate with patient improvement   
 
 
 
Research Protocol 
Version 8.0 
  December 2020  
 
NCT# 03773562 
 
 
Principal Investigators 
 
Todd Schwedt, MD 
Professor of Neurology 
Chair of Neurology Research, Mayo Arizona 
Mayo Clinic 
5777 E Mayo Blvd 
Phoenix, AZ 85255 
Schwedt.todd@mayo.edu 
 
Catherine Chong, PhD 
Assistant Professor of Neurology 
Research Scientist 
Mayo Clinic 
5777 E Mayo Blvd 
Phoenix, AZ 85255 
Chong.catherine@mayo.edu 
 
 
 
 
Funding: Amgen ISS 20187183 
 
 
 
 
 
 

 
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Imaging the migraine brain pre-and post-erenumab: an MRI study to identify 
functional and structural changes that correlate with patient improvement   
 
Table of Contents 
 
Page(s) 
 
Summary…………………………………………………………………………………………………………..... 3 
Research Team …………………………………………………………………………………………………… 4-5 
Background ……………………………………………………………………………........................................ 6 
Published Work and Preliminary Data …………………………………………………………………. 7-10 
Specific Aims ………………………………………………………………………………………………………. 11 
Methods 
Study Design ……………………………………………………………………………………………. 12 
Participants ……………………………………………………………………………………………… 12 
Subject Eligibility Criteria …………………………………………………………………………. 12-16 
Run-in Phase ……………………………………………………………………………………………. 16 
Baseline (first treatment) Visit ………………………………………………………………….. 16-17 
Case Report Forms ……………………………………………………………………………………. 17-19 
Pain Threshold Testing …………………………………………………………………………….. 19 
Imaging Protocol ………………………………………………………………………………………. 19 
N-Back Test ……………………………………………………………………………………………… 19 
Trails A and B …………………………………………………………………………………………… 19 
Treatment with Erenumab ………………………………………………………………………… 20 
Daily Headache Diary ………………………………………………………………………………… 20-21 
Follow-up Visits One through Four ……………………………………………………………. 21 
Acute Migraine Therapy ……………………………………………………………………………. 21 
Other Migraine Preventive Therapy …………………………………………………………… 21 
Imaging Data Plans …………………………………………………………………………………… 21-22 
Sample Size ………………………………………………………………………………………………. 23 
Subject Recruitment and Screening ……………………………………………………………. 23 
Subject Compensation ……………………………………………………………………………….. 24 
Informed Consent …………………………………………………………………………………….... 24 
Adverse Events …………………………………………………………………………………………. 24-25 
Subject Risks and Benefits …………………………………………………………………………. 26-27 
Subject Retention ……………………………………………………………………………………… 27 
Analysis Plans …………………………………………………………………………………………… 27-29 
Protocol Maintenance ………………………………………………………………………………... 29 
Study Registration ……………………………………………………………………………………... 29 
Appendix – Case Report Forms ……………………………………………………………………………… 30-73 
Appendix – Safety Data Exchange Requirements…………………………………………………….. 74 
References …………………………………………………………………………………………………………… 75-77 
 
 

 
3
 
 
Summary 
 
Compared to healthy people without migraine, migraine is associated with alterations in brain 
structure and function. This is a prospective, longitudinal, open-label study that will investigate brain 
magnetic resonance imaging changes amongst individuals with migraine following treatment with 
erenumab.  
 
The Specific Aims of this study are to:  
 
1. Identify changes in brain function and structure that correlate with response to 
erenumab.  
 
2. Develop models using imaging data to predict which patients will respond to erenumab. 
Pre-treatment and early post-treatment imaging data will be used separately for predictive 
modeling.  
  
The study will include 50 subjects with migraine aged 18-65 years who have 6-25 migraine days per 
month at baseline. Following a 4-week run-in phase, subjects will be treated twice with once monthly 
subcutaneous injections of erenumab 140 mg. Questionnaires, structured interviews, cognitive tests, 
quantitative sensory testing and brain imaging will be performed prior to and following erenumab 
treatment. These data will be collected at early time points after the first treatment as well as at eight 
weeks following the first treatment to allow for identification of early and late effects of erenumab on 
clinical, physiologic, and imaging outcomes and to determine if early physiologic and imaging 
outcomes predict clinical outcomes at eight weeks. Physiologic and imaging data will be compared to 
already collected data from healthy controls so as to interpret changes that are seen following 
treatment with erenumab. 
 
The primary hypothesis is that improvements in migraine patterns associated with erenumab 
treatment will be associated with “normalization” of brain function. Secondarily, it is hypothesized that 
improvements in migraine patterns associated with erenumab treatment will be associated with 
“normalization” of brain structure, pain thresholds, and cognitive performance. Finally, it is 
hypothesized that exploratory analyses will demonstrate that there are early changes in brain function 
following the first treatment with erenumab and that these early changes will be predictive of longer-
term clinical responsiveness to erenumab.  
 
 
 
 
 
 
 
 
 
 

 
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Research Team 
 
Principal Investigators 
 
Todd J. Schwedt, MD MS is a Professor of Neurology and Chair of Neurology Research at the Mayo 
Clinic in Arizona. He is the principal investigator for the Neuroimaging of Headache Disorders 
Laboratory at the Mayo Clinic.  
 
Schwedt.todd@mayo.edu 
Phone: 480-342-2695 
Fax: 480-342-6546 
5777 East Mayo Blvd 
Phoenix, Arizona 85054 
 
Catherine D. Chong, PhD is an Assistant Professor of Neurology and Research Scientist at the Mayo 
Clinic in Arizona within the Neuroimaging of Headache Disorders Laboratory.  
 
Chong.catherine@mayo.edu 
Phone: 480-342-4196 
Fax: 480-342-6546 
5777 East Mayo Blvd 
Phoenix, Arizona 85054 
 
Collaborators 
 
Teresa Wu, PhD is a Professor of Industrial Engineering at Arizona State University and Director of 
the Arizona State University – Mayo Clinic Center for Innovative Imaging. 
 
Jing Li, PhD is an Associate Professor of Industrial Engineering and Computer Engineering at Arizona 
State University and Co-Director of the Arizona State University – Mayo Clinic Center for Innovative 
Imaging. 
 
 
Research Team Staff 
 
Michael Leonard is the Research Program Manager for the Schwedt and Chong research program at 
the Mayo Clinic in Arizona.  
 
Leonard.michael@mayo.edu 
Phone: 480-342-2908 
Fax: 480-342-6546 
5777 East Mayo Blvd 
Phoenix, Arizona 85054 
 

 
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Teri Radam, Senior Research Coordinator in the Schwedt and Chong Research Program at the Mayo 
Clinic Arizona, is the research coordinator for this study. 
  
Radam.teresa@mayo.edu 
Phone: 480-342-3775 
Fax: 480-342-6546 
5777 East Mayo Blvd 
Phoenix, AZ 85255 
 
 
 
Erica Boyd, RN, Registered Nurse Clinical Research Coordinator in the Clinical Studies Unit at the 
Mayo Clinic, is the nurse research coordinator for this study. 
 
Boyd.Erica@mayo.edu  
Phone: 480-342-1316 
Fax: 480-342-6546 
5777 East Mayo Blvd 
Phoenix, AZ 85255 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Background 
  
Migraine is a highly prevalent disorder that affects 38 million people in the US and is associated with 
moderate to severe pain, hypersensitivities to sensory stimuli, nausea, vomiting, and reduced quality 
of life. (1-3) Annual costs from migraine are estimated at $20 billion in the United States and €27 
billion in Europe. (4, 5) Migraine remains poorly treated and there are currently few options for the 
preventive treatment of migraine. The release of erenumab to the market represents a substantial 
improvement in the landscape of migraine preventive treatment. 
 
Phase 2 and 3 randomized, double-blind, placebo-controlled studies have demonstrated that 
erenumab is safe and effective for the prevention of episodic and chronic migraine. (6-8) Erenumab 
received US Food and Drug Administration approval for the prevention of migraine in May 2018. 
Structural and functional neuroimaging could provide important insights into central mechanisms of 
treatment response and imaging biomarkers that track treatment response or are indicators for early 
treatment response. A few studies have demonstrated normalization of functional activation patterns, 
reorganization of functional connectivity, and normalization of brain metabolism following migraine 
treatment with external trigeminal neurostimulation, topiramate, and precision ophthalmic tints. (9-
12) However, the effects of erenumab on brain function and structure, including the processing of 
painful stimuli, have been inadequately investigated. Furthermore, it is possible that measures of 
brain function and structure could serve as predictors for clinical response to erenumab, either prior 
to treatment or early after the first treatment. It is of clinical interest to interrogate whether 
neuroimaging is a useful technique for establishing a brain biomarker for predicting treatment 
response and measuring treatment responses earlier than is possible using clinical measures alone.  
 
This study will investigate longitudinal changes in brain structure and function in high frequency 
episodic migraine and chronic migraine patients who are responding to erenumab treatment 
compared to those patients who are non-responders. In addition, pre-treatment and early post-
treatment brain imaging data will be used to build models that predict which individual migraine 
patients will respond to erenumab treatment. 
 
The Specific Aims of this study are to:  
 
1. Identify changes in brain function and structure that correlate with response to 
erenumab. This objective of this aim is to investigate effects of treatment with erenumab on 
brain function and structure in patients who respond to treatment with erenumab and in 
patients who do not respond to treatment with erenumab.  
 
2. Develop models to predict which patients will respond to erenumab. The goal of this aim is 
to identify structural and functional brain magnetic resonance imaging predictors of response to 
erenumab in patients with migraine. Specifically, this aim seeks to identify those migraine 
patients who are going to have a positive response to erenumab treatment versus those who will 
not respond to treatment. Pre-treatment and early post-treatment imaging data will be used 
separately, and in combination, for predictive modeling.  
 

 
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Published Work and Preliminary Data  
 
Our team has performed multiple studies that are directly relevant to the goals of this project and 
serve as evidence of our ability to successfully conduct this study. We have completed studies 
comparing noxious heat-induced brain activation patterns in people with migraine vs. healthy 
controls. (13) These studies showed that migraineurs have greater pain-induced activation in several 
brain regions, many of which participate in cognitive aspects of pain processing. For several of these 
regions, the extent of greater activation correlated with the frequency of headaches, serving as strong 
evidence for a direct relationship between having migraine and greater activation of these pain-
processing brain regions and at least suggesting that reductions in headache frequency would 
correlate with reductions in pain-induced activation. Our resting-state functional connectivity studies 
have investigated functional connectivity of affective-emotional pain processing regions and of 
descending pain modulatory brainstem regions. (14, 15) These studies demonstrated that 
migraineurs have atypical functional connectivity and the extent of atypical connectivity correlates 
with measures of migraine disease burden such as number of years with migraine and allodynia 
symptoms. Our structural MRI studies have shown migraineurs to have atypical structure of the 
brainstem and abnormal cortical thinning with age, aberrant correlations between brain cortical 
thickness and cutaneous pain thresholds, atypical cortical thickness correlations, and abnormal white 
matter tract integrity. (16-18) Furthermore, our work has shown migraineurs with interictal 
photosensitivity to have thicker cerebral cortex in parieto-occipital and fronto-parietal regions. (19) 
Finally, our machine-learning multivariate pattern analyses have yielded migraine classifiers that use 
brain structural data to differentiate the brain of an individual chronic migraineur from that of a 
healthy control (see Figure 1) or episodic migraineur (see Figure 2) with high accuracy (American 
Headache Society Wolff Award winning paper). (20) Our classifiers based on resting state functional 
connectivity data differentiate the brain of an individual migraineur from a healthy control with high 
accuracy (American Academy of Neurology Harold Wolff – John Graham Award winning research, see 
Figure 3). (20, 21) In addition, we developed a decision support system using multi-modality imaging 
data to interrogate the utility of combining structural and functional imaging data for migraine 
patient discrimination and the accuracy of such discrimination. (see Figure 4) (22) Results showed 
better classification accuracy when combining structural and functional data than using either data 
type alone.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Figure 1: Regions that allow for accurate discrimination of the chronic migraine brain from that of a 
healthy control. (20) Structural measures (i.e. cortical thickness, volume, surface area) of the colored 
brain regions allow for classification of the individual brain MRI as belonging to a person with 
chronic migraine vs. a healthy control with 86.3% average accuracy.  Similar model-building 
techniques can be used to construct classifiers that predict response to erenumab. 
 
