A Multidisciplinary Translational Approach to Investigate the Mechanisms, Predictors, and Prevention of Persistent Post-Traumatic Headache
Phase: PHASE2
Conditions: Post-Traumatic Headache
Sponsor: Mayo Clinic

 
 
A Multidisciplinary Translational Approach to 
Investigate the Mechanisms, Predictors, and 
Prevention of Persistent Post-Traumatic 
Headache 
 
NCT04098250 
 
14August2024 

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A Multidisciplinary Translational Approach to Investigate the Mechanisms, Predictors, and 
Prevention of Persistent Post-Traumatic Headache 
 
 
Human Studies Protocol: Clinical Trial 
 
August 2024 
 
 
 
 
 
 
 
Funding: United States Department of Defense; PR180415; CDMRP PRMRP Focused Program 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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A Multidisciplinary Translational Approach to Investigate the Mechanisms, Predictors, and 
Prevention of Persistent Post-Traumatic Headache 
 
Human Studies Protocol: Clinical Trial 
 
 
Table of Contents 
 
Page(s) 
 
Summary………………………………………………………………………………………………………….......       3 
Research Participant Flow Through the Human Studies …………………………………………       3-4 
Participant Eligibility Criteria for those with PTH      
Path A/D ………………………………………………………………………………………………………………      5-8 
Path C …………………………………………………………………………………………………………………..      8-10 
Recruitment and Enrollment …………………………………………………………………………………      11 
Participating Site Responsibilities…………………………………………………………………………..      11 
Clinical Trial Individual Project  
Principal Investigator ……………………………………………………………………………………….........     12 
Brief Summary ……………………………………………………………………………………….......................     12 
Background ……………………………………………………………………………............................................  12-14 
Hypothesis/Objective ……………………………………………………………………………………….........     14 
Specific Aims/Study Endpoints …………………………………………………………….…………………     14 
Methods 
Data Collection …………………………………………………………………………………………….……….... 14-16 
Stratification, Randomization and Masking …………………………..…..………………………………    16 
Treatment with Erenumab ………………………………………………………………………………….…..     16 
Statistical Plan ………………………………………………………………….………...........…………………….     17 
IRB Approvals and Informed Consent ………………………………………………….…………………..     17 
Study Materials …………………………………………………………………………………………….…..........     17 
Participant Compensation ……………………………………………………………………….………………     18 
Adverse Events……………………………………………………………………………......................................   18-19 
Data and Safety Monitoring and Reporting to Regulatory Agency……………………………..    19-20 
Study Registration ………………………………………………………………………………………………....       20 
Risks and Benefits…………………………………………………………………………….................................   20-21 
Patient Retention……………………………………………………………………………...................................     22 
Protocol Maintenance……………………………………………………………………………...........................    22 
ISS – Timeframes for Submission of Safety Data to Amgen…………………………………………. 22-23 
Data Sharing……………………………………………………………………………………………………………..    23 
References……………………………………………………………………………................................................. 23-24 
 
 
 
 
 
 

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Summary 
 
This protocol describes the background, objectives, and methods for the Clinical Trial that is part 
of the Focused Program entitled “A Multidisciplinary Translational Approach to Investigate the 
Mechanisms, Predictors, and Prevention of Persistent Post-Traumatic Headache”. Other Individual 
Projects that are part of this Focused Program are described in a separate protocol subtitled 
“Individual Projects Excluding Clinical Trial” and include: phenotyping and neurophysiology, 
neuroimaging, molecular biomarkers, and multivariate modeling. 
 
 
Research Participant Flow Through the Human Studies 
 
Individuals with post-traumatic headache (PTH) will be enrolled into the clinical trial. In total, up 
to 112 individuals with acute PTH attributed to mTBI will participate in the clinical trial that is 
part of this Focused Program. 
 
Those with PTH who will be enrolled into the clinical trial will come from Paths A, C, and D as 
described:   
 
1) Path A: all of the human individual projects including phenotyping and neurophysiology, 
neuroimaging, molecular/genetic biomarker studies, and the clinical trial (n=82); or 
 
2) Path B (this path will be carried out under a separate protocol subtitled “Individual Projects 
Excluding Clinical Trial”): each of the human individual projects including phenotyping and 
neurophysiology, neuroimaging, and molecular/genetic biomarker but not the clinical trial 
(n=82); or 
 
3) Path C: only the phenotyping (but not neurophysiology or neuroimaging), molecular/genetic 
biomarker studies, and the clinical trial (n=60, half of which will qualify for the clinical trial); 
or 
 
4) Path D (Rochester and Florida sites only): the human individual projects including 
phenotyping, neuroimaging, and molecular/genetic biomarker studies.  Entry into the clinical 
trial will be dependent on headache diary entries. This path will not include neurophysiology 
testing (cutaneous and visual pain threshold testing) and will not include the event-related 
runs during fMRI. 
 
