Conditions: Migraine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 512
Healthy volunteers: no

Brief summary:
The primary objective of this study is to evaluate the treatment benefit of erenumab on headache duration of at least moderate pain intensity.

Detailed description:

Arms:
arm 1: The 4-month DBTP has 2 phases:

* Main double-blind treatment phase (M-DBTP, months 1 to 3) that will assess the effect of erenumab on metrics such as time spent in at least moderate pain, peak migraine severity, and functional impairment.
* Exploratory DBTP (E-DBTP, month 4) that will assess the impact of erenumab on the acute response to treatment with oral triptan therapy as well as non-ictal burden. arm 2: The 4-month DBTP has 2 phases:

* Main DBTP (M-DBTP, months 1 to 3) that will assess the effect of erenumab on metrics such as time spent in at least moderate pain, peak migraine severity, and functional impairment.
* Exploratory DBTP (E-DBTP, month 4) that will assess the impact of erenumab on the acute response to treatment with oral triptan therapy as well as non-ictal burden.

Interventions: intervention 1: Erenumab intervention 2: Placebo
Intervention descriptions: intervention 1: 140 mg, 2 consecutive injections of 70 mg intervention 2: 2 consecutive injections

Protocol document:
Prot_000.pdf: 
Product:  Erenumab 
Protocol Number:  20190008 
Date:  29 June 2022 
Page 1 of 90 
CONFIDENTIAL 
FORM-001520, v.24, 21 May 2019 
Title Page 
Protocol Title: 
Comprehensive Assessment of Erenumab 
Efficacy in Subjects With High Frequency 
Episodic Migraine With at Least 1 Previously 
Failed Preventive Treatment:  a Global, 
Double-blind, Placebo-controlled Phase 4 Study 
Short Protocol Title: 
Erenumab – Comprehensive Assessment of 
Efficacy in (High-Frequency) Episodic Migraine 
(EMBRACE) 
Protocol Number: 
20190008 
Investigational Product: 
Erenumab 
Trade Name: 
AIMOVIG® 
Sponsor 
Name of Sponsor: 
Amgen, Inc. 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Telephone Number: 
805-447-1000
Protocol 
Approver 
Name: 
 
Function: 
Vice President of Global Development 
Key 
Sponsor 
Contact 
Name: 
 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Telephone Number: 
Email Address: 
 
EudraCT Number: 
2019-003646-33 
NCT Number: 
Not applicable 
Protocol Version Date: 
Document Version 
Date 
Original 
25 September 2019 
Amendment 1 (v2.0) 
25 April 2022 
Superseded 
Amendment 1 
29 June 2022 
Data Elements Standards 
Version: 
Version 6.2 
This protocol was developed, reviewed, and approved in accordance with Amgen’s 
standard operating procedures.   
NCT Number: NCT04252742
This NCT number has been applied to the document
for purposes of posting on Clinicaltrials.gov


Product:  Erenumab 
Protocol Number:  20190008  
Date:  29 June 2022 
Page 2 of 90 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Confidentiality Notice 
 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1-800-77-AMGEN; Canadian sites, 
1-866-50-AMGEN; Amgen’s general number in the US, 1-805-447-1000. 


Product:  Erenumab 
Protocol Number:  20190008  
Date:  29 June 2022 
Page 3 of 90 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Investigator’s Agreement: 
I have read the attached protocol entitled Comprehensive Assessment of Erenumab 
Efficacy in Subjects With High Frequency Episodic Migraine With at Least 1 Previously 
Failed Preventive Treatment:  a Global, Double-blind, Placebo-controlled Phase 4 Study, 
dated 29 June 2022, and agree to abide by all provisions set forth therein.   
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP), Declaration of Helsinki, and applicable 
national or regional regulations/guidelines.   
I agree to ensure that Financial Disclosure Statements will be completed by:  
me (including, if applicable, my spouse or legal partner and dependent children) and 
my subinvestigators (including, if applicable, their spouses or legal partners and 
dependent children) at the start of the study and for up to 1 year after the study is 
completed, if there are changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc. 
 