 
 
 
 
Figure 2: Regions that allow for accurate discrimination of the chronic migraine brain from that of an 
episodic migraineur. (20) Structural measures (i.e. cortical thickness, volume, surface area) of the 
colored brain regions allow for classification of the individual brain MRI as belonging to a person with 
chronic migraine vs. episodic migraine with 84.2% average accuracy. Similar model-building 
techniques can be used to construct classifiers that predict response to erenumab. 
 
 
 
 
 
 
 
 

 
9
Figure 3: Functional connectivity patterns for the left and right amygdala that contribute to the 
classification accuracy of distinguishing between individual migraine patients and individual healthy 
controls. (21) Whole-brain functional connectivity patterns of 6 regions distinguished migraine 
patients from healthy controls with a best classification accuracy of 86.1%. Migraineurs with longer 
disease durations were more accurately classified than migraine patients with shorter disease 
durations. Similar model building techniques could be used to track and predict response to 
erenumab treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Figure 4: Key brain areas (based on brain structural imaging) and functional connections 
(based on resting-state imaging) that contribute to distinguishing migraine patients from 
healthy controls. (22) The combined model that included structural and functional data 
provided greater accuracy (83%) compared to the model based on structural data alone 
(80%) and the model built on functional connectivity data alone (75%). The combination of 
structural and functional brain imaging data may increase the classification accuracy for 
predicting/determining treatment response to erenumab.  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Specific Aims 
 
1. Identify changes in brain function and structure that correlate with response to 
erenumab. The objective of this aim is to investigate effects of treatment with erenumab on 
brain function and structure in patients who respond to treatment with erenumab and in 
patients who do not respond to treatment with erenumab. Specifically, this aim will assess 
changes in brain structure (cortical thickness, volume, area, white matter integrity), brain 
perfusion, resting-state functional connectivity, and pain-induced brain activation patterns in 
treatment responders and in treatment non-responders. This aim will identify structural and 
functional brain biomarkers for treatment response with erenumab. 
 
2. Develop models to predict which patients will respond to erenumab. The goal of this aim is 
to identify structural and functional brain magnetic resonance imaging predictors of response to 
erenumab in patients with migraine. Specifically, this aim seeks to identify those migraine 
patients who are going to have a positive response to erenumab treatment versus those who will 
not respond to treatment. Pre-treatment and early post-treatment imaging data will be used 
separately, and also in combination, for predictive modeling.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Methods 
 
Study Design: This is a prospective, open-label, longitudinal, pre- and post-treatment magnetic 
resonance imaging (MRI) study of patients treated with erenumab. A summary of the study flow is 
presented in Table 1.  
 
Table 1- Study Flow. 
 
 
 
 
 
Participants: Up to 67 adult patients who are at least 18 years of age but younger than 66 years of age 
with high frequency episodic migraine or chronic migraine with and/or without aura will be enrolled 
into the run-in phase of this study at Mayo Clinic Arizona.  Enrollment will stop once 50 subjects 
provide headache diary during the run-in phase that meets eligibility criteria (i.e. documented 6-25 
migraine days per 28 days).  Previously collected data of healthy control subjects (n=50) will be used 
for data comparison.  Exclusion and inclusion criteria will be modeled after those used in the phase 2 
and 3 trials of erenumab for the prevention of migraine. (6, 8) In addition, patients who have 
contraindications to MRI (e.g. metal implants, aneurysm clips, severe claustrophobia) will be excluded 
from study participation. Potential participants will be excluded if they have active chronic pain 
conditions other than migraine (e.g. chronic pelvic pain) or acute pain conditions (e.g. recent surgery). 
Potential participants who have sensory disorders that might affect the perception of cutaneous 
thermal stimuli will also be excluded (e.g. peripheral neuropathy). 
 
Subject Eligibility 
 
Inclusion Criteria 
 
 Adults 18-65 years of age 
 
Run 
 
in 
 
P hase 
 
(time : -4 
 
wks )
Base l i ne 
( ti me: 0) 
 
First Follow-up  
(ti m e: 
 
2  
 
wks) 
Se cond F oll ow-up 
(time: 4  wks)
Third Follo w-up 
(time: 8 wks)
Fo urt h Fo llow-up 
(time: 1 2 wks)
Deter mi ne 
 
Eli gi bi l ity 
x 
x 
Que sti on naires
x 
x 
x
x
x
x
QS T 
x 
x
x
M R Imaging
x 
x
x
Cogn i ti v e  Test ing
x 
x
x
V i t al Signs
 
x 
x
x
x
x
U rine P r egnancy  
 
T est
 
x 
x
Erenumab Tr eat ment
x 
x
Headach e 
 
D iary 
x 
x 
x
x
x
x

 
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 Episodic migraine (with or without aura) or chronic migraine according to the diagnostic 
criteria included within the International Classification of Headache Disorders 3 (ICHD-3) (23) 
 
o Episodic Migraine 
A. At least 5 attacks fulfilling criteria B-D 
B. Headache attacks lasting 4-72 hours (when untreated or unsuccessfully treated) 
C. Headache has at least two of the following four characteristics: 
a. Unilateral location 
b. Pulsating quality 
c. Moderate or severe pain intensity 
d. Aggravation or causing avoidance of routine physical activity  
D. During headache at least one of the following:  
a. Nausea and/or vomiting 
b. Photophobia and phonophobia 
E. Not better accounted for by another ICHD-3 diagnosis 
 
o Chronic Migraine 
A. Headache (migraine-like or tension-type like) on at least 15 days per month for 
longer than 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  
“episodic migraine” (above) 
C. On at least 8 days per month for longer than 3 months, fulfilling any of the 
following: 
a. Criteria C and D for migraine without aura 
b. Criteria B and C for migraine with aura 
c. Believed by the patient to be a migraine at onset and relieved by a triptan 
or ergot derivative 
D. Not better accounted for by another ICHD-3 diagnosis 
 
 6-25 migraine days per month on average over the 3 months prior to screening, confirmed by 
run-in phase prospective data collection 
 
 Duration since migraine onset of at least 12 months prior to screening based on medical 
records and/or patient self-report  
 
Exclusion Criteria 
 
 Older than 50 years of age at migraine onset 
 
 History of cluster headache or hemiplegic migraine 
 
 Continuous headache pain (i.e. no pain-free periods of any duration during the one month 
before screening) 
 

 
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 Opioid- or butalbital-containing analgesics on 6 or more days per month during the 2 months 
prior to the start of the baseline phase 
 
 History of major psychiatric disorder such as schizophrenia and bipolar disorder 
 
 History or evidence of any unstable or clinically significant medical condition, that in the 
opinion of the investigator, would pose a risk to subject safety or interfere with the study 
evaluation, procedures, or completion 
 
 No therapeutic response in migraine prevention after an adequate therapeutic trial of 4 or 
more of the following medication categories: 
o Category 1: divalproex sodium, sodium valproate 
o Category 2: topiramate 
o Category 3: beta-blockers 
o Category 4: tricyclic antidepressants 
o Category 5: venlafaxine or desvenlafaxine, duloxetine or milnacipran 
o Category 6: flunarizine, verapamil 
o Category 7: lisinopril, candesartan 
o Category 8: botulinum toxin 
 
No therapeutic response is defined as no reduction in headache frequency, duration, or 
severity after administration of the medication for at least 6 weeks at the generally accepted 
therapeutic dose(s) based on the investigator’s assessment. Lack of sustained response to a 
medication and failure to tolerate a therapeutic dose are not considered to be “no therapeutic 
response”. 
 
 Concomitant use of 3 or more of the following medications for migraine prevention within 2 
months before the start of the baseline phase or throughout the study:  divalproex sodium, 
sodium valproate, topiramate, carbamazepine, gabapentin, beta-blockers, tricyclic 
antidepressants, venlafaxine, desvenlafaxine, duloxetine, milnacipran, flunarizine, verapamil, 
lomerizine, lisinopril, candesartan, clonidine, guanfacine, cyproheptadine, methysergide, 
pizotifen, butterbur, feverfew, magnesium (at least 600 mg per day), riboflavin (at least 100 
mg per day).  
 
Use of up to two medications is permitted as long as the dose has been stable for at least 2 
months before the start of the run-in phase and during the study. 
 
 Botulinum toxin (in the head and/or neck region) within 4 months before the start of the 
baseline phase and throughout the study 
 
 Ergotamine derivatives, steroids, and triptans used for migraine prophylaxis within 2 months 
before the start of the baseline phase and throughout the study 
 
 Procedures (e.g. nerve blocks) used for migraine prophylaxis within 2 months before the start 
of the baseline phase and throughout the study 

 
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 History of myocardial infarction, stroke, transient ischemic attack, unstable angina, coronary 
artery bypass surgery, or other revascularization procedures within 12 months prior to 
screening. 
 
 Contraindications to MRI including, but not limited to: 
o Metal implants 
o Aneurysm clips 
o Severe claustrophobia 
o Implanted electronic devices 
o Insulin or infusion pump 
o Cochlear/otologic/ear implant 
o Non-removable prosthesis 
o Implanted shunts/catheters 
o Certain intrauterine devices 
o Tattooed makeup 
o Body piercings that cannot be removed 
o Metal fragments 
o Wire sutures or metal staples 
 
 Factors that Reduce MR Image Quality and Interpretability 
o Dental braces or other non-removable devices (e.g. retainers) 
o Prior brain surgery 
o Known brain MRI abnormality that in the investigator’s opinion will significantly 
impact MRI data 
 
 Sensory disorders that in the investigator’s opinion might affect perception of cutaneous 
thermal stimuli (e.g. peripheral neuropathy) 
 
 Pregnancy 
 
 Lactation 
 
 Not willing to use a reliable form of contraception (for women of childbearing potential) 
through 16 weeks after the last dose of erenumab. Acceptable methods of birth control include 
not having intercourse, hormonal birth control methods, intrauterine devices, surgical 
contraceptive methods, or two barrier methods (each partner must use a barrier method) with 
spermicide. A reliable form of contraception must be started prior to or at the time of starting 
the run-in phase. Not being of childbearing potential is defined as any woman who:  
 
o Is post-menopausal by history, defined as:  
 At least 55 years of age with cessation of menses for 12 or more months, OR 
 Younger than 55 years of age but no spontaneous menses for at least 2 years, OR 
 Younger than 55 years of age and spontaneous menses within the past 1 year, 
but currently amenorrheic (e.g. spontaneous or secondary to hysterectomy), 

 
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AND with postmenopausal gonadotropin levels (luteinizing hormone and 
follicle-stimulating hormone levels at least 40 IU/L) or postmenopausal 
estradiol level (less than 5 ng/dL) or according to the definition of 
“postmenopausal range” for the laboratory involved. 
 
OR 
o Underwent bilateral oophorectomy OR 
o Underwent hysterectomy OR 
o Underwent bilateral salpingectomy 
 
 Currently receiving treatment in another drug study or an investigational device study, or less 
than 90 days prior to screening since ending treatment on another investigational device or 
drug study(-ies) 
 
 Has received CGRP monoclonal antibody within 4 months of the start of the run-in phase 
 
 Active chronic pain condition that in the investigator’s opinion is unrelated to migraine (e.g. 
chronic pelvic pain) 
 
 Acute pain condition that in the investigator’s opinion is unrelated to migraine (e.g. post-
surgical pain) 
 
 Unable to provide informed consent  
 
 Less than 80% compliance with providing headache diary data during the run-in phase (i.e. 
provides data on less than 80% of days) 
 
Run in Phase (4 weeks) 
At this initial visit , whether in person or via telephone, participants will be screened for 
inclusion/exclusion and data on their demographics, headache characteristics, current and past 
treatments, and medical history will be collected. Those meeting criteria for further participation will 
be trained on how to use the headache diary. Patients will be instructed to keep a prospective 
headache diary for the next 4 weeks. We assume that up to 25% of individuals participating in the 
run-in phase will not meet the migraine day frequency inclusion criteria and/or diary compliance 
minimum and thus will not continue in this study. 
 