 
 
 
 
 
 
 
 
 

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Participant flow through this Focused Program is illustrated within the Figure inserted 
below.  
 
 
 
It is anticipated that approximately 50% of patients with PTH who enter Path A/B or D will have 4 
or more moderate-to-severe headache days during the 4-week run-in period and thus will qualify 
for the clinical trial. These individuals will continue down Path A/D, while those individuals not 
meeting eligibility criteria for the clinical trial will continue down Path B/D. If clinical trial 
enrollment goals are met, participants will still have the opportunity to participate in other 
research procedures as outlined in the flow diagram.   
 
 
 
 
 
 
 
 
 
 
 

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Participant Eligibility Criteria for those with PTH 
 
Path A/D (all studies including the clinical trial) 
 
Inclusion Criteria 
 
• Have a diagnosis of acute PTH attributed to mild traumatic injury to the head as defined by the 
International Classification of Headache Disorders (ICHD-3).1  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• PTH onset 7- 56 days prior to the time of enrollment  
 
• Adults 18-70 years of age 
 
• Willing to receive erenumab treatment 
 
• Willing to maintain a headache diary 
 
• Willing and able to return for follow-up visits  
 
 
Additional Inclusion Criteria for the Clinical Trial (assessed after run-in phase) 
 
• 4 or more moderate or severe headache days during the 4-week run-in phase 
 

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• An increase of at least 2 moderate to severe headache days compared to pre-TBI 
 
• At least a 30% increase in moderate to severe headache days compared to pre-TBI 
 
• At least 80% compliant with diary keeping during the 4-week run-in phase (i.e. provides data 
on at least 80% of days) 
 
Exclusion Criteria 
 
• Chronic headache (i.e. at least 15 headache days/month for more than 3 months) within 
12 months prior to the mTBI that led to the current PTH, including PPTH, chronic migraine, 
medication overuse headache, new daily persistent headache, hemicrania continua, chronic 
tension-type headache.   
 
• Diminished decision-making capacity that in the investigator’s opinion would interfere 
with the person’s ability to provide informed consent and complete study procedures 
 
• Started or changed dose of a headache preventive medication within the 3 months prior 
to screening. 
  
• Use of onabotulinumtoxinA in the head, neck or face region within 6 months of 
screening 
 
• During the 6 months before screening, use of opioids or barbiturates on an average of at 
least 4 days per month 
  
• Subjects who underwent an intervention or used a device (e.g., nerve blocks, 
transcranial magnetic stimulation, vagal nerve stimulation, or electrical trigeminal nerve 
stimulation) for headache within 3 months of screening. 
 
• 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 
 
• History of positive neuroimaging findings that indicate a moderate or severe TBI 
 
• Contraindications to magnetic resonance imaging, including, but not limited to: 
o Metal implants 
o Aneurysm clips 
o Severe claustrophobia 
o Implanted electronic devices 
o Insulin or infusion pump 

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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) *criteria not applicable for Rochester and Florida 
sites 
 
• Pregnancy 
 
• Breastfeeding 
 
• History of myocardial infarction, stroke, transient ischemic attack, unstable angina, 
coronary artery bypass surgery, or other revascularization procedures within 12 
months prior to screening. 
 
• 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), 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 

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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 or within 90 days prior to screening: received treatment in another drug 
study or an investigational device study 
 
• Has previously received any CGRP ligand or receptor targeted monoclonal antibody  
 
 
Path C (phenotyping, molecular/genetic biomarker, clinical trial) 
 
Inclusion Criteria 
 
• Have a diagnosis of acute PTH attributed to mild traumatic injury to the head as defined by the 
International Classification of Headache Disorders (ICHD-3).1  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• PTH onset 7-56 days prior to the time of enrollment  
 
• Adults 18-70 years of age 
 

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• Willing to receive  erenumab treatment 
 
• Willing to maintain a headache diary 
 
• Willing and able to return for follow-up visits  
 
 
Additional Inclusion Criteria for the Clinical Trial (assessed after run-in phase) 
 
• 4 or more moderate or severe headache days during the 4-week run-in phase 
 
• An increase of at least 2 moderate to severe headache days compared to pre-TBI 
 
• At least a 30% increase in moderate or severe headache days compared to pre-TBI 
 
• At least 80% compliant with diary keeping during the 4-week run-in phase (i.e. provides data 
on at least 80% of days) 
 
 
Exclusion Criteria 
 
 
• Chronic headache (i.e. at least 15 headache days/month for more than 3 months) within 
12 months prior to the mTBI that led to the current PTH, including PPTH, chronic migraine, 
medication overuse headache, new daily persistent headache, hemicrania continua, chronic 
tension-type headache.   
 