_______________________________ 
Signature 
 
_______________________________ 
 
____________________________ 
Name of investigator  
 
 
 
 
Date (DD Month YYYY) 


Product:  Erenumab 
Protocol Number:  20190008  
Date:  29 June 2022 
Page 4 of 90 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Table of Contents 
Table of Contents ............................................................................................................ 4 
1. 
Protocol Summary .................................................................................................. 8 
1.1 
Synopsis ..................................................................................................... 8 
1.2 
Study Schema ........................................................................................... 12 
1.3 
Schedule of Activities (SoA) ...................................................................... 13 
2. 
Introduction ........................................................................................................... 18 
2.1 
Study Rationale ......................................................................................... 18 
2.2 
Background ............................................................................................... 18 
2.2.1 
Disease ..................................................................................... 18 
2.2.2 
Amgen Investigational Product Background:  
Erenumab ................................................................................. 19 
2.3 
Benefit/Risk Assessment ........................................................................... 20 
3. 
Objectives and Endpoints ..................................................................................... 21 
4. 
Study Design ........................................................................................................ 24 
4.1 
Overall Design........................................................................................... 24 
4.2 
Number of Subjects ................................................................................... 25 
4.2.1 
Replacement of Subjects ........................................................... 25 
4.2.2 
Number of Sites ......................................................................... 25 
4.3 
Justification for Investigational Product Dose ............................................ 25 
4.4 
End of Study ............................................................................................. 26 
4.4.1 
End of Study Definition .............................................................. 26 
4.4.2 
Study Duration for Subjects ....................................................... 26 
4.5 
Patient Input on Study Design ................................................................... 26 
5. 
Study Population................................................................................................... 26 
5.1 
Inclusion Criteria ....................................................................................... 27 
5.2 
Exclusion Criteria ...................................................................................... 28 
5.3 
Subject Enrollment .................................................................................... 30 
5.4 
Screen Failures ......................................................................................... 30 
5.5 
Run-in and Baseline Periods ..................................................................... 31 
6. 
Treatments ........................................................................................................... 31 
6.1 
Treatment(s) Administered ........................................................................ 32 
6.1.1 
Investigational Products ............................................................ 32 
6.1.2 
Medical Devices ........................................................................ 32 
6.1.3 
Other Protocol-required Therapies ............................................ 33 
6.1.4 
Other Treatment Procedures ..................................................... 33 
6.1.5 
Product Complaints ................................................................... 33 
6.1.6 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 33 


Product:  Erenumab 
Protocol Number:  20190008  
Date:  29 June 2022 
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6.2 
Dose Modification ...................................................................................... 35 
6.2.1 
Dose-cohort Study Escalation/De-escalation and 
Stopping Rules .......................................................................... 35 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 35 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 35 
6.3 
Preparation/Handling/Storage/Accountability ............................................ 36 
6.4 
Measures to Minimize Bias:  Randomization and Blinding ......................... 36 
6.4.1 
Method of Treatment Assignment .............................................. 36 
6.4.2 
Blinding ..................................................................................... 36 
6.4.2.1 
Site Personnel Access to Individual 
Treatment Assignments .......................................... 36 
6.4.2.2 
Access to Individual Subject Treatment 
Assignments by Amgen or Designees ..................... 36 
6.5 
Treatment Compliance .............................................................................. 37 
6.6 
Treatment of Overdose ............................................................................. 37 
6.7 
Prior and Concomitant Treatment ............................................................. 37 
6.7.1 
Prior Treatment ......................................................................... 37 
6.7.2 
Concomitant Treatment ............................................................. 37 
7. 
Discontinuation Criteria ......................................................................................... 37 
7.1 
Discontinuation of Study Treatment ........................................................... 38 
7.2 
Discontinuation From the Study ................................................................ 38 
7.2.1 
Reasons for Removal From Washout Period, Run-in 
Period, or Invasive Procedures .................................................. 39 
7.2.2 
Reasons for Removal From Study ............................................. 39 
7.3 
Lost to Follow-up ....................................................................................... 39 
8. 
Study Assessments and Procedures .................................................................... 40 
8.1 
General Study Periods .............................................................................. 40 
8.1.1 
Screening Period ....................................................................... 40 
8.1.2 
Run-in Period ............................................................................ 40 
8.1.3 
Baseline Period ......................................................................... 41 
8.1.4 
Treatment Period ....................................................................... 41 
8.1.5 
End of Study .............................................................................. 41 
8.2 
Description of General Study Assessments and Procedures ..................... 41 
8.2.1 
General Assessments ............................................................... 41 
8.2.1.1 
Informed Consent .................................................... 41 
8.2.1.2 
Demographics ......................................................... 42 
8.2.1.3 
Medical History ........................................................ 42 
8.2.1.4 
Physical Measurements .......................................... 42 
8.2.1.5 
Substance Use History ............................................ 42 
8.2.2 
Efficacy Assessments ................................................................ 42 
8.2.3 
Safety Assessments .................................................................. 46 


