Erenumab For Treatment of Hemicrania Continua
Phase: PHASE2
Conditions: Hemicrania Continua
Sponsor: Mayo Clinic

 
Erenumab For Treatment of 
Hemicrania Continua 
 
 
NCT04303845 
 
 
10/6/2021 

 
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Erenumab For Treatment of Hemicrania Continua 
Regulatory Sponsor: Rashmi Halker Singh, M.D 
Mayo Clinic 
 
Scottsdale, AZ 85259 
Study Product: erenumab 
Funding sponsor:  Amgen 
Protocol Number: (IRBe): 19-007088 
Protocol Version: 3.0 – October 6, 2021 
Background:   
Hemicrania Continua (HC) is a primary headache disorder manifested by severe, continuous, unilateral 
head pain with associated ipsilateral cranial autonomic symptoms such as lacrimation, rhinorrhea, nasal 
congestion, or even a sense or restlessness or agitation1.  The ICHD-3 classifies it as a Trigeminal 
Autonomic Cephalalgia (TAC), as it shares features with cluster headache and other TACs. Functional 
imaging studies using positron emission tomography (PET) have demonstrated activation of the 
contralateral posterior hypothalamus with HC, which is an area of activation also seen in cluster 
headache, and hypothesized as potentially responsible for the autonomic symptoms associated with 
these headache disorders by disinhibiting the trigeminal autonomic reflex2.  Furthermore, these PET 
studies have also shown activation of other brainstem areas with HC, including the ipsilateral dorsal 
rostral pons and periaqueductal gray, an area also implicated in migraine pathophysiology and may help 
explain the overlap in associated symptoms between these two primary headache disorders3.  
By definition, HC responds to treatment with indomethacin, a nonsteroidal anti-inflammatory drug 
(NSAID) that has a structural similarity to serotonin and also inhibits nitric oxide-induced vasodilation4,5. 
As with other indomethacin-responsive headache disorders, the mechanism by which it treats HC is not 
clear but there is some speculation that indomethacin may inhibit trigeminal nociceptive transmission 
and trigeminoautonomic activation6,7.  While patients with HC tend to respond within a matter of days 
to indomethacin, the literature reveals that most patients will relapse when it is discontinued and 
therefore will need to remain on it as a chronic treatment8.  This can be problematic, as tolerability and 
risks of adverse effects with continued use remains a significant concern9.  As an NSAID, the most 
common issue with indomethacin involves gastrointestinal complications, from indigestion and 
worsening acid reflux to gastric ulceration and hemorrhage.  Patients may also experience renal 
insufficiency, and the drug can have an impact on blood pressure and platelet functioning among other 
things4.  These risks are likely greater in patients with other co-morbid medical problems or on other 

 
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medications, or in the elderly who may have baseline renal and cardiac issues. There is a real need to 
find new treatment options for HC. 
As there is significant overlap between HC and migraine, we anticipate that patients with HC will 
respond to treatment with erenumab.  
Specific Aims: 
1. Evaluate the response of hemicrania continua to treatment with erenumab 
2. Evaluate the safety and tolerability of erenumab in patients with hemicrania continua 
Methods: 
Study Design: This is a prospective, open-label, study of patients with hemicrania continua treated with 
a single dose of erenumab 140 mg SQ.   
Participants: Up to 25 adult patients who are at least 18 years of age with hemicrania continua will be 
enrolled into the screening phase of this study at Mayo Clinic Arizona.  Enrollment will stop once 25 
subjects provide headache diary during the screening phase that meets eligibility criteria (i.e. meet 
diagnostic criteria for hemicrania continua). Exclusion and inclusion criteria will be modeled after those 
used in the phase 2 and 3 trials of erenumab for the prevention of migraine and adapted for the 
diagnosis of hemicrania continua.10,11 Potential participants will be excluded if they have active chronic 
pain conditions other than hemicrania continua (e.g. chronic pelvic pain) or acute pain conditions (e.g. 
recent surgery).  
Subject Eligibility 
Inclusion Criteria 
• 
Adults ages 18 and over 
• 
At least a 12 month history of hemicrania continua according to International 
Classification of Headache Disorders, 3rd Edition (ICHD-3)1 
• 
Previous or current complete response to indomethacin 
• 
Stable preventive treatment for at least 2 months and no anticipated need to adjust/add 
current headache prevention treatment 
Exclusion Criteria 
• 
Nonresponse to a therapeutic dose of indomethacin for hemicrania continua when used 
for at least 1 week 
• 
Pregnant or lactating subjects  
• 
Use of barbiturate or opioid >6 days per month; history of chronic migraine 
• 
History of previous trigeminal-autonomic cephalalgia 