• Diminished decision-making capacity that in the investigator’s opinion would interfere 
with the person’s ability to provide informed consent and complete study procedures 
 
• Started or changed dose of a headache preventive medication within the 3 months prior 
to screening.  
 
• Use of onabotulinumtoxinA in the head, neck or face region within 6 months of 
screening 
 
• During the 6 months before screening, use of opioids or barbiturates on average at least 
4 days per month 
  
• Subjects who underwent an intervention or used a device (e.g., nerve blocks, 
transcranial magnetic stimulation, vagal nerve stimulation, or electrical trigeminal nerve 
stimulation) for headache within 3 months of screening. 
 
• History of major psychiatric disorder such as schizophrenia and bipolar disorder 

10 
 
 
• 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 
 
• Pregnancy 
 
• Breastfeeding 
 
• History of myocardial infarction, stroke, transient ischemic attack, unstable angina, 
coronary artery bypass surgery, or other revascularization procedures within 12 
months prior to screening. 
 
• 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), 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 or within 90 days prior to screening: received treatment in another drug 
study or an investigational device study 
 
• Has previously received any CGRP ligand or receptor targeted monoclonal antibody  
 
 
 

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Recruitment and Enrollment 
 
Research participants will be recruited from the Mayo Clinic in Arizona, the Phoenix VA 
Healthcare System, Luke Air Force Base, Mayo Clinic in Rochester, and Mayo Clinic in Florida. 
Participants will be consented and enrolled from the Mayo Clinic in Arizona, the Phoenix VA 
Healthcare System, Mayo Clinic in Rochester, and Mayo Clinic in Florida. When Luke Air Force 
Base identifies a potentially eligible individual who may be interested in participating, they will 
refer the individual to the Mayo Clinic in Arizona for further discussion, determination of 
eligibility, and enrollment as appropriate. The Phoenix VA Healthcare System will identify and 
enroll research participants and will complete clinical phenotyping (i.e. study questionnaires). 
These research participants will then be referred to the Mayo Clinic in Arizona at which all clinical 
trial procedures will occur. 
 
 
Participating Site Responsibilities 
 
Mayo Clinic in Arizona: The Mayo Clinic in Arizona will be responsible for all clinical trial specific 
procedures including participant recruitment, consenting and enrollment, clinical phenotyping 
and neurophysiology, neuroimaging, collection of blood specimens, and conducting the clinical 
trial.  
 
Phoenix VA Healthcare System: The Phoenix VA Healthcare system will be recruiting, consenting 
and enrolling research participants and then completing the clinical phenotyping. These patients 
will then be referred to the Mayo Clinic in Arizona for their participation in the other aspects of 
this Focused Program, including the clinical trial. 
 
Luke Air Force Base: Luke Air Force Base will identify potentially eligible individuals for 
participation in this Focused Program. Such individuals will be referred to the Mayo Clinic in 
Arizona for further assessment, including participation in the clinical trial.  
 
Mayo Clinic in Rochester and Mayo Clinic in Florida:  The Mayo Clinic in Rochester and the Mayo 
Clinic in Florida will be responsible for all clinical trial specific procedures except for 
neurophysiology testing and the event-related fMRI runs. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Clinical Trial 
 
Principal Investigator 
 
Todd Schwedt, MD. Professor of Neurology. Mayo Clinic Arizona. 
 
 
Brief Summary 
 
There are currently no evidence-based or approved treatments for PTH. This clinical trial will 
determine whether intervention with a CGRP receptor mAb in a population of patients who have 
PTH for 35-84 days prevents the further persistence of PTH. In children, adults, athletes, civilian, 
and military populations, the most common phenotype of persistent PTH is migraine. CGRP has 
been demonstrated to play an integral role in the pathophysiology of migraine in humans and in 
preclinical animal models of PTH. Our group has shown that a single mTBI in a rodent animal 
model of PTH leads to a marked elevation in CGRP blood levels which when blocked with an anti-
CGRP mAb, prevents the development of cephalic allodynia and headache-related behavior. 
Several anti-CGRP mAbs targeting the CGRP ligand or its receptor have been demonstrated to be 
effective and well tolerated for the preventive treatment of episodic and chronic migraine.76,77 
Erenumab is an anti-CGRP receptor mAb that was recently approved by the US FDA for the 
preventive treatment of migraine. This study will determine whether intervention with erenumab 
prevents the persistence of PTH in a group of individuals who have already demonstrated 
evidence for a high likelihood for PTH persistence (i.e. those who have had PTH for 35-84 days). 
Individuals with PTH will receive open-label monthly subcutaneous administration of erenumab 
140 mg.1 The primary endpoint will be the mean number of moderate-to-severe headache days 
between 9-12 weeks vs. the frequency during the 4 weeks prior to treatment (baseline diary 
phase).  
 