Product:  Erenumab 
Protocol Number:  20190008  
Date:  29 June 2022 
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8.2.4 
Adverse Events and Serious Adverse Events ............................ 46 
8.2.4.1 
Time Period and Frequency for Collecting 
and Reporting Safety Event Information .................. 46 
8.2.4.2 
Method of Detecting Adverse Events and 
Serious Adverse Events .......................................... 47 
8.2.4.3 
Follow-up of Adverse Events and Serious 
Adverse Events ....................................................... 47 
8.2.4.4 
Regulatory Reporting Requirements for 
Serious Adverse Events .......................................... 47 
8.2.4.5 
Safety Monitoring Plan ............................................ 48 
8.2.4.6 
Pregnancy and Lactation ......................................... 48 
8.2.4.7 
Adverse Device Effects ........................................... 49 
8.2.5 
Clinical Laboratory Assessments ............................................... 49 
8.2.6 
Pharmacogenetic Assessments................................................. 50 
8.2.7 
Biomarkers ................................................................................ 50 
8.2.7.1 
Biomarker Development/Future Research ............... 50 
9. 
Statistical Considerations ...................................................................................... 50 
9.1 
Statistical Hypotheses ............................................................................... 50 
9.2 
Sample Size Determination ....................................................................... 51 
9.3 
Analysis Sets, Subgroups, and Covariates ................................................ 51 
9.3.1 
Analysis Sets ............................................................................. 51 
9.3.1.1 
Full Analysis Set ...................................................... 51 
9.3.1.2 
Efficacy Analysis Set ............................................... 52 
9.3.1.3 
Safety Analysis Set ................................................. 52 
9.3.2 
Covariates ................................................................................. 52 
9.3.3 
Subgroups ................................................................................. 52 
9.3.4 
Handling of Missing and Incomplete Data .................................. 52 
9.4 
Statistical Analyses ................................................................................... 53 
9.4.1 
Planned Analyses ...................................................................... 53 
9.4.1.1 
Primary Analysis ..................................................... 53 
9.4.2 
Methods of Analyses ................................................................. 53 
9.4.2.1 
General Considerations ........................................... 53 
9.4.2.2 
Efficacy Analyses .................................................... 54 
9.4.2.3 
Safety Analyses ...................................................... 54 
10. 
References ........................................................................................................... 56 
11. 
Appendices ........................................................................................................... 58 
11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms ...................... 59 
11.2 
Appendix 2.  Clinical Laboratory Tests ...................................................... 63 
11.3 
Appendix 3.  Study Governance Considerations ....................................... 64 
Regulatory and Ethical Considerations ...................................................... 64 
Recruitment Procedures ............................................................................ 64 
Informed Consent Process ........................................................................ 65 


Product:  Erenumab 
Protocol Number:  20190008  
Date:  29 June 2022 
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Data Protection/Subject Confidentiality ..................................................... 66 
Publication Policy ...................................................................................... 67 
Investigator Signatory Obligations ............................................................. 68 
Data Quality Assurance ............................................................................. 68 
Source Documents .................................................................................... 69 
Study and Site Closure .............................................................................. 70 
Compensation ........................................................................................... 71 
11.4 
Appendix 4.  Safety Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ....................................... 72 
Definition of Adverse Event ....................................................................... 72 
Definition of Serious Adverse Event .......................................................... 73 
Definition of Adverse Device Effect ........................................................... 74 
Recording Adverse Events and Serious Adverse Events .......................... 75 
Evaluating Adverse Events and Serious Adverse Events .......................... 75 
Reporting of Serious Adverse Event .......................................................... 77 
Adverse Device Effects:  Recording, Evaluating and Reporting ................. 77 
11.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ........................................................ 83 
Definition of Females of Childbearing Potential ......................................... 83 
Collection of Pregnancy Information .......................................................... 84 
Collection of Lactation Information ............................................................ 86 
11.6 
Appendix 6.  Sample Storage and Destruction .......................................... 89 
 