 
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• 
History within previous 2 months of interventional procedure for headache (occipital or 
other extracranial nerve block, sphenopalatine ganglion block, cervical facet block, facet 
rhizotomy) 
• 
History of cranial nerve/rhizolysis 
• 
Botulinumtoxin injection within previous 4 months 
• 
Parenteral infusion of an oral corticosteroid use for more than 3 days within 4 weeks 
prior to screening phase 
Screening Phase (1 week) (Day -7) 
At this initial visit, 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 have measurement of vital signs and urine pregnancy 
testing (for women of childbearing potential), and will be trained on how to use the headache diary. 
Patients will be instructed to keep a prospective headache diary for the next week. We assume that up 
to 20% of individuals participating in the screening phase will not meet the inclusion criteria and/or 
diary compliance minimum and thus will not continue in this study.  It is anticipated that 25 patients will 
be enrolled in the screening phase of the study to obtain 20 evaluable patients.  If a subject is on 
indomethacin for the prevention of hemicrania continua, indomethacin will be stopped at this visit.  
Baseline (treatment) Visit (Day 0) 
Patients will return for a baseline visit after 1 week (i.e. 7 days since start of screening 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).  
Treatment with Erenumab (Day 0) 
Patients will receive treatment with 140 mg of erenumab via subcutaneous injection during their 
baseline visit. 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. 
 

 
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Daily Headache Diary 
A daily headache diary will be completed for the next 4 weeks to allow for assessment of changes in 
headache frequency and intensity. Headache diary data will be analyzed to classify patients as 
“responders” (50% or greater reduction in headache frequency at week 4 post erenumab treatment 
compared to frequency during the screening phase) or “non-responders” (less than 50% reduction in 
headache frequency at week 4 post erenumab treatment compared to the frequency during the 
screening phase). Since patient outcomes will be measured at 4 weeks (opposed to 12 weeks like it is 
done in the majority of clinical trials), depending upon patient outcomes other definitions of “response” 
and “non-response” could be used.  
Acute Headache Therapy: Patients will be allowed to use acute headache treatments including NSAIDs 
during the study if needed.  The use of these treatments will be recorded.   
Table:  Schedule of Events  
 
Screening 
Phase (7 days) 
(Day -7) 
Baseline Visit 
(Day 0) 
Weekly, 
weeks 1-4 
(Day 0 to Day 28) 
Follow-up 
Visit, week 4 
(Day 28) 
Safety 
follow-up 
visit, week 8 
(Day 56) 
Visit Window (days) 
-2 
+/- 0  
n/a 
+/- 3 
+/- 3 
Eligibility: I/E 
criteria 
X 
 
 
 
 
Vital signs 
X 
X 
 
X 
X 
Demographics, PMH 
X 
 
 
 
 
Urine pregnancy 
test 
X 
X 
 
 
 
Headache 
characteristics 
X 
 
 
X 
X 
Concomitant 
medications / 
treatments 
X 
 
 
X 
X 
BDI 
 
X 
 
X 
 
STAI 
 
X 
 
X 
 
MIDAS 
 
X 
 
X 
 
PGIC 
 
 
 
X 
 
Adverse events 
 
 
X 
X 
X 
Headache diary, 
daily   
X 
 
X 
 
 
Treatment:  
Erenumab injection 
 
X 
 
 
 
 
Sample Size 
A sample size of 20 will have 80% power to detect a decrease of frequency of headache days (in 28-day 
period) of 2 or more from baseline, assuming a standard deviation of 3, using a paired t-test with a 0.05 