Background 
 
There are no evidence-based treatments for PTH. Specifically, there are no acute or preventive 
medications indicated for the treatment of PTH. The majority of military operators with persistent 
post-traumatic headache (PPTH) do not respond to first-line migraine preventive drugs.78 PTH 
diagnosis and treatment are further complicated by the potential for analgesic overuse leading to 
a pattern of medication overuse headache.79,80 Without established therapies for the treatment of 
PTH or other secondary headaches, it is common to try to match the treatment to the headache 
phenotype. In other words, drugs and other treatments that are typically used for migraine would 
be used in those with PTH that has a the characteristics of migraine (i.e. migraine-like 
phenotype).81,82 However, limited clinical research is available investigating preventive 
treatments for PTH, and clinical experience suggests that these commonly used treatments are not 
effective.79,81 Moreover, the symptoms that are often associated with concussion and accompany 
PTH, including those related to cognitive, vestibular, vegetative (fatigue, lethargy), mood and 
autonomic dysfunction, may be exacerbated by these medications and thus poorly tolerated by 
patients.83 Other treatments that are used in the absence of controlled evidence and without 
significant clinical effect include trigger point injections, occipital nerve blocks, botulinum toxin 

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injections, and nonpharmacological treatments such as transcutaneous nerve stimulators, physical 
therapy, biofeedback, and cognitive behavioral therapy.81 Given the gap in evidence for treating 
PTH and the large unmet medical need, there is an urgent need for well-designed clinical trials 
investigating treatments that target the pathophysiology of PTH. There is evidence that CGRP 
plays an integral role in the pathophysiology of PTH. In a preclinical mTBI rodent model, the 
development of headache pain-related behaviors appear to be mediated through a CGRP-
dependent mechanism.84 Our group has also shown in pre-clinical rodent models that a single 
mTBI induces cephalic allodynia that is accompanied by elevated CGRP blood levels, followed by a 
persistent period during which allodynia may be provoked by a brief period of stress - the most 
common trigger of migraine headache as well as other headache types. CGRP therefore induces a 
period of long-lasting latent trigeminal sensitization that may be responsible for the persistence of 
PTH.  
 
Erenumab is a CGRP receptor mAb that has been demonstrated in phase 2 and phase 3 studies to 
be effective, safe, and well tolerated for the preventive treatment of episodic (< 15 headache days 
per month) and chronic migraine (> 15 headache days per month). Erenumab received FDA 
approval for the prevention of migraine in May 2018. In a phase 3 placebo-controlled trial in 
subjects with episodic migraine (STRIVE), 955 patients were randomized to receive monthly 
subcutaneous injections of erenumab 70mg, erenumab 140mg, or placebo over 6 months.77 The 
primary endpoint (mean monthly migraine days; MMDs) and all secondary endpoints were 
achieved. The responder rates (> 50% reduction in MMDs) to erenumab 70mg (43%) and 140mg 
(50%) were superior to placebo (27%; p<0.001). Adverse events were experienced by 64% in the 
placebo group vs. 57% and 56% in the 70mg/140mg groups respectively. There were no 
treatment-related serious adverse events in either erenumab group. In another phase 3 
randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of 
erenumab 70mg in episodic migraine prevention (ARISE), 577 adults were randomized to 
subcutaneous, monthly placebo, or erenumab (70mg).76 Erenumab significantly reduced MMD 
(primary endpoint) at weeks 9-12. A ≥50% reduction in MMDs was achieved by 40% and 30% in 
erenumab 70mg and placebo groups (odds ratio: 1.6; p=0.010). Erenumab-treated subjects also 
experienced a significant reduction in monthly use of acute migraine-specific medications 
compared to placebo (p=0.002). Similar to STRIVE, erenumab 70mg was well tolerated, and there 
were no treatment-related serious adverse events. In a recently conducted randomized, double-
blind, placebo-controlled study to evaluate the efficacy and safety of erenumab 70mg and 140mg 
for the preventive treatment of chronic migraine, 667 patients were randomized to receive 
monthly subcutaneous injections over a 3-month period.85Erenumab was demonstrated to be 
superior for the primary endpoint of MMD reduction at weeks 9-12. Responder rates were also 
superior for erenumab 70mg (40%; p<0.001) and 140mg (40%; p<0.001) compared to placebo 
(24%). Similar to the episodic migraine trials, erenumab was demonstrated to be well tolerated, 
with an adverse event profile similar to placebo. In a long-term open-label extension study (total 
exposure of 555.4 patient-years), the safety and tolerability of erenumab was similar to that in the 
double-blind phase (25.9 and 34.1 patient-years for erenumab 70 mg and placebo, respectively).86 
At week 64, 65%, 42% and 26% of patients had response of ≥ 50%, ≥ 75% or 100%. Erenumab 
resulted in durable, clinically meaningful improvements across measures of disability, headache 
impact, and migraine-specific quality of life. Anti-AMG 334 antibodies occurred in 2.4% of the 
study population, but in all were transient except in one. Anti-AMG 334 antibodies did not impact 
efficacy or safety. With erenumab exposure of more than 2 years, safety and tolerability profiles 