List of Tables 
Table 1-1.  Schedule of Activities ................................................................................... 13 
Table 6-1.  Study Treatments ........................................................................................ 32 
Table 6-2.  Excluded Treatments, Medical Devices, and Procedures ............................ 34 
Table 9-1.  Sample Size Assumptions and Statistical Powers for Primary and 
Secondary Efficacy Endpoints for a Total Sample Size of 
576 Subjects Including a 10 Attrition Rate due to Dropout ................... 51 
Table 11-1.  Analyte Listing ........................................................................................... 63 
List of Figures 
Figure 1-1.  Study Schema ............................................................................................ 12 
Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Form .................. 78 
Figure 11-2.  Sample Serious Adverse Event Report Form ........................................... 80 
Figure 11-3.  Pregnancy and Lactation Notification Forms ............................................. 87 


Product:  Erenumab 
Protocol Number:  20190008  
Date:  29 June 2022 
Page 8 of 90 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title:  Comprehensive Assessment of Erenumab Efficacy in Subjects With 
High Frequency Episodic Migraine With at Least 1 Previously Failed Preventive 
Treatment:  a Global, Double-blind, Placebo-controlled Phase 4 Study  
Short Protocol Title:  Erenumab – Comprehensive Assessment of Efficacy in 
(High-Frequency) Episodic Migraine (EMBRACE) 
Study Phase:  4 
Indication:  Preventive treatment of migraine in adults 
Rationale 
In phase 2 and 3 clinical studies, erenumab has demonstrated a reduction in monthly 
migraine days (MMD) as the primary endpoint.  Since treatment benefits can extend 
beyond MMD, Study 20190008 will evaluate the impact of erenumab treatment on other 
aspects of migraine, including:  duration and peak severity of pain, functional 
impairment, response to acute treatment, and non-ictal burden. 
Objective(s)/Endpoint(s) 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the treatment benefit of 
erenumab on headache duration of at 
least moderate pain intensity 
 
Change from baseline in mean monthly 
hours of at least moderate headache pain 
intensity over months 1, 2, and 3 
Secondary 
 
To evaluate the treatment benefit of 
erenumab on functional impairment 
 
Change from baseline in mean monthly 
function domain score as measured by the 
Migraine Functional Impact Questionnaire 
(MFIQ) over months 1, 2, and 3: 
 
Impact on physical functioning 
 
Impact on usual activities 
 
Impact on emotional functioning 
 
Impact on social functioning 
 
To evaluate the treatment benefit of 
erenumab on duration of migraine pain 
of at least moderate intensity 
 
Change from baseline in mean monthly 
average duration of at least moderate pain 
intensity in migraine attacks occurring over 
months 1, 2, and 3 (migraine attacks as 
defined in Section 11.1) 
 
To evaluate the treatment benefit of 
erenumab on peak migraine pain 
intensity 
 
Change from baseline in mean monthly 
average peak migraine pain intensity as 
assessed by the 11-point Numeric Rating 
Scale (NRS) over months 1, 2, and 3 
 
Overall Design 
Study 20190008 is a phase 4, interventional, prospective, double-blind, randomized, 
placebo-controlled, multicenter, global study, evaluating the effects of erenumab on 
aspects of migraine beyond MMD reduction in adult subjects with high-frequency 
episodic migraine (HFEM) who have previously failed at least 1 preventive treatment.  


Product:  Erenumab 
Protocol Number:  20190008  
Date:  29 June 2022 
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Subjects who meet eligibility criteria will be enrolled in a run-in period (2 weeks in 
duration), during which they will record oral triptan-treated migraine attacks in an 
episode electronic diary (eDiary).  Details of what will be recorded in the eDiary are 
provided in Section 8.2.2.  At the end of the run-in period, subjects who have at least 
1 qualifying oral triptan-treated migraine attack (defined in Section 11.1) where pain 
freedom (defined as reduction of headache pain severity from moderate or severe to 
none) is not achieved within 1 hour following oral triptan intake during a migraine attack, 
will be eligible to enter the 4-week baseline period.  If a subject reports more than 
1 qualifying oral triptan-treated migraine attack where pain freedom is achieved in 
 1 hour following oral triptan intake during that migraine attack, the subject will be 
eligible to enter the 4-week baseline period as long as pain freedom in  1 hour following 
oral triptan intake occurs in < 50% of migraine attacks during the run-in period.  During 
the baseline period, subjects will keep a daily eDiary.  At the end of the baseline period, 
subjects who meet specific eligibility criteria will be able to enter the double-blind 
treatment period (DBTP). 
The 4-month DBTP has 2 phases: 
 
Main DBTP (M-DBTP, months 1 to 3) that will assess the effect of erenumab on 
metrics such as time spent in at least moderate pain, peak migraine severity, and 
functional impairment 
 