Baseline (first treatment) Visit 
Patients will return for a baseline visit after 4 weeks (i.e. 28 days +/- 3 days since start of run-in 
phase) of prospective headache diary collection. Diary compliance and eligibility for study inclusion 
will be assessed. Patients who still meet eligibility criteria will have measurement of vital signs and 
urine pregnancy testing will be conducted for women of childbearing potential. Levels of depression 
and anxiety will be measured using the Beck Depression Inventory and State-Trait Anxiety Inventory, 
respectively. Functional disability will be assessed with the Migraine Disability Assessment (MIDAS) 
and the Migraine Functional Impairment Questionnaire (MFIQ). Symptoms of cutaneous allodynia will 
be assessed using the Allodynia Symptom Checklist 12. Symptoms of cognitive dysfunction associated 
with migraine will be assessed using the Mig-Scog Questionnaire. (24, 25) Patients will undergo 

 
17
quantitative sensory testing (QST) for determination of heat pain thresholds and the temperature that 
results in moderate intensity heat pain. (13, 26, 27) To assess cognitive function, patients will 
complete two attention tasks; a computer version of the n-back task and Trails A and B. 
 
 
Case Report Forms 
 
Case report forms include:  
1) 
Inclusion and Exclusion Criteria 
2) 
Contact Information 
3) 
Demographics: birthdate, gender, race, ethnicity, handedness 
4) 
Vital Signs 
5) 
Urine Pregnancy Test Results (for women of childbearing potential) 
6) 
Headache Characteristics: headache frequency, duration, location, quality, intensity; associated 
symptoms; aura; number of years with migraine; current preventive and acute therapies 
7) 
Personal Medical History 
8) 
Current Medications and Non-Medication Treatments 
9) 
Prior Migraine Medications 
10) Migraine Functional Impact Questionnaire (MFIQ) 
11) Beck Depression Inventory (BDI) 
12) State-Trait Anxiety Inventory (STAI) 
13) Migraine Disability Assessment (MIDAS) 
14) Allodynia Symptom Checklist 12 (ASC-12): ictal and interictal 
15) Migraine Scog 
16) N-back task 
17) Trails A and B 
18) Quantitative Sensory Testing Results 
19) Two Week Follow-up Headache Characteristics 
20) Four Week Follow-up Headache Characteristics 
21) Eight Week Follow-up Headache Characteristics 
22) Twelve Week Follow-up Headache Characteristics 
23) Patient Global Impression of Change 
24) Adverse Events 
25) Headache Diary 
26) 26 Connor-Davidson Resilience Scale 25 (CD-RISC-25) 
 
The case report forms are included within Appendix 1.  
 
 
 

 
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Questionnaires 
First  
Visit 
(start of  
run-in 
phase) 
First Tx 
Visit 
Two-
Week 
Visit 
Four-Week 
Visit 
(second tx)
Eight-
Week 
Visit 
Twelve-
Week Visit
Contact Information 
X 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
Demographics 
X 
 
 
Headache 
Characteristics 
X 
X 
 
 
 
 
Follow-up Headache 
Characteristics 
 
 
X 
X 
X 
X 
Current Medications 
and Other 
Treatments 
X 
X 
X 
X 
X 
X 
Prior Migraine 
Treatments 
X 
 
 
 
 
 
Medical History 
X 
 
 
ASC-12 
(ictal/interictal) 
 
X 
X 
X 
X 
X 
MFIQ 
X 
X 
X 
X 
X 
MIDAS 
X 
 
X 
BDI 
 
X 
X 
X 
X 
X 
STAI 
X 
X 
X 
X 
X 
Mig-Scog  
 
X 
X 
X 
X 
X 
PGIC 
 
 
X 
X 
X 
X 
CD-RISC-25 
 
X 
X 
X 
X 
X 

 
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Adverse Events 
 
X 
X 
X 
X 
X 
Tx = treatment; ASC-12 = allodynia symptom checklist – 12; MFIQ = migraine functional 
impact questionnaire; MIDAS = migraine disability assessment; BDI = Beck Depression 
Inventory; STAI = state-trait anxiety inventory; PGIC = patient global impression of change 
 
Pain Threshold Testing 
QST for determining cutaneous heat pain thresholds has been used extensively in our lab. (13, 26, 27) 
A Medoc Pathway platform with a 30 mm x 30 mm thermode is used for testing. Heat pain thresholds 
are determined for the right and the left forearm and for the right and left forehead. The thermode is 
applied to the skin and fastened with a Velcro strap. The method-of-limits is used: thermode starts at 
32 degrees Celsius and increases in temperature at a rate of 1 degree Celsius per second until the 
subject presses a button on the response unit, indicating that the sensation changed from heat to pain. 
Testing will be performed three times at each body site and the average of the three measurements 
will be considered that individuals heat pain threshold.  
 
The temperature required to cause moderately intense heat pain will be determined by using the 
ramp and hold method. Moderately intense heat pain is defined by an individual rating their pain 
intensity between 4 and 7 using an 11 point scale in which zero indicates no pain and 10 indicates the 
most severe pain. Initially, subjects are stimulated for 7.5 seconds with a temperature equal to their 
heat pain threshold plus 1 degree Celsius. Individuals then rate the pain intensity. If pain intensity is 
rated below 4, the temperature is increased in 0.5 degree Celsius increments until rated between 4 
and 7. Conversely, if the pain intensity is rated greater than 7, the stimulation temperature is 
decreased in 0.5 degree Celsius increments. 
 
Imaging Protocol 
Brain MRI will be performed on a Siemens 3T scanner at the Mayo Clinic. The MRI paradigm will 
include: 1) high-resolution T1-weighted imaging allowing for advanced structural analyses such as 
determining regional volumes, cortical thickness and surface area; 2) T2-weighted imaging to rule out 
pre-existing structural brain abnormalities (e.g. incidental findings); 3) Diffusion Tensor Imaging 
(DTI) used for assessing white matter integrity; 4) ten minutes of resting-state Blood Oxygen Level 
Dependent (BOLD) signal collection for resting state functional connectivity analyses; 5) event-
related paradigm during which patients are exposed to cutaneous thermal stimuli causing moderately 
intense heat pain so that brain responses to pain can be measured; and 6) Arterial Spin Labeling 
(ASL) to assess cerebral blood flow. 
 
N-Back Task 
For purposes of test standardization and data interpretation, all subjects will complete the computer-
based version of the n-back task on one of two MacBook laptops. The software for the n-back task will 
be downloaded on the laptops and subject task performance will be automatically calculated and 
summarized- thus eliminating testing bias.  
 
Trails A and B 
Subjects will complete the standardized worksheets of Trails A and B. On Trails A, subjects are asked 
to connect consecutive numbers from 1-25. On Trails B, subjects are asked to alternate between 

 
20
connecting numbers and letters. (i.e., 1-A-2-B-3-C, and so forth)  Both tests are measuring attention 
and processing speed. For both tests, number of errors are recorded as well as the number of seconds 
required to complete each task.  
 
Treatment with Erenumab 
Patients receive treatment with 140 mg of erenumab via subcutaneous injection during their baseline 
visit and then again 4 weeks later. Patients will either be taught how to self-inject by a qualified 
research team member and then will do so under research team observation or receive the injections 
administered by a qualified research team member. Injections will be administered in the abdomen 
(except for a two inch area right around the navel), thigh, or outer area of upper arm (if someone else 
is injecting the patient) according to patient preference and will consist of two consecutive 70 mg 
injections.  The second injection will not be given in the same spot as the first injection. 
 
Erenumab will be stored refrigerated at 2°C to 8°C (36°F to 46°F) until time of use. Once removed 
from the refrigerator, it will be kept at room temperature and used within 7 days. Prior to 
administration, erenumab will sit at room temperature for at least 30 minutes, protected from direct 
sunlight. 
 
Daily Headache Diary 
A daily headache diary will be completed for the next 12 weeks to allow for assessment of changes in 
headache and migraine frequency. Headache diary data will be analyzed to classify patients as 
“responders” (50% or greater reduction in migraine day frequency between weeks 5-8 post first 
erenumab treatment compared to frequency during the run-in phase) or “non-responders” (less than 
50% reduction in migraine day frequency during weeks 5-8 post first erenumab treatment compared 
to the frequency during the run-in phase). Since patient outcome will be measured at 8 weeks 
(opposed to 12 weeks like is done in the majority of clinical trials), depending upon patient outcomes 
other definitions of “response” and “non-response” could be used. Furthermore, correlations between 
changes in migraine frequency and imaging outcomes could also be assessed.  
 
A migraine day will be defined as follows: any calendar day during which a person experiences a 
qualified migraine headache (onset, continuation, or recurrence of the migraine headache). A 
qualified migraine headache is defined as a migraine with or without aura, lasting for at least 30 
minutes, and meeting at least one of the following criteria (a and/or b): 
 
a) At least 2 of the following pain features: unilateral, throbbing, moderate to severe, exacerbated 
with exercise/physical activity 
b) At least 1 of the following associated symptoms: nausea and/or vomiting, photophobia and 
phonophobia 
 
If the participant takes a migraine-specific medication (i.e. triptan or ergotamine) during aura or to 
treat headache on a calendar day, then it will be counted as a migraine day regardless of the duration 
and pain features/associated symptoms. 
 
Missing values may exist in headache dairy data due to various reasons such as subjects’ missed 
recording, early withdrawal, or inadequate entries prohibiting evaluation of the end point (responder 
vs. non-responder). To impute the missing data and allow for evaluation of migraine frequency, 

 
21
classic imputation methods commonly used in clinical trials will be adopted.(6) Specifically, for 
months with 20-27 days of dairy data, the values for missing entries will be imputed by prorating 
scores of 28-day post-treatment periods. That is, monthly migraine frequency can be calculated as the 
ratio of number of observed migraine days to number of observed days multiplied by 28. For months 
with less than 10 days of dairy data, monthly migraine frequency will be estimated by the substitution 
of the patient’s previous 28-day period score, multiplied by the ratio of the mean for all patients in the 
same period to the mean for all patients in the previous period. For post-treatment periods with 10–
19 days of diary data, scores will be estimated using a mean of both methods. 
 
Follow up visits One through Four (see table 1): Four follow-up visits will be scheduled: at weeks 2, 4, 
8 and 12 post-initial treatment with erenumab (week 2 = 14 days +/- 2 days since first visit; week 4 = 
28 days +3 days since first visit; week 8 = 56 days +/- 3 days since first visit; week 12 = 84 days +/- 5 
days since first visit). The early follow-up at 2 weeks will be utilized for repeat QST, brain imaging and 
cognitive testing so that data are available for investigating early markers/predictors of treatment 
response. A second treatment with erenumab will occur during the 4-week visit. Imaging, QST and 
neurocognitive testing will be repeated during the 8-week visit, allowing for determination of 
biomarkers for treatment response that might not have been found at the early time-point of 2 weeks 
and that can be correlated with clinical measures of treatment response (i.e. changes in migraine day 
frequency). The 12-week visit will allow for further assessment of safety and efficacy.  
 
Acute Migraine Therapy: Patients will be allowed to use acute headache treatments including 
migraine-specific medication (e.g. triptans, ergotamine derivatives) and NSAIDs during the study. 
 
Other Migraine Preventive Therapy: Patients will be allowed to use two or fewer migraine preventive 
therapies in addition to erenumab as long as the dose has been stable for at least 2 months before the 
start of the run-in phase. Changes to the dose of such treatments will not be allowed during this study 
unless necessary due to safety issues or lack of tolerability.   
 