 
5 
two-sided significance level.  It is anticipated that up to 25 patients will be enrolled in the study in order 
to obtain 20 evaluable patients for the primary outcome.   
Subject Recruitment and Screening 
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 $50 per research visit and $50 at study completion provided they are at 
least 80% compliant with the headache diary (i.e. provide data on at least 80% of days in the 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 

 
6 
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 (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 

 
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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 member of the research team who receives the information from the participant about the adverse 
event will complete the Adverse Event case report form. 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.  
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.   Please see Appendix 1.  
Annual reporting requirements:  
Adverse events, any protocol non-compliance and UPIRTSOs will be reported to the reviewing Institution 
Review Board (Mayo Clinic IRB) at the time of annual IRB continuing review, in accordance with Mayo 
Clinic research policies. 
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 headache 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: 
According to the FDA label for erenumab, it is contraindicated in patients with serious hypersensitivity 
to erenumab-aooe or to any of the excipients. Reactions have included anaphylaxis and angioedema.  
 
Erenumab has been shown to be well tolerated and associated with few side effects. The most common 
side effects are injection site pain, erythema, and edema. Less than 5% of patients in the phase II and III 
clinical trials reported these side effects. In addition, constipation was reported by approximately 3% of 
individuals receiving erenumab. 

 
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Hypersensitivity Reactions: If a serious hypersensitivity reaction occurs, discontinue administration of 
AIMOVIG and initiate appropriate therapy.  Hypersensitivity reactions can occur within hours to more 
than one week after administration.  
 
Hypertension: 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. Hypertension may occur at any time during 
treatment but was most frequently reported within seven days of dose administration.  
 
Constipation with Serious Complications:  Serious complications of constipation may occur.  
 
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.  
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 REDCap12. 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 analyses12,13. 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.  

 
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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 screening 
phase will be withdrawn from the study.  
Statistical Methods & Analysis  
This is a prospective, open-label, study of patients with hemicrania continua treated with a single dose 
of erenumab 140 mg SQ.  Estimates of efficacy (decrease in frequency of headache) will be assessed.  
For the primary endpoint, patients will be classified as a responder (50% or greater reduction by week 4 
post erenumab treatment) or a non-responder (less than 50% reduction in headache frequency).   SAS 
version 9.4 (SAS Institute, Cary, NC) will be used for analysis.  The analysis will be kept descriptive and 
efficacy will be evaluated based on clinical meaningfulness threshold.  
Analysis Plans 
Primary endpoint & analyses:  All eligible patients that successfully complete the screening phase and 
have initiated treatment with erenumab will be considered evaluable for assessing the primary 
endpoint.  The primary endpoint of this trial will consist of the proportion of patients who are 
considered to have a response as defined above at the end of week 4 divided by the total number of 
evaluable patients on the study.  Patients will not be considered evaluable if they did not complete the 
screening phase requirements or discontinued the study due to withdrawal before receiving erenumab.  
A point estimate and two-sided 95% confidence interval will be computed for this endpoint based on 
properties of the binomial distribution. 
The analysis plan for additional (secondary) endpoints are listed below.  
Headache days (>4 hours moderate/severe pain) weeks 4 compared to baseline:  Change in headache 
days at the  end of weeks 4 will be compared to baseline.  Headache frequency will be described at each 
time point using the mean, 95% confidence interval, median, and range. Changes from baseline in 
headache frequency will also be described using the mean, 95% confidence interval, median and range, 
and assessed using paired t-tests or non-parametric Wilcoxon signed-rank tests as appropriate. 
Graphical procedures will include plots of average headache frequency over time. The proportion of 
responders will be computed at week 4. Response at the end of week 4 is the primary endpoint.  
Headache hours (moderate/severe pain intensity:  Change in the amount of total headache hours (with 
moderate or severe pain) at the end of week 4 will be compared as separate time points to baseline. 
Headache hours will be analyzed similar to specific aim #1 as above.  
Acute medication use (# days over weeks 4):  Acute medication use at the end of week 4 will be 
compared as separate time points to baseline. Medication usage will be analyzed similar to specific aim 
#1 as above. 

 
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Remission rate (proportion of patients free of headache weeks 4): The proportion of patients who do not 
have any occurrence of headache at the end of week 4 will be divided by the total number of evaluable 
patients in the study.  A point estimate and confidence interval will be computed for these endpoints, 
headache freedom at week 4.  
 