Exploratory DBTP (E-DBTP, month 4) that will assess the impact of erenumab on the 
acute response to oral triptan therapy as well as non-ictal burden 
Throughout both phases of the DBTP, investigational product will be administered every 
4 weeks (Q4W).  Data entry will follow a daily eDiary collection during the M-DBTP and 
transition to an episode eDiary during the E-DBTP. 
Number of Subjects 
Approximately 576 subjects will be enrolled in the study, with approximately 288 subjects 
per treatment group. 
Summary of Subject Eligibility Criteria 
Key inclusion criteria include: 
 
Age ≥ 18 years upon entry into initial screening 
 
Documented history of migraine with or without aura according to the International 
Headache Society (IHS) International Classification of Headache Disorders, Third 
Edition (ICHD-III) for  12 months 
 
Have HFEM: Defined as history of ≥ 7 to < 15 migraine days and < 15 headache 
days per month on average during the 3 months prior to screening 
 
History of ≥ 4 migraine attacks of at least moderate severity per month on average 
during the 3 months prior to screening 
 
History of treatment failure with at least 1 preventive treatment for migraine.  Failure 
of preventive treatment for migraine is defined as treatment discontinuation due to 
lack of efficacy, adverse event, or general poor tolerability. 
 
Regular use of an oral triptan (using only eletriptan, rizatriptan, sumatriptan, or 
zolmitriptan) for acute migraine treatment, and typically initiating acute treatment with 
an oral triptan on > 50% of attacks of at least moderate pain intensity.  Regular use 
is defined as ≥ 4 days of oral triptan use per month during the 3 months prior to 
screening. 


Product:  Erenumab 
Protocol Number:  20190008  
Date:  29 June 2022 
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Key exclusion criteria include: 
 
History of hemiplegic migraine, cluster headache, or other trigeminal autonomic 
cephalalgia 
 
Has any medical contraindication to the use of an oral triptan 
 
Previously treated with erenumab 
 
Previously treated with a gepant (small molecule calcitonin gene related peptide 
receptor [CGRP-R] antagonist) in a preventive fashion 
 
Previously treated with a ligand-based anti-CGRP monoclonal antibody 
(ie, fremanezumab, galcanezumab and/or eptinezumab) in a manner consistent with 
migraine prevention that either: 
(a) in the opinion of the investigator, did not offer any evidence of a therapeutic 
response 
OR 
(b) was discontinued for less than 12 weeks from the date of initial screening 
OR 
(c) was previously discontinued due to a known adverse drug reaction 
 
Currently being treated with lasmiditan and/or a gepant in the acute setting 
 
No therapeutic response with > 4 of the defined medication categories after an 
adequate therapeutic trial 
 
Currently has a history of consistent excellent response to oral triptans, defined as 
achievement of pain-freedom in ≤ 1 hour for ≥ 50% of treated attacks of at least 
moderate pain intensity during the 3 months prior to screening 
 
Use of triptans administered via a non-oral (eg, subcutaneous [SC] or intranasal 
delivery systems) or sublingual route at the time of screening, during the run-in and 
baseline periods, and throughout the study duration 
For a full list of eligibility criteria, please refer to Section 5.1 and Section 5.2. 
Treatments 
Investigational product (140 mg erenumab [2 consecutive injections of 70 mg] or placebo 
[2 consecutive injections]) in prefilled syringes (PFS) will be administered by study staff 
Q4W during the 4-month treatment period. 
Procedures 
After signing the informed consent, subjects will enter the screening period.  The total 
screening period is up to 9 weeks, which consists of an initial screening up to 3 weeks, a 
2-week run-in period, and a 4-week baseline period.  The clinical outcome assessments 
will be collected from subjects using a handheld device with an eDiary.  The handheld 
device will have both an episode eDiary and a daily eDiary, which will be accessible by 
the subject during specified periods of the study.  During the run-in period, eligible 
subjects will be instructed to interact with the episode eDiary for oral triptan-treated 
migraine attacks.  Subjects will use the episode eDiary to report information about their 
migraine, migraine-related symptoms, and use of oral triptans.  At the baseline visit, the 
investigator will use the subject’s episode eDiary to confirm inclusion criteria for the 
baseline period have been met.  Once the subject has completed the run-in period and 
is considered eligible to enter the baseline period, the subject will be instructed to 
interact with the daily eDiary.  Subjects will use the daily eDiary to report information 
about their migraine and nonmigraine headaches, other migraine-related symptoms, and 
medication taken.  At the day 1 visit, the investigator will use information collected during 