14 
 
during the open label extension were similar to that observed in the double-blind phase and 
comparable to placebo. 
 
 
Hypothesis/Objective 
 
The objective of this study is to collect hypothesis generating data about whether intervention 
with erenumab is an effective treatment for PTH attributed to mTBI. Participants will receive 
erenumab when PTH has been present for 35-84 days. Once PTH has been persistent for this 
period of time, patients may be less likely to remit or improve spontaneously compared to if they 
were enrolled earlier after PTH onset. Thus, this population of individuals with PTH would be 
considered in high need of treatment.  
 
 
Specific Aims/Study Endpoints 
 
Primary endpoint 
 
• Moderate-to-severe headache day frequency measured at weeks 9-12 after administration of first 
dose of erenumab 140mg vs. frequency of moderate-to-severe headache days during the 4-week 
baseline phase (BP). A moderate-to-severe headache day is defined as any headache lasting at 
least 2 hours and which at any point reaches at least moderate intensity.  
 
 
Secondary endpoints 
 
• Percentage of patients with at least a 50% reduction in headache days during weeks 9-12 after 
administration of first dose of erenumab 140 mg compared to BP. 
 
• Percentage of patients with chronic headache defined as >15 headache days during weeks 9-12 
after administration of first dose of erenumab 140mg compared to BP. 
 
• Headache Impact Test (HIT-6) at weeks 9-12 after administration of first dose of erenumab 140 
mg compared to BP. 
 
• Acute treatment day frequency measured at weeks 9-12 after administration of first dose of 
erenumab 140mg compared to BP. (Acute treatment day is any day on which an analgesic, triptan, 
or ergotamine containing medication is taken, or device neuromodulation [e.g. vagal or trigeminal 
nerve electrical stimulation or single pulse transcranial magnetic stimulation] is administered to 
relieve headache) 
 
Methods 
 
This is a phase II prospective, open-label clinical trial of a CGRP receptor mAb for treatment of 
PTH. Of note, this was originally designed as a randomized, placebo-controlled clinical trial. 
However, recruitment into the clinical trial was slow.  Since the estimated total enrollment would 

15 
 
be inadequate for making comparisons between the placebo and erenumab groups, the study was 
revised to an open-label design. 
 
Individuals with PTH will be receive monthly subcutaneous administration of erenumab 140 mg 
over a 3-month period (total of 3 injections). The primary endpoint will be the mean number of 
moderate-to-severe headache days between 9-12 weeks after treatment vs. the number of 
moderate-to-severe headache days during the 4-week BP. Subjects will maintain an electronic 
daily diary during the 4-week BP, for the 12 weeks post-first treatment, and during weeks 21-24 
post-first treatment. 
 