Imaging Data Plans 
All imaging will be collected at Mayo Hospital on a 3-Tesla Siemens (Siemens MAGNETOM Skyra, 
Erlangen, Germany) scanner using a 20-channel head/neck coil. Structural analyses will utilize 
FreeSurfer 5.3 
(http://surfer.nmr.mgh.harvard.edu) a 
commonly used brain segmentation software 
for measurements of 68 regional volumes, 68 
measurements of cortical thickness, and 68 
measurements of cortical surface area. The 
methodology for FreeSurfer is well-
documented and established and includes 
skull stripping, automated Talairach 
transformation, segmentation of gray and 
white matter regions, intensity 
normalization, brain boundary tessellation, 
topology correction and deformation of 
surface structures.(28-32) Resting state (rs)-
fMRI data will be analyzed using SPM 8 

 
22
(Wellcome Department of Cognitive Neurology, Institute of Neurology, London, UK) and the toolbox 
DPARSF interfaced with MATLAB version 11.0 (MathWorks, Natick, Ma, USA).(33) Rs-fMRI data will 
be pre-processed using standard procedures including the following steps: slice-time correction, 
motion correction, re-alignment, skull and non-brain tissue removal, spatial smoothing, and 
alignment to an average Montreal Neurological Institute (MNI-305) template.(34, 35) Further post-
processing steps will include band-pass filtering, as well as removal of variance related to head 
motion, white matter signal and cerebrospinal fluid signal. Functional measurements will be imported 
into SPSS 21.0 (SPSS Inc, Chicago, IL) for further calculations. A region-of-interest approach will be 
utilized for functional connectivity analyses. The functional connectivity of 33 regions which 
commonly participate in pain-processing will be analyzed. Event-related BOLD data will be analyzed 
using a whole-brain analysis, comparing BOLD amplitude during painful stimuli vs. no stimuli. All 
preprocessing and general linear model (GLM) estimation of brain activation patterns for the event-
related portion of the fMRI will also be performed using SPM8, interfaced with Matlab. Functional 
images will be realigned to the mean volume in the series, motion-corrected, realigned to each 
individual’s structural images, normalized to standard stereotaxic space (Montreal Neurological 
Institute template) and smoothed using a 5 mm full width half maximum Gaussian kernel. Brain 
regions activated in response to painful stimuli will be identified by generating contrast maps 
representing brain activations associated with painful stimuli preceded by auditory cue vs. auditory 
cue with no painful stimuli. The BOLD signal will be modeled for each of eight successive MR frames 
(20 seconds) following stimulus presentation, with no assumption made about the shape of the 
hemodynamic response function. These contrast maps are entered into a mixed effects analysis. A 
main effects analysis will identify brain regions activated in subjects and a two-sample analysis will 
identify regions differentially activated when comparing subject cohorts. Cluster threshold correction 
and multiple comparisons correction will be utilized. 18 major fiber tracts will be reconstructed from 
DTI data using an automated technique based upon global probabilistic tractography (TRACULA).(36) 
This software toolbox is available online (http://surfer.nmr.mgh.harvard.edu/) and uses anatomical 
priors (T1-weighted data) as input.  The robustness of the TRACULA software algorithm has been 
validated in prior papers.(36, 37) For each of the 18 fibertracts, tract volume, path length, axial 
diffusivity, radial diffusivity, mean diffusivity, and fractional anisotropy will be calculated. Arterial 
Spin Labeling data will be analyzed using SPM 8 and the toolbox ASLtbx.(38) SPM 8 and ASLbtx are 
freely downloadable online and will be interfaced with MATLAB version 11.0. ASL data will be 
preprocessed using standard SPM preprocessing steps including orientation resetting, image 
reorienting, motion correction, and co-registration (of each subjects’ T1-weighted image with the ASL 
images) and data smoothing. Subsequent data post-processing steps will be conducted using the 
ASLtbx toolbox. Statistical analyses will be conducted using a GLM design.  
 
Quality control of structural and functional imaging data: Radiology technicians at Mayo Clinic are 
already expert with the scanning paradigm and are trained to quality-check images during the MRI. 
Immediately after imaging is completed, all scans will be checked for motion artifacts. If necessary, 
patients will be re-scanned on the sequence where excessive motion was detected to ensure proper 
image quality in each individual. All image post-processing will be conducted on a single Mac 
workstation running OSX Lion 10.7.5 software to avoid post-processing irregularities related to the 
use of multiple workstations. All structural brain segmentations and parcellations will be reviewed by 
a trained technician for data quality. DTI and rs-fMRI data are very sensitive to movement artifacts. 
Therefore, we will exclude patients that exceed 2 degrees rotational, and/or 2mm translational 
movement, which are well-recognized cut-off points for movement.(39, 40) 

 
23
 
 
 
 
Sample Size 
The total sample size of 50 patients accounts for the likely scenario in which up to 15% of patients 
will not have full datasets due to loss-to-follow-up or unusable MRI data (e.g. patient motion, 
abnormal brain MRIs).  Based upon the results of the phase 2 and 3 trials of erenumab and the fact 
that this is an open-label study, we anticipate that approximately 50% of patients will be “responders” 
at 8 weeks. (6-8) Thus, we would have at least 21 responders and 21 non-responders for this analysis, 
a sample size that is adequate for the imaging and multivariate modeling aims of this study.  Sample 
size was determined by calculating the number of subjects needed per group to detect a difference in 
pain induced BOLD signal of 0.1% pre-erenumab to post-erenumab, assuming a standard deviation of 
0.1. Based on a type I error of .05, a sample size of 21 patients per group will give 88% power to 
detect pre-treatment to post-treatment differences for responders and non-responders. The use of % 
signal change as the measure for calculating effect size is the standard recommendation when 
determining sample size for fMRI studies.(41)  
 
Desmond and Glover, in their paper entitled “Estimating sample size in functional MRI (fMRI) 
neuroimaging studies: statistical power analyses”, used data from fMRI studies of cognitive function 
and somatosensory stimulation to estimate sample sizes needed for fMRI studies. [Desmond 2002] 
They concluded that for a threshold of 0.05, about 12 subjects are required to achieve 80% power at 
the single voxel level for typical activations. However, they state that at more realistic thresholds that 
approach those used after correcting for multiple comparisons, the number of subjects doubles 
(n=24) to maintain this level of power.  
 
As Mumford and colleagues point out, the number of stimulations/events that are included in the 
fMRI paradigm must also be considered when calculating power – the more stimulations/events, the 
greater the power to detect a difference.(41) 
 
Russo et. al. used a similar study design as the one we have proposed to investigate pain-induced 
activations in migraine pre- and post-external trigeminal neurostimulation. [Russo 2017] In the 
Russo study there was a pre- to post-treatment change in pain-induced activation of the anterior 
cingulate of approximately 0.2% with a standard deviation of approximately 0.1%.  Given this effect 
size, a sample size of 16 individuals (81% of whom were responders) was adequate to demonstrate 
significant pre- to post-treatment changes in pain-induced activation of the anterior cingulate cortex. 
 
With limited available data to ensure that our effect size will be as large as 0.2%, we are more 
comfortable powering the analysis for an effect size half of that found in Russo et. al. (i.e. 0.1%).(11) 
The resultant sample size is consistent with that recommended by Desmond and Glover and 
considers the impact of the number of painful stimulations as recommended by Mumford.(41, 42)  
 
Subject Recruitment and Screening 
 

 
24
Subjects will be recruited from the Mayo Clinic Arizona Headache and Neurology clinics, from the 
clinical practices of colleagues practicing in the Phoenix region, and via posting of IRB-approved 
recruitment materials. 
 
 
 
 
Subject Compensation 
 
Subjects will be compensated $70 per research visit and $30 per month during which they are at least 
80% compliant with the headache diary (i.e. provide data on at least 80% of days in a 4 week period).  
 
Informed Consent 
 
Informed consent procedures will be performed according to the requirements and recommendations 
of the Mayo Clinic Institutional Review Board. Written informed consent will be obtained from all 
subjects prior to their participation in this research. The informed consent process will be based upon 
principles discussed in the Declaration of Helsinki and in accordance with US 21CFR. Applicable 
HIPAA privacy notifications will be included. Participants will be given ample time and opportunities 
to ask questions about this study prior and following consent. All consent forms will require IRB 
approval prior to their use. Patients will always have the right and will be informed of their right to 
withdraw from the study at any time. De-identified data collected until the time of withdrawal will be 
included in further analyses. Enrolling clinicians will be made aware that the needs of their patients 
come first and thus the safety and wellbeing of study participants is of primary concern. The study 
will be done in accordance with the principles of Good Clinical Practice and with US Food and Drug 
Administration (FDA) and International Committee for Harmonization guidelines for safety 
monitoring. Any member of the research team who obtains informed consent from a subject will need 
to be approved by the Institutional Review Board. The informed consent process will occur in a 
location that is approved by the Institutional Review Board. Consent documents will be stored for a 
minimum of 3 years after conclusion of the study. The study participant will retain a copy of their 
signed consent document.  
 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial patient. The event 
does not necessarily have a causal relationship with study treatment. The investigator is responsible 
for ensuring that any adverse events observed by the investigator or reported by the subject are 
recorded in the patient’s record. The definition of adverse events includes worsening of a pre-existing 
medical condition. Worsening indicates that the pre-existing medical condition or underlying disease 
has increased in severity, frequency, and/or duration more than would be expected, and/or has an 
association with a significantly worse outcome than expected. A pre-existing condition that has not 
worsened more than anticipated during the study or involves an intervention such as elective 
cosmetic surgery or a medical procedure while on study is not considered an adverse event.  
 
Definition of Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the following serious 
criteria: 

 
25
• fatal 
• life threatening (places the subject at immediate risk of death) 
• requires in-patient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• congenital anomaly/birth defect 
• other medically important serious event 
 
An adverse event would meet the criterion of “requires hospitalization,” if the event necessitated an 
admission to a health care facility (e.g., overnight stay). If an investigator considers an event to be 
clinically important, but it does not meet any of the serious criteria, the event could be classified as a 
serious adverse event under the criterion of “other medically important serious event.” Examples of 
such events could include allergic bronchospasm, hypersensitivity reaction, or events that necessitate 
an urgent intervention. 
 
Reporting Procedures for Adverse Events That do not Meet Serious Criteria 
The investigator is responsible for ensuring that all adverse events observed by the investigator or 
reported by the subject that occur after the dose of investigational product through the end of the 
safety follow-up visit (8 weeks after the last dose of investigational product) are reported using the 
Adverse Event case report form. The Adverse Event case report form is included within the Appendix 
of this protocol. 
 
The investigator must assign the following adverse event attributes: 
 adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms) 
 dates of onset and resolution (if resolved) 
 intensity 
 outcome 
 action taken 
 assessment of relatedness to investigational product 
 
Assessment of whether the adverse event is possibly related to the investigational product is 
indicated by a “yes” or “no” response to the question: “Is there a reasonable possibility that the event 
may have been caused by the investigational product?” 
 
The Adverse Event case report form will be completed by the member of the research team that 
receives the information from the participant about the adverse event. The Principal Investigator will 
always be responsible for initially and dating the form, indicating that the Principal Investigator has 
reviewed the adverse event with the research team member, determining the relationship of the 
adverse event to the study, and determining if the adverse event meets criteria for a serious adverse 
event.  
 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by the 
investigator or reported by the subject that occur after signing of the informed consent through the 
end of the safety follow-up visit (8 weeks after the last dose of investigational product) are recorded 
in the subject’s record and to the local Institutional Review Board according to that Board’s policy.  

 
26
 
Reporting of adverse events to Amgen will occur in accordance with the “Safety Data Exchange 
Requirements” as provided by Amgen. These requirements dictate the need for and timing of 
reporting adverse events to Amgen. A copy of the “Safety Data Exchange Requirements” has been 
included within the Appendix of this protocol. 
 
 
Subject Risks and Benefits 
 
Possible Benefits: 
As this is an open-label study, all participants will receive treatment with erenumab. It is likely that 
many patients will have improvements in their migraine patterns following treatment with 
erenumab, as has been demonstrated in the phase II and III clinical trials and by the US Food and Drug 
Administration approval. 
 
Possible Risks: 
 
The most common side effects are injection site reaction, constipation, muscle spasm and pruritis.  
With the exception of injection site reaction (5.2%), these side effects were reported by less than 5% 
of patients in the phase II and III clinical trials.  Constipation, sometimes with serious complications, 
was reported by approximately  3% of individuals receiving erenumab. 
 
 
Development of hypertension and worsening of pre-existing hypertension have been reported 
following the use of AIMOVIG in the postmarketing setting. Many of the patients had pre-existing 
hypertension or risk factors for hypertension. There were cases requiring pharmacological treatment 
and, in some cases, hospitalization. Hypertension may occur at any time during treatment but was 
most frequently reported within seven days of dose administration. In the majority of the cases, the 
onset or worsening of hypertension was reported after the first dose. 
 
The FDA has added a safety-related label change to erenumab to include a contraindication for 
patients with serious hypersensitivity to erenumab or to any of the excipients due to the risk of 
anaphylaxis and angioedema. Most hypersensitivity reactions were not serious and occurred within 
hours of administration, although some occurred more than one week after administration. 
 
Hypersensitivity reactions including rash and swelling/edema have been reported with erenumab in 
postmarketing experience. 
 
Additional risks that have been reported since erenumab was approved in May 2018 include 
mouth/lip sores and skin and subcutaneous tissue disorders such as alopecia and rash. 
 
 
Potential risks associated with erenumab use during pregnancy and lactation are not established.  
 

 
27
Protected health information (PHI) is being collected. Although measures are taken to reduce the risk, 
it is possible that there could be inappropriate access to the PHI by individuals not approved for such 
access.  
 