Product:  Erenumab 
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Date:  29 June 2022 
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the baseline period by the daily eDiary to confirm additional inclusion criteria have been 
met.  Eligible subjects will then be enrolled and randomized into the 4-month DBTP and 
will begin to receive investigational product SC Q4W.  During the M-DBTP (months 1 
to 3), subjects will continue to use the daily eDiary and will use the device to complete 
additional clinical outcome assessments.  During the E-DBTP (month 4), subjects will 
use the episode eDiary to complete additional clinical outcome assessments 
(Figure 1-1). 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 8.2 and the Schedule of Activities in Table 1-1. 
Statistical Considerations 
Summary statistics will be computed by treatment group and visit.  For continuous 
endpoints, the following descriptive statistics will be computed:  number of observations, 
means, medians, standard deviations, standard errors, first and third quartiles, 
minimums and maximums, and 2-sided 95% CIs of the means (CIs will be provided for 
efficacy endpoints only).  For categorical endpoints, the summaries will contain the 
number and percentage of subjects in each category. 
The primary analysis method utilizing a repeated measures linear mixed effects model 
will include all observed data regardless of treatment adherence. 
A sequential testing procedure will be used to maintain the family-wise type 1 error 
α = 0.05 between the primary and secondary endpoints following the prespecified order 
below.  An endpoint will only be tested for statistical significance if the endpoint tested in 
the previous step is statistically significant at 2-sided significance level of 0.05. 
1. Primary endpoint: change from baseline in mean monthly hours of at least moderate 
headache pain intensity over months 1, 2, and 3 
2. Secondary endpoints:  change from baseline in mean monthly function domain score 
over months 1, 2, and 3, as measured by the MFIQ using the Hochberg procedure 
 
Impact on physical functioning 
 
Impact on usual activities 
 
Impact on emotional functioning 
 
Impact on social functioning 
3. Secondary endpoint:  change from baseline in mean monthly average duration of at 
least moderate pain intensity in migraine attacks occurring over months 1, 2, and 3 
(migraine attacks as defined in Section 11.1)  
4. Secondary endpoint:  change from baseline in mean monthly average peak migraine 
pain intensity over months 1, 2, and 3, as assessed by the 11-point NRS 
For a full description of statistical analysis methods, please refer to Section 9. 
Statistical Hypotheses 
The primary hypothesis is that preventive treatment with monthly administration of 
erenumab is superior to placebo in reducing duration of moderate or severe headache 
pain in subjects with HFEM who have previously failed at least 1 migraine preventive 
treatment. 
Sponsor Name:  Amgen, Inc. 
 


Product:  Erenumab 
Protocol Number:  20190008 
Date:  29 June 2022 
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1.2 
Study Schema 
Figure 1-1.  Study Schema 
 
 


Product:  Erenumab 
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1.3 
Schedule of Activities (SoA) 
Table 1-1.  Schedule of Activities 
PROCEDURE 
Screening Period 
Double-blind Treatment Period (weeks)c 
(± 3 days) 
Notes 
Initial 
Screening 
(up to 
3 weeks, 
21 days) 
Run-ina 
(2 weeks, 
14 days 
[+4 days]) 
Baseline 
Periodb 
D -28 to 
D -1 
(+7 days) 
Day 1 
(± 3 days) 
W 4 
(± 3 days) 
W 8 
(± 3 days) 
W 12d 
(± 3 days) 
W 16/ 
EOSd 
(± 3 days) 
 
GENERAL AND SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
Xe 
Xe 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Physical measurements 
X 
 
 
 
 
 
 
 
Height and weight 
Medical history 
X 
 
 
 
 
 
 
 
Neurological medical history 
X 
 
 
 
 
 
 
 
 
Headache and migraine 
frequency medical history 
X 
 
 
 
 
 
 
 
 
Cardiovascular medical history 
X 
 
 
 
 
 
 
 
 
Cardiac risk factors medical 
history 
X 
 
 
 
 
 
 
 
 
Gastrointestinal medical history 
X 
 
 
 
 
 
 
 
 
Prior migraine preventive 
medication history 
X 
 
 
 
 
 
 
 
 
Substance use history 
X 
 
 
 
 
 
 
 
Substances: drugs, alcohol, 
tobacco 
Page 1 of 4  
Footnotes defined on the last page of the table. 