All participants in this clinical trial will complete baseline and follow-up questionnaires described 
in detail in the separate human studies protocol subtitled “Individual Projects Excluding Clinical 
Trial” within the “Phenotyping and Neurophysiology” section. In brief, the following 
questionnaires will be used to collect baseline and follow-up data:   
 
1) TBI and PTH characteristics 
2) Post-TBI symptoms using the 22-item Symptom Evaluation Checklist from the Sport 
Concussion Assessment Tool (SCAT)  
3)  Headache Impact Test (HIT-6) 
4)  Self-Rating Questionnaire on Hypersensitivity to Sound 
5)  Photosensitivity Assessment Questionnaire 
6)  Allodynia Symptom Checklist (ASC-12) 
7)  State Trait Anxiety Inventory (STAI) 
8)  Beck Depression Inventory (BDI) 
9)  Posttraumatic Stress Disorder Checklist 
10) Survey of Autonomic Symptoms  
11) Pain Catastrophizing Questionnaire 
12) Insomnia Severity Index 
13) Cognitive Function 
14) Dizziness Handicap Inventory 
15) Trail Making Test A and B 
16) Controlled Oral Word Association Test (COWAT) 
17) Global Impression of Change 
18) Follow-up Headache Characteristics 
19) Adverse Events  
20) Sensory Testing Results *not applicable for Rochester and Florida sites 
21) Vital Signs 
22) Pregnancy Test Results 
 
In addition, all research participants will maintain a daily electronic headache and symptom diary 
to provide data on headaches, treatment, and presence and severity of associated symptoms. The 
diary will be maintained for the first 4 weeks, starting with enrollment (i.e. first research visit) and 
through week 16 (i.e. third research visit), and again during weeks 21-24 post-first treatment. The 
electronic diary requires individuals to record whether they did or did not have a headache each 
day, the severity of their pain, headache duration, level of functional disability due to the 
headache, and use of medication. To optimize compliance with diary maintenance, the amount of 

16 
 
time required to complete the daily entries has been minimized to less than 2 minutes. Subjects 
are asked to complete their headache diary at the end of each day. Data from the headache and 
symptom diary will be used to assess changes in symptoms over time, to prospectively determine 
who has persistence vs. resolution of PTH, to determine enrollment in the clinical trial depending 
on PTH persistence and frequency of moderate to severe headache days, and to track response to 
treatment for those individuals enrolled into the clinical trial. 
 
 
 
 
Stratification, Randomization and Masking: This is an open-label study in which there is no 
stratification, randomization, or masking.  
 
All study drugs will be prepared by a Mayo Clinic pharmacist who has no other role in the 
study. The drug will be delivered by pharmacy staff to the enrolling investigator clinician or 
research nurse, who will be responsible for delivering the injection. There will be strict 
adherence to inclusion and exclusion criteria. Participants will receive instructions and 
training from a study coordinator on how to use the electronic diary for daily reporting of 
headaches. A urine pregnancy test will be required for female participants prior to each of 
the erenumab treatments. Throughout the study, participants will record data in the daily 
diary for the previous 24 h period.  
  
Treatment with Erenumab: Patients receive treatment with 140 mg of erenumab via 
subcutaneous injection. Treatment will be administered under research team observation. 
Injections will be administered using two 70 mg/1 mL prefilled syringes in the abdomen 
(except for a two-inch area right around the navel), thigh, or outer area of upper arm 
according to patient preference. If using the same body site for the two separate injections, 
the second injection is not to be given at the same spot used for the first injection. 
 

17 
 
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. 
Concomitant Therapy 
There are no restrictions on the use of as needed headache/pain therapies. Patients will 
record their use of such therapies within the headache diary and these data will be used 
when measuring patient outcomes. 
 
For patients who are participating in the clinical trial, no preventive therapy for headache 
should be started. Preventive therapies include drugs, biologics, devices, procedures, and 
non-pharmacological modalities. 
 
Statistical Plan:  
Sample Size- all individuals who qualify for the clinical trial and are interested in participating will 
be enrolled, up to a maximum of 112 participants. This sample size is empirical and results will be 
used for hypothesis generation.  
 
Headache Diary - Values for missing calendar day entries in a given month will be imputed by 
prorating scores of 4-week post-treatment periods with 20–27 days of diary data. For months 
with less than 10 days of diary data, scores will be estimated by the substitution of the patient’s 
previous 28-day period mean score, multiplied by the ratio of the mean for all patients in the same 
period and divided by the mean for all patients in the previous period. For post-treatment periods 
with 10–19 days of diary data, scores were estimated using a mean of both methods.  
 
Outcomes - Efficacy analyses will be conducted in the full analysis set, which includes all subjects 
(intent-to-treat population) who received at least one dose of study drug and have at least 10 days 
of efficacy assessments for the primary endpoint measured during weeks 9-12. Safety analyses 
will be performed in all subjects who receive at least one dose of study drug. The primary and 
secondary endpoints will be analyzed using a within-person one-sample t-test. Signed rank test 
will be used for the primary analysis if there is a deviation from normality assumption as assessed 
by Shapiro Wilk’s test. Confidence intervals will be calculated. SAS version 9.4 (SAS Institute, Cary 
NC) will be used for all statistical analyses. 
 