Protection Against Risks: 
 
Individuals who are known to be pregnant or lactating will be excluded from study participation. 
Women of childbearing potential who are not known to be pregnant will have urine pregnancy testing 
before the 4 week run-in phase and prior to each of the two erenumab treatments. Women found to 
be pregnant will not receive any additional treatments with erenumab. Women of childbearing 
potential will be required to use a reliable form of contraception from the start of the run-in phase 
through 16 weeks after the last dose of erenumab (details provided in ‘eligibility criteria’ section of 
this protocol). 
 
Measures that will be taken to protect PHI: All information collected from study participants will be 
locked in a secure location. Identifying information will be removed from the data forms and replaced 
by unidentifiable codes. Electronic databases/spreadsheets will be password protected and only 
accessible to those with access rights. Data will be entered into REDCap. (43) REDCap is a secure web-
based application used for designing and managing clinical research databases. REDCap’s design 
addresses the National Center for Research Resources statement that the future of biomedical 
research will involve collaborations amongst many scientists in different locations linked by high-
speed computer networks thus enabling data submission, data sharing and data analyses. (43, 44) 
REDCap is accessible to study investigators via any computer with a Web browser. Once data are 
entered into data collection forms, data automatically upload to the registry data file. The registry 
complies with all HIPAA regulations, requires a log-in ID and password, and users only have access to 
specific functions (e.g. view data, add data, change data, etc.) once granted rights for those specific 
functions. Data can be exported into numerous formats utilized by several frequently used statistical 
packages including SPSS, SAS, R, Excel, Stata and others.  
 
Subject Retention 
 
Subject retention and diary compliance will be essential for study success.  
 
At the time of considering an individual for participation in this study, it will be ensured that the 
individual will be available for the duration of the study. The responsibilities of the subject will be 
clearly defined. All research visits will be scheduled at the time of enrollment. Subjects will be 
contacted with reminders prior to each research appointment. 
 
Diary compliance will be monitored on a daily basis. Subjects will be contacted immediately if non-
compliance is observed. Individuals who have diary compliance less than 80% during the run-in 
phase will be withdrawn from the study.  
 
Analysis Plans 
 
Specific Aim #1 (i.e. identify changes in brain structure and function that correlate with response to 
erenumab): Pre-treatment and post-treatment MRI data will be used for within and between subject 

 
28
comparisons. Within subject analyses will compare baseline brain activation and perfusion patterns 
and functional connectivity patterns pre-treatment to post-treatment. Between subject group 
analyses will compare post-treatment MRI data in erenumab responders to non-responders.  
 
Similar comparisons will be made for pre- and post-treatment pain thresholds (i.e. results of 
quantitative sensory testing) and cognitive testing. 
 
So as to help with the interpretation of differences between responders and non-responders, MRI 
data from erenumab-treated patients will be compared to healthy non-migraine control data that we 
have already collected during the conduction of previous studies, when available (although we have 
plenty of data for the majority of analyses, we have limited ASL data and no n-back data from healthy 
controls). Differences in brain structure and function of migraine patients prior to erenumab 
treatment compared to healthy controls will be identified. Results of this analysis will determine 
alterations of brain structure and functions in migraine patients compared to healthy controls. Areas 
where migraine patients show altered structure and function will be used as regions of interest (ROIs) 
to assess the longitudinal, within-group changes of erenumab responders and non-responders. 
 
Although multiple analyses are planned using functional, structural, and perfusion data, the primary 
analysis for specific aim #1 will be the comparison of pre-treatment pain-induced regional activation 
strength vs. post-treatment pain-induced regional activation strength in erenumab responders and 
separately in erenumab non-responders.  
 
Post-treatment changes in other measures of brain function as well as measures of brain perfusion, 
brain structure, cutaneous pain thresholds and cognitive function in those responding to erenumab 
and in those not responding will be explored. 
 
Two–tailed T-Tests or Mann-Whitney U tests will be used to perform group comparisons on 
demographic and cognitive measures and on pain threshold data. Neuroimaging data will be analyzed 
using general linear model designs. Within-group changes on cognitive measures, sensory testing and 
neuroimaging data will be assessed by applying a general linear mixed model design. 
 
Specific Aim #2 (i.e. Develop models to predict which patients will respond to erenumab): Pre-treatment 
scans will be used to identify MRI predictors of erenumab response. Multivariate machine-learning 
modeling of brain structural and functional data will be utilized for developing the predictive model. 
Because there are many imaging features available, but only a limited set of patients for this analysis, 
principal components analysis (PCA) will be performed on features collected from each imaging type 
to reduce the dimensionality of the data. The principal components (PCs) that result from PCA are 
linear combinations of the original imaging features, and can consolidate the information from the 
original features in such a way that only a few PCs are needed to explain most of the data variance. 
PCA will be performed separately on features from each imaging type to enhance clinical 
interpretability of PCs chosen for the predictive model. 
 
To maximize the prediction accuracy, we will employ an ensemble learning approach by including a 
number of contemporary and complementary machine learning algorithms for building the predictive 
model, including Linear Discriminant Analysis (LDA), Quadratic Discriminant Analysis (QDA), Support 
Vector Machines (SVM), and Decision Tree (DT). Integrating these algorithms with Particle Swarm 

 
29
Optimization (PSO)-based feature selection, we will identify the subset of features (PCs) that 
maximizes cross-validated accuracy of predicting responders and non-responders. Feature selection 
is a key step to avoid overfitting when building a predictive model with limited samples. PSO is a bio-
inspired optimization algorithm that mimics the collective and collaborative behavior of social 
swarms in nature, e.g., colonies, honeybees, and bird flocks, in finding the optimal feature subset, and 
has been shown to outperform conventional feature selection algorithms in numerous recent 
publications.  
 
Additionally, noting that this study will collect both widely accessible imaging data such as that 
derived from T1-weighted sequences as well as less accessible types such as pain-induced functional 
activations, we aim to determine how widely useable our predictive model is in clinical practice. To 
achieve this goal, we will first limit our PSO-based feature selection to select only PCs derived from 
structural measures of T1-weighted sequences. Then we will compare the accuracy to that of another 
analysis allowed to select resting state functional connectivity data, followed by selection of 
additional PCs from more advanced imaging data. This result will help determine how much value is 
added when using advanced imaging data in predicting treatment response; and if advanced imaging 
is not available in a clinic, how good the predictive accuracy can be. 
 
Patient characteristics, cognitive function, and sensory thresholds can also be included in predictive 
models.  
 
Safety Analysis: The proportion of subjects experiencing adverse events, the nature of the adverse 
events, as well as severity and relationship of the adverse events to the study will be reported using 
descriptive statistics. The proportion of subjects with adverse events that led to withdrawal from the 
study will also be reported. All subjects who received at least one dose of erenumab will be included 
in the safety analysis.  
 
Protocol Maintenance 
 
Protocol modifications will be approved by the principal investigators and submitted to the Mayo 
Clinic IRB in accordance with Mayo IRB rules and regulations. Modifications will be documented 
separately and within the main protocol document with a newly assigned date and version number. 
 
Study Registration 
 
The study will be submitted to clinicaltrials.gov. 
 
 
 
 
 
 
 
 
 
 

 
30
 
 
 
 
 
 
 
 
 
 
 
Appendix – Case Report Forms 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
31
 
 
 
 
 
 
 
 
 
 
 
Contact Information 
 
 
Name: ___________________________            _______________________________ 
 
        (First) 
 
 
 
 
      (Last) 
 
 
 
 
Home:  (_____) ______-___________    
 
 Work:   (_____) ______-___________ 
 
 
Mobile: (_____) ______-___________      
 
Email:  ________________________ 
 
 
Address:  
 
________________________________________ Unit/Apt#_______________ 
 
(Street)   
  
City_________________________ State_____________ Zip_______________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
32
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
 
Inclusion Criteria (all must by “yes”) 
 
o 18-65 years of age 
 
 
 
 
 
 
 
 
Yes 
No 
 
o Episodic or Chronic Migraine 
 
 
 
 
 
 
Yes 
No 
 
o 6-25 migraine days per month 
 
 
 
 
 
 
Yes 
No 
 
o Migraine started at least 12 months ago 
 
 
 
 
 
Yes 
No 
 
Exclusion Criteria (all must be “no”) 
 
o Older than 50 years of age at migraine onset 
 
 
 
 
Yes 
No 
 
o History of cluster headache or hemiplegic migraine 
 
 
 
Yes 
No 
 
o Continuous headache 
 
 
 
 
 
 
 
Yes 
No 
 
o Opioid or butalbital meds on 6 or more days per month  
 
 
Yes 
No 
 
o History of major psychiatric disorder 
 
 
 
 
 
Yes 
No 
 
o History of medical condition that contraindicates research participation 
Yes 
No 
 
o No preventive therapeutic response to 4 or more medication classes  
Yes 
No 
 
o Concomitant use of 3 or more meds for migraine prevention 
 
 
Yes 
No 
 
o Botulinum toxin in head or neck within 4 months 
 
 
 
Yes 
No 
 
o Ergotamines, steroids, or triptans for migraine prevention within 2 months Yes 
No 
 
o Procedures for migraine prevention within 2 months 
 
 
 
Yes 
No 

 
33
 
o Investigational meds or devices within 90 days  
 
 
 
Yes 
No 
 
o History of MI, stroke, TIA, unstable angina, CABG or other revascularization 
Procedure within 12 months 
 
 
 
 
 
 
Yes 
No 
 
o Contraindications to MRI 
 
 
 
 
 
 
 
Yes 
No 
 
 
 
 
Exclusion Criteria (cont.) 
 
o Factors that reduce MR image quality 
 
 
 
 
 
Yes 
No 
 
o Sensory disorders that affect sensory testing 
 
 
 
 
Yes 
No 
 
o Pregnancy 
 
 
 
 
 
 
 
 
 
Yes 
No 
 
o Lactation 
 
 
 
 
 
 
 
 
 
Yes 
No 
 
o Not using reliable contraception (if woman of childbearing potential)       Yes         No        N/A 
 
o Currently receiving treatment in another study  
 
 
 
Yes 
No 
 
o Has received CGRP monoclonal antibody within prior 4 months 
 
Yes 
No 
 
o Active chronic pain condition 
 
 
 
 
 
 
Yes 
No 
 
o Acute pain condition  
 
 
 
 
 
 
 
Yes 
No 
 
o Unable to provide informed consent 
 
 
 
 
 
Yes 
No 
 
o Less than 80% compliant with headache diary 
 
 
 
 
Yes 
No 
 
 
 
 
 
 
 
 
 
 
 
 

 
34
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
DOB:     ___   ___ / ___   ___ / ___   ___ 
                  Month            Day           Year 
 
 
Current age (years): __________ 
 
 
Gender (circle one):     
1 = Man                     2 = Woman 
3 = Other 
 
Sex at Birth (circle one):  
1 = Male 
 
2 = Female 
 
 
Race (circle all that apply): 
 
      
1 = American Indian/Alaska Native  
2 = Asian 
 
      
3 = Black/African American  
 
4 = Native Hawaiian/Other Pacific Islander 
 
      
5 = White/Caucasian  
 
 
6 = Other ___________________ 
 
Ethnicity:    1 = Hispanic       2 = Non-Hispanic         
 
Handedness: 1 = Right Handed          2 = Left Handed  
 
 
 
 
 
 
 
 

 
35
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
 
 
Heart Rate: 
 
______ beats per minute 
 
Blood Pressure: 
_____ /_____  mmHg 
 
Respiratory Rate:       ______ breaths per minute 
 
Temperature (oral):  
______ °F 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
36
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test 
 
 
Result (circle one):    
Positive  
 
Negative 
N/A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
37
 
 
 
 
 
 
 
 
 
 
 
Headache Characteristics (structured interview) 
 
 
How many days per month (28 days) with headache of any kind/severity:  _______/ 28 days 
 
How many days per month (28 days) with complete headache freedom:     _______/ 28 days 
  
 
How long do headaches last if untreated/inadequately treated:  
 
hours 
 
How long do headaches last if successfully treated:  
 
 
hours 
 
 
Where are they usually located (circle all that apply): 
 
 
 
Right   
Left 
 
Front  
Back   
Side 
 
 
Unilateral location:   
Yes 
 
No 
 
 
Quality (circle all that apply):  
 
 
 
Pulsating/Throbbing          Pressure/Aching          Stabbing          Burning 
 
 
Intensity: 
 
 
Mild 
 
Moderate 
Severe 
 
 
 