Product:  Erenumab 
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Table 1-1.  Schedule of Activities 
PROCEDURE 
Screening Period 
Double-blind Treatment Period (weeks)c 
(± 3 days) 
Notes 
Initial 
Screening 
(up to 
3 weeks, 
21 days) 
Run-ina 
(2 weeks, 
14 days 
[+4 days]) 
Baseline 
Periodb 
D -28 to 
D -1 
(+7 days) 
Day 1 
(± 3 days) 
W 4 
(± 3 days) 
W 8 
(± 3 days) 
W 12d 
(± 3 days) 
W 16/ 
EOSd 
(± 3 days) 
 
GENERAL AND SAFETY ASSESSMENTS (CONTINUED) 
Prior/concomitant therapies 
review 
X 
X 
X 
X 
X 
X 
X 
X 
Includes all prior medications 
(other than prior migraine 
preventive medications) that 
were being taken/used within 
120 days prior to screening 
through the signing of the 
informed consent and all 
concomitant medications. 
PHQ-9 
X 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
X 
X 
X 
X 
X 
 
Serious adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
After end of study, serious 
adverse events suspected to 
be related to investigation 
product will be reported to 
Amgen. 
Adverse device effects 
 
 
 
X 
X 
X 
X 
X 
 
Product complaints 
 
 
 
X 
X 
X 
X 
X 
 
Page 2 of 4 
Footnotes defined on the last page of the table. 


Product:  Erenumab 
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Table 1-1.  Schedule of Activities 
PROCEDURE 
Screening Period 
Double-blind Treatment Period (weeks)c 
(± 3 days) 
Notes 
Initial 
Screening 
(up to 
3 weeks, 
21 days) 
Run-ina 
(2 weeks, 
14 days 
[+4 days]) 
Baseline 
Periodb 
D -28 to 
D -1 
(+7 days) 
Day 1 
(± 3 days) 
W 4 
(± 3 days) 
W 8 
(± 3 days) 
W 12d 
(± 3 days) 
W 16/ 
EOSd 
(± 3 days) 
LABORATORY ASSESSMENTS 
Urine pregnancy test (females of 
childbearing potential only) 
X 
X 
X 
Additional on-treatment 
pregnancy testing may be 
performed at the 
investigator’s discretion if 
there is suspicion that a 
female subject is pregnant or 
per local laws and 
regulations 
Urine drug testing 
X 
Urine drug testing can be 
done as needed throughout 
the study per investigator 
discretion. 
BIOMARKER AND PHARMACOGENETIC ASSESSMENTS (OPTIONAL) 
Biomarker development, blood 
X 
Pharmacogenetic studiesf 
X 
Page 3 of 4 
Footnotes defined on the last page of the table. 


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Table 1-1.  Schedule of Activities 
PROCEDURE 
Screening Period 
Double-blind Treatment Period (weeks)c 
( 3 days) 
Notes 
Initial 
Screening 
(up to 
3 weeks, 
21 days) 
Run-ina 
(2 weeks, 
14 days 
[4 days]) 
Baseline 
Periodb 
D -28 to 
D -1 
(7 days) 
Day 1 
( 3 days) 
W 4 
( 3 days) 
W 8 
( 3 days) 
W 12d 
( 3 days) 
W 16/ 
EOSd 
( 3 days) 
 
CLINICAL OUTCOME ASSESSMENTS 
Episode eDiary 
 
Xg 
 
 
 
 
 
Xg 
 
Daily eDiary 
 
 
Daily 
Daily 
 
 
MFIQ 
 
 
 
X 
X 
X 
X 
 
 
MSSS 
 
 
 
X 
X 
X 
X 
 
 
Change in most troublesome 
symptom 
 
 
 
X 
 
 
X 
 
 
PGI-S 
 
 
 
X 
 
 
X 
 
 
MIBS-4 
 
 
 
X 
X 
X 
X 
X 
 
HIT-6 
 
 
 
X 
X 
X 
X 
 
 
PCS 
 
 
 
X 
 
 
X 
 
 
STUDY-RELATED DEVICE ASSIGNMENT 
Assign eDiary device 
 
X 
 
 
 
 
 
 
 
STUDY TREATMENT 
Amgen investigational product 
 
 
 
X 
X 
X 
X 
 
Site staff will administer the 
dose as the last procedure of 
the visit. 
Page 4 of 4 