IRB Approvals and Informed Consent: IRB approvals will be obtained from the Mayo Clinic IRB, 
the Phoenix VA IRB and the DOD HRPO prior to starting any human study research. Written 
informed consent will be obtained from all subjects prior to their participation. The informed 
consent process will be based upon the Declaration of Helsinki principles 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. All consent forms will require IRB 
approval prior to their use. Patients will be informed of their right to withdraw from the study at 
any time. 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 

18 
 
monitoring. Consent documents will be stored for a minimum of 3 years after conclusion of the 
study. The research participant will retain a copy of their signed consent document. 
 
Study Materials: Study drug will be provided by Amgen, Inc, the manufacturer of erenumab.  
 
 
Participant Compensation 
 
Participants will be compensated $50 per research visit and $35 per month for headache diary 
completion at least 80% of the time for a total of up to $175. 
 
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: 
• 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 (eg, 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 (12 weeks after administration of investigational product) are reported 
using the applicable case report form (CRF) (eg, Adverse Event Summary). 
 

19 
 
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) 
• severity 
• assessment of relatedness to investigational product 
• action taken 
 
The adverse event grading scale used will be the Common Terminology Criteria for Adverse 
Events (CTCAE). The investigator must assess whether the adverse event is possibly related to the 
investigational product and/or medical device. This relationship 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 criteria for grade 4 in the CTCAE grading scale differs from the regulatory criteria for serious 
adverse events. It is left to the investigator’s judgment to report these grade 4 abnormalities as 
serious adverse events. If the severity of an adverse event changes from the date of onset to the 
date of resolution, the adverse event should be recorded as a single event with the worst severity 
on the Adverse Event Summary CRF. 
 
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 (12 weeks after the last dose of investigational 
product) are recorded in the subject’s record and are submitted to Data Safety Monitoring 
Committee (DSMC). All serious adverse events must be submitted to the DSMC within 24 
hours following the investigator’s knowledge of the event via the applicable CRF. The 
investigator is to notify the appropriate IRB/IEC of serious adverse events occurring at the 
site in accordance with local procedures and statutes. Adverse events that occur during the 
clinical trial will be reported to Amgen according to the timelines described in the 
Appendix (“ISS – Timeframes for Submission of Safety Data to Amgen”). 
 
Data and Safety Monitoring and Annual Reporting to Regulatory Agency 
 
IND safety reports. The DSMB will notify FDA and all participating investigators in an IND 
safety report of potential serious risks, from clinical trials or any other source, as soon as 
possible, but in no case later than 15 calendar days after the DSMB determines that the 
information qualifies for reporting. Qualifications for reporting include: 
• Serious and unexpected suspected adverse reaction. This includes a single occurrence 
of an event that is uncommon and known to be strongly associated with drug 
exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome; one or more 
occurrences of an event that is not commonly associated with drug exposure, but is 
otherwise uncommon in the population exposed to the drug; an aggregate analysis 
of specific events observed in a clinical trial (such as known consequences of the 

20 
 
underlying disease or condition under investigation or other events that commonly 
occur in the study population independent of drug therapy) that indicates those 
events occur more frequently in the drug treatment group than in a concurrent or 
historical control group. 
• Findings from other studies. Investigators will report any findings from 
epidemiological studies, pooled analysis of multiple studies, or clinical studies 
whether or not conducted under an IND, and whether or not conducted by the 
sponsor, that suggest a significant risk in humans exposed to the drug. Ordinarily, 
such a finding would result in a safety-related change in the protocol, informed 
consent, investigator brochure (excluding routine updates of these documents), or 
other aspects of the overall conduct of the clinical investigation. 
• Findings from animal or in vitro testing. Investigators will report any findings from 
animal or in vitro testing, that suggest a significant risk in humans exposed to the 
drug, such as reports of mutagenicity, teratogenicity, or carcinogenicity, or reports 
of significant organ toxicity at or near the expected human exposure. Ordinarily, any 
such findings would result in a safety-related change in the protocol, informed 
consent, investigator brochure (excluding routine updates of these documents), or 
other aspects of the overall conduct of the clinical investigation. 
• Increased rate of occurrence of serious suspected adverse reactions. Investigators will 
report any clinically important increase in the rate of a serious suspected adverse 
reaction over that listed in the protocol or investigator brochure. 
• Submission of IND safety reports. Investigators will annually submit each IND safety 
report in a narrative format or on FDA Form 3500A or in an electronic format that 
FDA can process, review, and archive. Each notification to FDA will be transmitted 
to the review division in the Center for Drug Evaluation and Research or in the 
Center for Biologics Evaluation and Research that has responsibility for review of 
the IND. Upon request from FDA, the investigators will submit to FDA any additional 
data or information that the agency deems necessary, as soon as possible, but in no 
case later than 15 calendar days after receiving the request. 
• Unexpected fatal or life-threatening suspected adverse reaction reports. Investigators 
will notify FDA of any unexpected fatal or life-threatening suspected adverse 
reaction as soon as possible but in no case later than 7 calendar days after the 
sponsor's initial receipt of the information. 
 