Average on 0 (no pain) to 10 (most severe pain) scale:    /10 
 
 
 
Maximum on 0 (no pain) to 10 (most severe pain) scale:  /10 
 
 
Headaches worse with physical activity: 
 
Yes 
 
No 

 
38
 
Headache worse with mental activity: 
 
Yes 
 
No 
 
Nausea: 
 
 
 
 
 
Yes 
 
No 
 
Vomiting: 
 
 
 
 
 
Yes 
 
No 
 
Sensitivity to light: 
 
 
 
 
Yes 
 
No 
 
Sensitivity to sound:   
 
 
 
Yes 
 
No 
 
 
Conjunctival injection: 
 
 
 
Yes 
 
No 
 
Tearing: 
 
 
 
 
 
Yes 
 
No 
 
Nasal congestion/rhinorrhea:  
 
 
Yes 
 
No 
 
Eyelid drooping:  
 
 
 
 
Yes 
 
No 
 
 
 
Auras with headaches:  
 
 
 
Yes 
 
No 
 
 
 
Visual:  
 
 
 
 
Yes 
 
No 
 
 
 
Sensory: 
 
 
 
 
Yes 
 
No 
 
 
 
Motor:  
 
 
 
 
Yes 
 
No 
 
 
 
Dysphasia: 
 
 
 
 
Yes 
 
No 
 
 
 
Other:   
 
 
 
 
Yes 
 
No 
 
 
Percentage of headaches you experience auras: __________________ 
 
 
 
When was your first headache (month and year): _________________ 
 
 
Family history of migraine:   
 
 
 
Yes 
 
No 
 
If yes, who:  
 
 
Medications 
 
Currently taking medications to prevent headaches:   
Yes 
 
No 

 
39
 
 
If yes, list medications:  
_______________________________ 
 
____________________________ 
_______________________________ 
 
_____________________________ 
_______________________________ 
 
_____________________________ 
_______________________________ 
 
_____________________________ 
 
 
 
 
 
 
 
Days per month (28 days) taking abortive medications:    _______ days  
 
 
 
Medication Name 
 
 
 
 
Days/month taking 
_______________________________ 
 
 
_______________ 
_______________________________ 
 
 
_______________ 
_______________________________ 
 
 
________________ 
_______________________________ 
 
 
________________ 
_______________________________ 
 
 
________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
40
 
 
 
 
 
 
 
 
 
 
 
Personal Medical History 
 
Current Medical Conditions 
 
 
1. _______________________________________________________________________________________________________ 
 
 
2. _______________________________________________________________________________________________________ 
 
 
3. _______________________________________________________________________________________________________ 
 
 
4. _______________________________________________________________________________________________________ 
 
 
5. _______________________________________________________________________________________________________ 
 
 
6. _______________________________________________________________________________________________________ 
 
 
7. _______________________________________________________________________________________________________ 
 
 
8. _______________________________________________________________________________________________________ 
 
 
9. _______________________________________________________________________________________________________ 
 
 
10. _______________________________________________________________________________________________________ 
 
 

 
41
11. _______________________________________________________________________________________________________ 
 
 
12. _______________________________________________________________________________________________________ 
 
 
13. _______________________________________________________________________________________________________ 
 
 
14. _______________________________________________________________________________________________________ 
 
Past Medical Conditions/ Surgeries 
 
 
1. _______________________________________________________________________________________________________ 
 
 
2. _______________________________________________________________________________________________________ 
 
 
3. _______________________________________________________________________________________________________ 
 
 
4. _______________________________________________________________________________________________________ 
 
 
5. _______________________________________________________________________________________________________ 
 
 
6. _______________________________________________________________________________________________________ 
 
 
7. _______________________________________________________________________________________________________ 
 
 
8. _______________________________________________________________________________________________________ 
 
 
9. _______________________________________________________________________________________________________ 
 
 
10. _______________________________________________________________________________________________________ 
 
 
11. _______________________________________________________________________________________________________ 
 

 
42
 
12. _______________________________________________________________________________________________________ 
 
 
13. _______________________________________________________________________________________________________ 
 
 
14. _______________________________________________________________________________________________________ 
 
 
 
Current Medications and Other Treatments 
 
                 Medication/Treatment Name 
                 Dose               Frequency 
Start Date      Stop Date 
 
1. ___________________________________________          _____________      _______________    ____________    _____________ 
   
 
2. ___________________________________________          _____________      _______________    ____________    _____________ 
 
 
3. ___________________________________________          _____________      _______________    ____________    _____________ 
 
 
4. ___________________________________________          _____________      _______________    ____________    _____________ 
 
 
5. ___________________________________________          _____________      _______________    ____________    _____________ 
 
 
6. ___________________________________________          _____________      _______________    ____________    _____________ 
 
 
7. ___________________________________________          _____________      _______________    ____________    _____________ 
 
 
8. ___________________________________________          _____________      _______________    ____________    _____________ 
 
 
9. ___________________________________________          _____________      _______________    ____________    _____________ 
 
 
10. ___________________________________________          _____________      _______________    ____________    _____________ 
 
 
11. ___________________________________________          _____________      _______________    ____________    _____________ 

 
43
 
 
12. ___________________________________________          _____________      _______________    ____________    _____________ 
 
 
13. ___________________________________________          _____________      _______________    ____________    _____________ 
 
 
14. ___________________________________________          _____________      _______________    ____________    _____________ 
 
 
Prior Migraine Treatments 
 
Medication/Treatment Name 
                     Dose          Frequency 
Months of Use 
 
 
1. ______________________________________________      ____________     _____________ 
_________________ 
 
 
2. ______________________________________________      ____________     _____________ 
_________________ 
 
 
3. ______________________________________________      ____________     _____________ 
_________________ 
 
 
4. ______________________________________________      ____________     _____________ 
_________________ 
 
 
5. ______________________________________________      ____________     _____________ 
_________________ 
 
 
6. ______________________________________________      ____________     _____________ 
_________________ 
 
 
7. ______________________________________________      ____________     _____________ 
_________________ 
 
 
8. ______________________________________________      ____________     _____________ 
_________________ 
 
 
9. ______________________________________________      ____________     _____________ 
_________________ 
 
 
10. ______________________________________________      ____________     _____________ 
_________________ 
 
 

 
44
11. ______________________________________________      ____________     _____________ 
_________________ 
 
 
12. ______________________________________________      ____________     _____________ 
_________________ 
 
 
13. ______________________________________________      ____________     _____________ 
_________________ 
 
 
14. ______________________________________________      ____________     _____________ 
_________________ 
 
Allodynia Symptom Checklist 12 – Ictal 
 
How often do you experience increased pain or an unpleasant sensation on your skin 
during your most severe type of headache when you engage in each of the following? 
 
 
Does not 
apply to 
me 
Never 
Rarely 
Less than 
half the 
time 
Half the 
time or 
more 
Combing your hair
Pulling your hair back 
(e.g., ponytail)
 
 
 
 
 
Shaving your face
Wearing eyeglasses
Wearing contact lenses
Wearing a necklace
Wearing earrings
Wearing tight clothing
Taking a shower 
(when shower water hits 
your face)
 
 
 
 
 
Resting your face or head on 
a pillow
 
 
 
 
 
Exposure to heat

 
45
(e.g., cooking, washing your 
face with hot water)
Exposure to cold 
(e.g., using an ice pack, 
washing your face with cold 
water)
 
 
 
 
 
 
 
 
 
Allodynia Symptom Checklist 12 – Interictal 
 
How often do you experience increased pain or an unpleasant sensation on your skin 
when you do not have a severe headache when you engage in each of the following? 
 
 
Does not 
apply to 
me 
Never 
Rarely 
Less than 
half the 
time 
Half the 
time or 
more 
Combing your hair
Pulling your hair back 
(e.g., ponytail)
 
 
 
 
 
Shaving your face
Wearing eyeglasses
Wearing contact lenses
Wearing a necklace
Wearing earrings
Wearing tight clothing
Taking a shower 
(when shower water hits 
your face)
 
 
 
 
 
Resting your face or head on 
a pillow
 
 
 
 
 
Exposure to heat

 
46
(e.g., cooking, washing your 
face with hot water)
Exposure to cold 
(e.g., using an ice pack, 
washing your face with cold 
water)
 
 
 
 
 
 
 
 
 
 
Beck Depression Inventory 
 
Instructions: Choose one statement from among the group of four statements in each 
question that best describes how you have been feeling during the past few days. Circle 
the number beside your choice. 
 
1)  
0 = I do not feel sad. 
 
1 = I feel sad. 
 
2 = I am sad all the time and I can’t snap out of it. 
 
3 = I am so sad or unhappy that I can’t stand it. 
 
2)  
0 = I am not particularly discouraged about the future. 
 
1 = I feel discouraged about the future. 
 
2 = I feel I have nothing to look forward to. 
 
3 = I feel that the future is hopeless and that things cannot improve. 
 
3)  
0 = I do not feel like a failure. 
 
1 = I feel I have failed more than the average person. 
 
2 = As I look back on my life, all I can see is a lot of failure. 
 
3 = I feel I am a complete failure as a person. 
 
4)  
0 = I get as much satisfaction out of things as I used to.  
 
1 = I don’t enjoy things the way I used to. 
 
2 = I don’t get any real satisfaction out of anything anymore. 
 
3 = I am dissatisfied or bored by everything. 
 
5) 
0 = I don’t feel particularly guilty. 
 
1 = I feel guilty a good part of the time. 
 
2 = I feel quite guilty most of the time. 
 
3 = I feel guilty all of the time. 
 
6) 
0 = I don’t feel I am being punished. 
 
1 = I feel I may be punished. 
 
2 = I expect to be punished. 

 
47
 
3 = I feel I am being punished. 
 
7)  
0 = I don’t feel disappointed in myself. 
 
1 = I am disappointed in myself. 
 
2 = I am disgusted with myself. 
 
3 = I hate myself. 
 
8) 
0 = I don’t feel I am any worse than anybody else. 
 
1 = I am critical of myself for my weaknesses or mistakes. 
 
2 = I blame myself all the time for my faults. 
 
3 = I blame myself for everything bad that happens. 
 
9) 
0 = I don’t have any thoughts of killing myself. 
 
1 = I have thoughts of killing myself, but would not carry them out. 
 
2 = I would like to kill myself. 
 
3 = I would kill myself if I had the chance. 
 
10) 
0 = I don’t cry any more than usual. 
 
1 = I cry more now than I used to. 
 
2 = I cry all the time now. 
 
3 = I used to be able to cry, but now I can’t cry even though I want to. 
 
11)  
0 = I am no more irritated by things than I ever am.  
 
1 = I am slightly more irritated now than usual. 
 
2 = I am quite annoyed or irritated a good deal of the time. 
 
3 = I feel irritated all the time now. 
 
12) 
0 = I have not lost interest in other people. 
 
1 = I am less interested in people than I used to be. 
 
2 = I have lost most of my interest in other people. 
 
3 = I have lost all of my interest in other people. 
 
13)  
0 = I make decisions about as well as I ever could. 
 
1 = I put off making decisions more than I used to. 
 
2 = I have greater difficulty in making decisions than before. 
 
3 = I can’t make decisions at all anymore. 
 
14) 
0 = I don’t feel that I look any worse than I used to.  
 
1 = I am worried that I am looking old or unattractive.  
 
2 = I feel that there are permanent changes in my appearance that make me look 
 
unattractive. 
 
3 = I believe that I look ugly.  
 
15)  
0 = I can work about as well as before.  
 
1 = It takes an extra effort to get started at doing something. 
 
2 = I have to push myself very hard to do anything. 

 
48
 
3 = I can’t do any work at all. 
 
16) 
0 = I can sleep as well as usual. 
 
1 = I don’t sleep as well as I used to. 
 
2 = I wake up 1-2 hours earlier than usual and find it hard to get back to sleep.  
 
3 = I wake up several hours earlier than I used to and cannot get back to sleep. 
 
17) 
0 = I don’t get more tired than usual. 
 
1 = I get tired more easily than I used to. 
 
2 = I get tired from doing almost anything. 
 
3 = I am too tired to do anything. 
 
 
18) 
0 = My appetite is no worse than usual. 
 
1 = My appetite is not as good as it used to be. 
 
2 = My appetite is much worse now. 
 
3 = I have no appetite at all anymore. 
 
19) 
0 = I haven’t lost much weight, if any, lately. 
 
1 = I have lost more than five pounds. 
 
2 = I have lost more than ten pounds. 
 