Patient-reported Outcomes:  Patients will complete the BDI, STAI, MIDAS, 4-week Follow-up Headache 
Characteristics and the PGIC.  Patient reported outcomes (BDI, STAI, MIDAS) will be scored using 
published scoring algorithms and described at each time point using the mean, 95% confidence interval, 
median, and range. Changes from baseline will also be described using the mean, 95% confidence 
interval, median and range, and assessed using paired t-tests or Wilcoxon signed-rank tests as 
appropriate. Graphical procedures will include plots of average values over time.  The PGIC will be 
described to assess patient perception of improvement.   
 
Adverse Events 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.  The maximum grade for each type of adverse event will be summarized as the 
number of patients experiencing the event divided by the total number of evaluable patients.  
Frequency tables will be constructed.  Additionally, the relationship of the adverse event(s) to the study 
treatment will be taken into consideration.  
Results Reporting on ClinicalTrials.gov:  At study activation, this study will have been registered within 
the “ClincialTrails.gov” website. The Primary and Secondary Endpoints (ie, “Outcome Measures”) along 
with other required information for this study will be reported on ClinicalTrials.gov.  
Protocol Approval and Maintenance by IRB  
Initial IRB application will be submitted for review by Mayo Clinic’s IRB, full board review committee.  
Mayo’s IRB has several meetings each week and there are no submission deadlines.   After review takes 
place by the full board review committee a meeting minute will be generated typically within 3 to 5 
business days on the approval decision.  
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. 
Case Report Forms 
Case report forms include:  
1) Inclusion and Exclusion Criteria 

 
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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 Headache Medications 
10) Beck Depression Inventory (BDI) 
11) State-Trait Anxiety Inventory (STAI) 
12) Migraine Disability Assessment (MIDAS) 
13) Four Week Follow-up Headache Characteristics 
14) Patient Global Impression of Change 
15) Adverse Events 
16) Headache Diary 
References: 
1. Headache Classification Committee of the International Headache Society (IHS) The 
International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1-211. 
2. Matharu MS, Cohen AS, McGonigle DJ, et al. Posterior hypothalamic and brainstem activation in 
hemicranias continua. Headache 2004;62:516-7. 
3. Matharu MS, Goadsby PH. Functional brain imaging in hemicranias continua: implications for 
nosology and pathophysiology. Curr Pain Headache Rep 2005;9(4):281-8. 
4. Lucas S. The pharmacology of indomethacin. Headache 2016 Feb;56(2):436-46. 
5. VanderPluym J. Indomethacin-responsive headaches. Curr Neurol Neurosci Rep 2015;15:516. 
6. Bordini EC, Bordini CA, Woldemanuel YW, Rapoport AM. Indomethacin responsive headaches: 
exhaustive systematic review with pooled analysis and critical appraisal of 81 published clinical 
studies. Headache 2016 Feb;56(2):422-35 
7. Akerman S, Holland PR, Summ O, Lasalandra MP, Goadsby PJ. A translational in vivo model of 
trigeminal autonomic cephalalgias: therapeutic characterization. Brain 2012;135:3364-75. 
8. Charlson RW and Robbins MS. Hemicrania continua. Curr Neurol Neurosci Rep 2014;14:436. 

 
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9. Prakash S, Husain M, Sureka DS, et al. Is there a need to search for alternatives to indomethacin 
in hemicrania continua? Case reports and a review. J Neurol Sci 2009;277(1):187-90. 
10. Goadsby PJ, Reuter U, Hallstrom Y, Broessner G, Bonner JH, Zhang F, et al. A Controlled Trial of 
Erenumab for Episodic Migraine. N Engl J Med. 2017;377(22):2123-32. 
11. Tepper S, Ashina M, Reuter U, Brandes JL, Dolezil D, Silberstein S, 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(6):425-34. 
12. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture 
(REDCap)--a metadata-driven methodology and workflow process for providing translational 
research informatics support. J Biomed Inform. 2009;42(2):377-81. 
13. National Center for Research Resources. Strategic plan: challenges and critical choices. 2004-
2008. 
 
 
 

 
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Appendix 1 
 
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