Study Registration 
 
The research program including the clinical trial will be registered at ClinicalTrials.gov. 
 
 
Risks and Benefits of Participating in this Research Program 
 

21 
 
Possible Benefits: 
It is possible that patients will have improvements in their PTH patterns following treatment with 
erenumab. 
 
 
 
 
Possible Risks: 
 
Erenumab has been shown to be well tolerated and associated with few side effects. 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 of migraine. 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 erenumab 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 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. 
 
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.  
 
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.  
 
There is a possibility that the stress and stimulation of participating in the research study 
could transiently exacerbate one’s headache. 
 
A research participant that indicates suicidal or homicidal intent on a study questionnaire 
will be referred to the Emergency Department for evaluation.  
 
Protection Against Risks: 
 
Individuals who are known to be pregnant or breastfeeding will be excluded from study 
participation. 

22 
 
 
Women of childbearing potential who are not known to be pregnant will have pregnancy testing at 
the baseline visit and prior to each treatment with study drug. Women found to be pregnant prior 
to treatment will not receive treatment. Women found to be pregnant after the initial treatment 
will not receive further study drug. Women of childbearing potential will be required to use a 
reliable form of contraception from the time of study enrollment through 16 weeks after the dose 
of erenumab. 
 
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.  
 
 
Patient 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. Subjects will be contacted with reminders prior to each research appointment. 
 
Diary compliance will be monitored on an ongoing basis. Subjects will be contacted immediately if 
non-compliance is observed.  
 
 
Protocol Maintenance 
 
Protocol modifications will be approved by the principal investigator and submitted to the IRB in 
accordance with IRB rules and regulations. Modifications will be documented separately and 
within the main protocol document with a newly assigned date and version number. 
 
 
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 

23 
 
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 
 
 
Data Sharing 
 
FITBIR (Federal Interagency Traumatic Brain Injury (FITBIR) informatics system):  
FITBIR is a computer system run by the National Institutes of Health that allows researchers to 
share information with each other. Data from this study will be submitted to FITBIR. Before data 
are submitted, PHI will be replaced with a code number. Subjects will have the ability to opt out 
from having their data shared to FITBIR. 
 
 
References 
 
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Headache Classification Committee of the International Headache Society 
(IHS) The International Classification of Headache Disorders, 3rd edition. 
Cephalalgia 2018;38:1-211. 

24 
 
2. 
Dodick DW, Ashina M, Brandes JL, et al. ARISE: A Phase 3 randomized trial of 
erenumab for episodic migraine. Cephalalgia 2018;38:1026-37. 
3. 
Goadsby PJ, Reuter U, Hallstrom Y, et al. A Controlled Trial of Erenumab for 
Episodic Migraine. N Engl J Med 2017;377:2123-32. 
4. 
Erickson JC. Treatment outcomes of chronic post-traumatic headaches after 
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5. 
Gladstone J. From psychoneurosis to ICHD-2: an overview of the state of the 
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Lenaerts ME. Post-traumatic headache: from classification challenges to 
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Seifert TD, Evans RW. Posttraumatic headache: a review. Curr Pain Headache 
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Theeler B, Lucas S, Riechers RG, 2nd, Ruff RL. Post-traumatic headaches in 
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Vargas BB, Dodick DW. Posttraumatic headache. Curr Opin Neurol 
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Bree D, Levy D. Development of CGRP-dependent pain and headache related 
behaviours in a rat model of concussion: Implications for mechanisms of post-
traumatic headache. Cephalalgia 2016. 
11. 
Tepper S, Ashina M, Reuter U, et al. Safety and efficacy of erenumab for 
preventive treatment of chronic migraine: a randomised, double-blind, placebo-
controlled phase 2 trial. Lancet Neurol 2017;16:425-34. 
12. 
Ashina M, Dodick D, Goadsby PJ, et al. Erenumab (AMG 334) in episodic 
migraine: Interim analysis of an ongoing open-label study. Neurology 
2017;89:1237-43.