3 = I have lost more than fifteen pounds. 
 
(Score 0 if you have been purposely trying to lose weight.) 
 
20) 
0 = I am no more worried about my health than usual. 
 
1 = I am worried about physical problems such as aches and pains, or upset stomach, 
 
 
or constipation. 
 
2 = I am very worried about physical problems, and it’s hard to think of much else. 
 
3 = I am so worried about my physical problems that I cannot think about anything 
 
 
else.  
 
21) 
0 = I have not noticed any recent change in my interest in sex. 
 
1 = I am less interested in sex than I used to be. 
 
2 = I am much less interested in sex now. 
 
3 = I have lost interest in sex completely. 
 
 
 
 
 
 
 
 
 
 
 
 

 
49
 
 
 
 
 
 
 
 
 
 
 
State Anxiety 
 
Directions:  A number of statements which people have used to describe themselves are given below.  
Read each statement and then circle the appropriate number to the right of the statement to indicate how 
you feel right now that is, at this moment.  There are no right or wrong answers.  Do not spend too 
much time on any one statement but give the answer which seems to describe your present feelings best. 
 
 
Not
at all 
 
Somewhat
Moderately
so 
Very
much so 
1. I feel calm 
1 
2 
3 
4 
2. I feel secure 
1 
2 
3 
4 
3. I am tense 
1 
2 
3 
4 
4. I feel strained 
1 
2 
3 
4 
5. I feel at ease 
1 
2 
3 
4 
6. I feel upset 
1 
2 
3 
4 
7. I am presently worrying over possible misfortunes 
1 
2 
3 
4 
8. I feel satisfied 
1 
2 
3 
4 
9. I feel frightened 
1 
2 
3 
4 
10. I feel comfortable 
1 
2 
3 
4 
11. I feel self-confident 
1 
2 
3 
4 
12. I feel nervous 
1 
2 
3 
4 
13. I am jittery 
1 
2 
3 
4 
14. I feel indecisive 
1 
2 
3 
4 
15. I am relaxed 
1 
2 
3 
4 
16. I feel content 
1 
2 
3 
4 
17. I am worried 
1 
2 
3 
4 

 
50
18. I feel confused 
1 
2 
3 
4 
19. I feel steady 
1 
2 
3 
4 
20. I feel pleasant
1
2
3
4
 
 
 
 
 
 
 
 
 
Trait Anxiety 
 
 
Directions:  A number of statements which people have used to describe themselves are given below.  
Read each statement and then circle the appropriate number to the right of the statement to indicate how 
you generally feel.  There are no right or wrong answers.  Do not spend too much time on any one 
statement but give the answer which seems to describe how you generally feel. 
 
 
Not
at all 
 
Somewhat
Moderately
so 
Very
much so 
21. I feel pleasant 
1 
2 
3 
4 
22. I feel nervous and restless 
1 
2 
3 
4 
23. I feel satisfied with myself 
1 
2 
3 
4 
24. I wish I could be as happy as others seem to be 
1 
2 
3 
4 
25. I feel like a failure 
1 
2 
3 
4 
26. I feel rested 
1 
2 
3 
4 
27. I am “calm, cool, and collected” 
1 
2 
3 
4 
28. I feel that difficulties are piling up so that I cannot overcome  
 
 
 
them 
1 
2 
3 
4 
29. I worry too much over something that really doesn’t matter 
1 
2 
3 
4 
30. I am happy 
1 
2 
3 
4 
31. I have disturbing thoughts 
1 
2 
3 
4 
32. I lack self-confidence 
1 
2 
3 
4 
33. I feel secure 
1 
2 
3 
4 
34. I make decisions easily 
1 
2 
3 
4 
35. I feel inadequate 
1 
2 
3 
4 
36. I am content 
1 
2 
3 
4 

 
51
37. Some unimportant thought runs through my mind and
 
 
 
 
bothers me 
1 
2 
3 
4 
38. I take disappointments so keenly that I can’t put them out of  
 
 
 
my mind
1
2
3
4
39. I am a steady person 
1 
2 
3 
4 
40. I get in a state of tension or turmoil as I think over my recent  
 
 
 
concerns and interests
1
2
3
4
 
 
 
 
Migraine Disability Assessment (MIDAS) 
 
Instructions: Please answer the following questions about all your headaches over the last 3 months. 
Write your answer in the box next to each question. Write zero if you did not do the activity in the last 3 
months.  
 
 
1) On how many days in the last 3 months did you miss work or school because of your      
headaches? (If you do not attend work or school enter zero in the box.) 
 
___   ___ 
Days
 
2) How many days in the last 3 months was your productivity at work or school reduced by 
half or more because of your headaches? (Do not include days you counted in question 1 
where you missed work or school. If you do not attend school or work enter zero in the box.)      
 
___   ___ 
Days 
3) On how many days in the last 3 months did you not do household work because of your 
headaches? 
 
___   ___ 
Days 
4) How many days in the last 3 months was your productivity in household work reduced by 
half or more because of your headaches? (Do not include days counted in question 3, where 
you did not do household work.) 
 
___   ___ 
Days 
5) On how many days in the last 3 months did you miss family, social, or leisure activities 
because of your headaches? 
 
___   ___ 
Days
                                                                                                         
                                                                                                        (Questions 1-5)          Total 
 
___   ___ 
A) On how many days in the last 3 months did you have a headache? (If headache lasted more 
than 1 day, count each day.) 
 
___   ___ 
Days
B) On a scale of 0-10, on average, how painful were these headaches? (Where 0=no pain at 
all, and 10=pain which is as bad as it can be.) 
 
___   ___ 
0-10 


ͷʹ
 
 
 
 
 
 
 
 
 
 
 
 
Migraine Functional Impact Questionnaire (MFIQ) 
 
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x migraineday-to-day activitiesǤ 
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

 
58
 
 
 
 
 
 
 
 
 
 
 
 
Migraine Scog 
 
In this section we want to understand whether your headaches affect your cognitive abilities while 
you experience a headache. We will provide you with a number of statements describing difficulties 
that you may face during a headache. We will ask you to indicate to what extent you experience these 
difficulties. The information you provide us with will inform how we approach your care and how 
well can deliver care to you. 
 
During your Headaches… 
 
Do you feel confused? 
2: Often 
1: Sometimes 
0: No 
 
Do you have trouble performing tasks at your normal speed? 
2: Often 
1: Sometimes 
0: No 
 
Is it difficult to follow a route or path (driving or walking)? 
2: Often 
1: Sometimes 
0: No 
 
Do you have trouble thinking? 
2: Often 
1: Sometimes 
0: No 
 
Do you have trouble maintaining a line of thought? 
2: Often 
1: Sometimes 
0: No 

 
59
 
Is it difficult to understand words spoken to you? 
2: Often 
1: Sometimes 
0: No 
 
Is it difficult to organize a sentence or a conversation? 
2: Often 
1: Sometimes 
0: No 
 
 
Do you have trouble speaking out other people’s names? 
2: Often 
1: Sometimes 
0: No 
 
Is it difficult to remember the correct name of objects? 
2: Often 
1: Sometimes 
0: No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
60
 
 
 
 
 
 
 
 
 
 
 
 
 
N-Back Task 
 
 
 
     Trial 1  
     Trial2 
      Trial 3 
  
Sum of Hits:  
                __________            __________           __________ 
 
Sum of False Alarms:   
  __________            __________           __________ 
 
 
Sum of Misses:                            __________            __________           __________ 
 
 
Sum of Correct Rejections:     ___________           __________           __________ 
 
 
 
 
Sum of total Hits across all Trials:                                             ___________ 
         
Sum of total False Alarms across all Trials:                            ___________ 
 
Proportion of (total Hits – total FA) /number of Trials:     ___________ 
 
 
 
 
 
 
 
 
 
 
 

 
61
 
 
 
 
 
 
 
 
 
 
 
 
 
Trails A and B  
 
 
Trails A: __________seconds     Trails A: ________number of errors 
 
Trails B: __________seconds      Trails B: ________number of errors 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
62
 
 
 
 
 
 
 
 
 
 
 
 
Quantitative Sensory Testing 
 
Pain or headache medications in the last 48 hours:  
Yes 
 
No 
 
Do you currently have a headache/migraine:  
 
Yes 
 
No 
 
If yes, Current Pain Level:   ________/ 10 
 
If no, on what day did your last headache/migraine end (month/day/year):  _____/_____/_______ 
 
 
At what time:   ________ AM/PM  (if went to sleep with it, list time woke up without) 
 
 
Instructions: 
 
As part of the research in which you are involved, we are going to test how sensitive your skin is to 
heat. The testing will use a piece of plastic, called a thermode.  We will place the thermode at 4 
different locations – each forearm and at 2 locations on the forehead.  The thermode will start at 
about skin temperature, and then get warmer or hot.  There are safety limits on the temperature so 
that you are not injured or burned.  Please concentrate on the intensity of the heat that you feel with 
each test. We will give you a computer mouse which you will use to stop the heating process. With 
each test, the thermode will get warm and then hot.  We want you to press the mouse button the 
moment that you begin to feel pain.  The thermode will then cool off.  We will do this three times at 
each body location.  Remember, press the button the moment you begin to feel pain. 
 
LIMITS 
Location 
Limit 1 
Limit 2 
Limit 3 
Average 
Left Forehead 
 
 
 
 
Right Forehead 
 
 
 
 

 
63
Right Forearm 
 
 
 
 
Left Forearm 
 
 
 
 
 
 
 
 
 
 
 
 
THERMAL STIMULATION 
Painful Stimulus 
For the next test we will leave the thermode on your left forearm.  The thermode will start at about skin 
temperature and then the temperature will gradually increase.  Once it reaches a pre-programmed 
temperature it will hold at that temperature for 7.5 seconds and then you will hear a bell.  At that time we 
will ask you to rate your pain on a scale of 0 to 10 (0 means no pain and 10 is the worst pain imaginable).   
Begin with the average of the left forearm limits test +1°.  
 If subject rates their pain level between 4-7 continue with the non-painful stimulus. 
 If subject rates their pain level as 8 or higher decrease temperature by 0.5° and repeat Ramp & 
Hold (continue to decrease temperature by 0.5° until subject rates their pain level between 4-
7). 
 If subject rates their pain level as 3 or lower increase temperature by 0.5° and repeat Ramp & 
Hold (continue to increase temperature by 0.5° until subject rates their pain level between 4-7). 
 
RAMP & HOLD  
Temp. 
Rating (0-10)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Non-painful Stimulus 
For the next test we will continue with the thermode on your left forearm.  The thermode will start 
at about skin temperature and then the temperature will gradually increase.  Once it reaches a pre-
programmed temperature it will hold at that temperature for 7.5 seconds and then you will hear a 
bell.  At that time we will ask if that temperature caused you any pain. 
Begin with the average of the left forearm limits test -2°.  
 If subject answers no continue with MRI instructions.. 

 
64
 If subject answers yes (that it caused pain) decrease temperature by 0.5° and repeat 
Ramp & Hold (continue to decrease temperature by 0.5° until subject answers no (it 
did not cause pain)). 
 
 
 
 
 
 
 
 
 
MRI Stimulations 
During the MRI the thermode will be placed on your left forearm.  For part of the MRI we will be running 3 
different tests during which the thermode will heat up.  Each test will last approximately 9 minutes.  During 
each of these tests you will hear a bell and then the thermode temperature may change to a pre-programmed 
temperature. If so, it will hold at that temperature for 7.5 seconds and then return to baseline.  This will be 
repeated 9 times during each test. You do not need to respond in any way during the tests.  
 
MRI – RAMP & HOLD – temps programmed
Painful  
Non-painful 
No stimulus 
 
 
 
 
BOLD STIMULATION #1
Sequence
Temp.
Secs before 
test
 
 
 
 
 
 
 
 
 
MRI Frame
 
BOLD STIMULATION #2
Sequence
Temp.
Secs before 
test
 
 
 
 
 
 
 
 
 
MRI Frame
 
BOLD STIMULATION #3
Sequence
Temp.
RAMP & HOLD  
Temp. 
Pain (yes/no) 
 
 
 
 
 
 
 
 
 
 

 
65
Secs before 
test
 
 
 
 
 
 
 
 
 
MRI Frame
 
 
 
 
 
 
 
 
 
 
 
Two Week Follow-up Headache Characteristics 
 
 
How many days since baseline visit with headache of any kind/severity:   
 
 
How many days since baseline visit with complete headache freedom:  
  
 
How long do headaches last if untreated/inadequately treated:  
 
hours 
 
How long do headaches last if successfully treated:  
 
 
hours 
 
 
Intensity: 
 
 
Mild 
 
Moderate 
Severe 
 
 
 
Average on 0 (no pain) to 10 (most severe pain) scale:     
 
/10 
 
 
 
Maximum on 0 (no pain) to 10 (most severe pain) scale:  
 
/10 
 
 
 
 
 
 
 
 
 
 
 
 

 
66
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Four Week Follow-up Headache Characteristics 
 
How many days during last month (28 days) with headache of any kind/severity:   
 
How many days during last month (28 days) with complete headache freedom:  
  
How long do headaches last if untreated/inadequately treated:  
 
hours 
 
How long do headaches last if successfully treated:  
 
 
hours 
 
Intensity: 
 
 
Mild 
 
Moderate 
Severe 
 
 
 
Average on 0 (no pain) to 10 (most severe pain) scale:    /10 
 
 
 
Maximum on 0 (no pain) to 10 (most severe pain) scale:  /10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
67
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eight Week Follow-up Headache Characteristics 
 
How many days during last month (28 days) with headache of any kind/severity:   
 
How many days during last month (28 days) with complete headache freedom:  
  
How long do headaches last if untreated/inadequately treated:  
 
hours 
 
How long do headaches last if successfully treated:  
 
 
hours 
 
Intensity: 
 
 
Mild 
 
Moderate 
Severe 
 
 
 
Average on 0 (no pain) to 10 (most severe pain) scale:    /10 
 
 
 
Maximum on 0 (no pain) to 10 (most severe pain) scale:  /10 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
68
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Twelve Week Follow-up Headache Characteristics 
 
How many days during last month (28 days) with headache of any kind/severity:   
 
How many days during last month (28 days) with complete headache freedom:  
  
How long do headaches last if untreated/inadequately treated:  
 
hours 
 
How long do headaches last if successfully treated:  
 
 
hours 
 
Intensity: 
 
 
Mild 
 
Moderate 
Severe 
 
 
 
Average on 0 (no pain) to 10 (most severe pain) scale:    /10 
 
 
 
Maximum on 0 (no pain) to 10 (most severe pain) scale:  /10 
 
 
 
 
 
 
 
 
 
 
 

 
69
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Global Impression of Change 
 
Since your first treatment, how would you describe the change (if any) in ACTIVITY 
LIMITATIONS, SYMPTOMS, EMOTIONS and OVERALL QUALITY OF LIFE related 
to your painful condition? 
 
Select One: 
1. No change (or condition has got worse) 
2. Almost the same, hardly any change at all 
3. A little better, but no noticeable change 
4. Somewhat better, but the change has not made any real difference 
5. Moderately better, and a slight but noticeable change 
6. Better, and a definite improvement that has made a real and worthwhile difference 
7. A great deal better, and a considerable improvement that has made all the difference 
 
In a similar way, please circle the number below that matches your degree of change since 
your first treatment: 
 
 
 

 
70
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
 

 
71
 
 
 
 
 
 

 
72
Headache Diary 
 
For what day are you recording information (month/day/year)?  _____ / _____ / _____ 
 
What time is it right now:  
____________ 
AM 
PM 
 
Did you have a headache today (circle one)?  
 
 
Yes 
 
No 
 
    If yes:  
 
What day and time did the headache begin: 
 
 
Date (month/day/year):    _____ / _____ / _____ 
 
 
Time:  ___________  AM / PM (circle one) 
 
 
 
 
 
Do you still have the headache?   
 
Yes 
 
No   
 
If no, what time did the headache end? ___________  AM / PM (circle one) 
 
 
 
What was the peak headache severity (circle one):  
Mild 
Moderate     Severe 
 
 
If pain reached moderate or severe intensity, how long did it remain at that intensity?  
 
 
 
 
____________  minutes or hours (circle one) 
 
 
Headache Location (circle one):        One side of head only  
Both sides of head 
 
 
During the headache:  
 
  Was the headache “throbbing” in quality?  
 
Yes 
 
No 
 
  Did lights bother you more than usual?   
 
Yes 
 
No 
 
  Did sounds bother you more than usual?   
 
Yes 
 
No 
  
  Were you nauseated?  
 
 
 
 
Yes 
 
No 
  
  Did you vomit? 
 
 
 
 
 
Yes 
 
No 
 

 
73
  Did routine physical activity (e.g. walking, climbing stairs) make your headache worse? 
   
 
 
 
   
 
 
 
 
 
 
 
Yes 
 
No 
 
How disabling was the headache/migraine (choose one): 
 
 
  
Able to function normally 
 
 
Function somewhat reduced  
 
  
 
  
Function severely reduced 
 
 
Not able to function at all (e.g. bedbound) 
  
 
Did you take a medication(s) to abort this headache?  
 
Yes 
 
No 
 
 If yes, which medication(s)? 
 
           Medication Name 
 
Number of Times Taken Today 
 
              _________________________________ 
                 __________  
 
                     
 
_________________________________ 
                   __________ 
 
 
 
 
_________________________________ 
                   __________ 
 
 
 
 
_________________________________ 
                   __________ 
 
 
                     
 
_________________________________ 
                   __________ 
 
 
                    
 
_________________________________ 
                   __________ 
 
 
                     
 
_________________________________ 
                    __________  
 
                     
 
 
In the past 24 hours, overall, how difficult was it to do your usual activities? 
□ Not difficult 
□ A little difficult 
□ Moderately difficult 
□ Very difficult 
□ Extremely difficult 
 
In the past 24 hours how much of the time did you have difficulty moving your head?  
□ None of the time 
□ A little of the time 
□ Some of the time 
□ Most of the time 
□ All of the time 
 

 
74
 
 
 
In the past 24 hours how much of the time did you have difficulty moving your body? 
□ None of the time 
□ A little of the time 
□ Some of the time 
□ Most of the time 
□ All of the time 
 
In the past 24 hours were you able to get out of bed?  
□ Without any difficulty 
□ With a little difficulty 
□ With some difficulty 
□ With much difficulty 
□ Unable to do 
 
In the past 24 hours were you able to bend over? 
□ Without any difficulty 
□ With a little difficulty 
□ With some difficulty 
□ With much difficulty 
□ Unable to do 
 
In the past 24 hours were you able to do your usual activities that required physical effort? 
□ Without any difficulty 
□ With a little difficulty 
□ With some difficulty 
□ With much difficulty 
□ Unable to do 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
75
Connor-Davidson Resilience Scale 25 (CD-RISC-25) 
For each item, please mark an “x” in the box below that best indicates how much you agree with the following statements 
as they apply to you over the last month. If a particular situation has not occurred recently, answer according to how you 
think you would have felt. 
 
 
 
 
 
 
 
    Not true          rarely      sometimes    often    true nearly 
 
 
 
 
 
 
 
      at all                true           true               true     all the time 
(0) 
             (1)              (2)                 (3)            (4) 
 
1. 
I am able to adapt when changes occur.                                           
              
           
             
          
   
2. 
I have at least one close and secure relationship that                    
              
           
             
          
   
helps me when I am stressed. 
 
3. 
When there are no clear solutions to my problems,                       
              
           
             
          
   
sometimes fate or God can help. 
 
4. 
I can deal with whatever comes my way.                
        
              
           
             
          
 
5. 
Past successes give me confidence in dealing with 
new challenges and difficulties.                                                          
              
           
             
          
  
  
6. 
I try to see the humorous side of things when I am 
faced with problems.                                                                            
              
           
             
          
  
  
7. 
Having to cope with stress can make me stronger.                         
              
           
             
          
  
8. 
I tend to bounce back after illness, injury , or other 
hardships.                                                                                                
              
           
             
          
  
9. 
Good or bad, I believe that most things happen for a 
reason.                                                                                                     
              
           
             
          
   
 
10. I give my best effort no matter what the outcome may be.          
              
           
             
          
   
11. I believe I can achieve my goals, even if there are obstacles.        
              
           
             
          
   
12. Even when things look hopeless, I don’t give up.                             
              
           
             
          
 
13. During times of stress/crisis I know where to turn for help.          
              
           
             
          
 
14. Under pressure, I stay focused and think clearly.                             
              
           
             
          
 
15. I prefer to take the lead in solving problems rather than               
              
           
             
          
 
letting others make all the decisions. 
 
16. I am not easily discouraged by failure.                                               
              
           
             
          
 
17. I think of myself as a strong person when dealing                           
              
           
             
          
 
with life’s challenges and difficulties. 

 
76
18. I can make unpopular or difficult decisions that affect other        
              
           
             
          
 
people, if it is necessary. 
 
19. I am able to handle unpleasant or painful feelings like                   
              
           
             
          
 
sadness, fear and anger. 
 
20. I dealing with life’s problems, sometimes you have to act on           
              
           
             
          
 
a hunch without knowing why. 
 
21. I have a strong sense of purpose in life.                                                
              
           
             
          
 
22. I feel in control of my life.                                                                        
              
           
             
          
 
23. I like challenges.                                                                                         
              
           
             
          
 
24. I work to attain my goals no matter what roadblocks I                      
              
           
             
          
 
encounter along the way. 
 
25. I take pride in my achievements.                                                            
              
           
             
          
 
 
 
Add up your score for each column   
 
         0   + ____  + ____ + ____ + ____  
 
Add each of the column totals to obtain CD-RISC score = ___________________________  
 
 
 
 
All rights reserved. No part of this document may be reproduced or transmitted in any form without permission in writing from 
Dr. Davidson at mail@cd-risc.com. . Copyright © 2001, 2018 by Kathryn M. Connor, M.D., and Jonathan R.T. Davidson 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
77
ISS – Timeframes for Submission of Safety Data to Amgen 
 
For Interventional studies with Amgen IMP*: 
 
Safety Data 
Timeframe for Submission to Amgen 
Suspected Unexpected Serious Adverse 
Reaction (SUSARs) 
Sent to Amgen at time of regulatory 
submission 
Serious Adverse Events (SAEs) 
Not required, unless contractually 
specified per study 
Adverse Events not meeting serious 
criteria 
Not required, unless contractually 
specified per study 
Events of Interest 
Not required, unless contractually 
specified per study 
Pregnancy/Lactation 
Within 10 calendar days of Sponsor 
awareness 
Event listing for reconciliation 
As specified per contract 
*Specific requirements are to be outlined in the Research Agreement 
 
For all studies – aggregate reports*: 
 
Safety Data 
Timeframe for submission to Amgen 
Annual Safety Report 
(eg, EU Clinical Trial Directive [CTD] 
DSUR, and US IND Annual Report) 
Annually 
Other Aggregate Analyses 
(any report containing safety data 
generated during the course of a study) 
At time of ISS sponsor submission to 
any body governing research conduct 
(eg, RA, IRB, etc) 
Final (End of Study Report, including): 
 Unblinding data for blinded 
studies 
 Reports of unauthorized use of a 
marketed product 
At time of ISS sponsor submission to 
any body governing research conduct 
(eg, RA, IRB, etc) but not later than 1 
calendar year of study completion 
*Specific requirements are to be outlined in the Research Agreement 
 
 
 
 
References: 

 
78
 
1. 
Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF. Migraine 
prevalence, disease burden, and the need for preventive therapy. Neurology. 
2007;68(5):343-9. 
2. 
Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and 
burden of migraine in the United States: data from the American Migraine Study II. 
Headache. 2001;41(7):646-57. 
3. 
Terwindt GM, Ferrari MD, Tijhuis M, Groenen SM, Picavet HS, Launer LJ. The 
impact of migraine on quality of life in the general population: the GEM study. 
Neurology. 2000;55(5):624-9. 
4. 
Stewart WF, Ricci JA, Chee E, Morganstein D, Lipton R. Lost productive time and 
cost due to common pain conditions in the US workforce. Jama. 2003;290(18):2443-54. 
5. 
Stovner LJ, Andree C. Impact of headache in Europe: a review for the Eurolight 
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6. 
Goadsby PJ, Reuter U, Hallstrom Y, Broessner G, Bonner JH, Zhang F, et al. A 
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32. 
7. 
Sun H, Dodick DW, Silberstein S, Goadsby PJ, Reuter U, Ashina M, et al. Safety 
and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-
blind, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(4):382-90. 
8. 
Tepper S, Ashina M, Reuter U, Brandes JL, Dolezil D, Silberstein S, et al. Safety 
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