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D  day; eDiary  electronic diary; EOS  End of Study; HIT-6  Headache Impact Test; MFIQ  Migraine Functional Impact Questionnaire; MIBS-4  Migraine Interictal 
Burden Scale; MSSS  Migraine Symptom Severity Score; PCS  Pain Catastrophizing Scale; PGI-S  Patient Global Impression of Severity; PHQ-9  Patient Health 
Questionnaire; W  Week 
a The run-in period ends when at the end of the period the subject does not meet inclusion criterion 108 or enters the baseline period (see Section 8.1.2).  
b The baseline period starts when the subject has met all initial eligibility criteria, has completed the run-in period, and has met inclusion criterion 108.  The baseline 
period ends when the subject does not meet inclusion criterion 109 through to 112 and is screen-failed or when subject meets all eligibility criteria and is enrolled and 
randomized.  The total duration of the baseline period must be at least 28 days and no more than 35 days (see Section 8.1.3).  
c The day 1 visit (randomization day) must occur 29 to 35 days after baseline entry.  Study visits after day 1 may be completed within  3 days of the scheduled visit.  
All study visit target dates are to be calculated from the day 1 study date.  All study procedures for a given study visit are to be completed on the same day (see 
Section 8.1.4). 
d The end of study visit occurs at week 16 or 4 weeks after last dose of investigational product for subjects who discontinue the study.  If a subject discontinues 
treatment or the study prior to week 12, the week 12 assessments should be conducted for their early termination visit (see Section 8.1.5). 
e At the start of the baseline period, data collected during the run-in period will be assessed to determine if the subject meets the eligibility criteria to enter the baseline 
period.  On day 1, data collected during the baseline period will be assessed to determine if the subject meets the eligibility criteria to enter the double-blind treatment 
period. 
f For subjects who provided informed consent for the pharmacogenetic studies, DNA will be obtained from the cell pellet collected in the plasma tube used for the 
biomarker development sample.  Therefore, additional sampling is not required. 
g The episode eDiary will be collected based on episodes during the run-in period and during weeks 13 to 16. 
 


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2. 
Introduction 
2.1 
Study Rationale 
Impact on monthly migraine days (MMD) has served as 1 of the most common 
standards in assessing efficacy of treatments for migraine prevention.  Reduction in 
MMD has often been associated with improvements of migraine-related impairments and 
disability in physical function, emotional wellness, work productivity, and general daily 
routine (Silberstein, 2015; Buse et al, 2009).  However, therapeutic benefit can extend 
beyond the commonly evaluated MMD reduction and its subsequent effects.  Patients 
who may not have experienced a decrease in the number of days spent with migraine 
following preventive treatment have anecdotally reported improvement, which has been 
described as attacks of lesser severity and duration, migraine-associated symptoms of 
lesser severity, and faster and/or better response to acute medications. 
In phase 2 and 3 clinical studies, erenumab demonstrated a reduction in MMD as the 
primary endpoint as well as improvement in function (Dodick et al, 2018; 
Goadsby et al, 2017; Tepper et al, 2017).  Study 20190008 will evaluate the impact of 
erenumab treatment on other aspects of migraine, including duration and peak severity 
of pain, functional impairment, response to acute treatment, and non-ictal burden. 
2.2 
Background 
2.2.1 
Disease 
Migraine is a debilitating disease with worldwide prevalence of approximately 11.7% in 
the United States (US), 14.6% in Canada, 14.7% in Europe, and 8.4% in Japan 
(Stovner and Andree, 2010; Lipton et al, 2007; Sakai and Igarashi, 1997).  Migraine is 
characterized by primary recurrent headaches with or without aura lasting 4 to 72 hours 
with at least 2 of the following pain characteristics:  unilateral, pulsating, moderate or 
severe intensity, or aggravated by routine physical activity.  In addition, the migraine 
attacks are often accompanied by nausea, vomiting, and sensitivity to light 
(photophobia) and sound (phonophobia).  Migraine is divided into 2 broad classifications 
based on the frequency of attacks:  episodic migraine (EM) and chronic migraine (CM).  
Episodic migraine is characterized by < 15 headache days per month, while CM is 
characterized by ≥ 15 headache days per month of which 8 or more days must meet 
criteria for migraine with or without aura, for more than 3 months.  Episodic migraine and 
CM share many common features in their clinical presentation, which include headache 
pain features and associated symptoms.  Although EM and CM are arbitrarily 
distinguished based on migraine headache frequency, numerous lines of evidence 


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support that they are a continuum of the same disorder.  A common pathophysiology is 
supported by similar clinical symptoms and functional imaging results demonstrating the 
activation of similar brain regions (Aurora and Wilkinson, 2007; Afridi et al, 2005; 
Aurora et al, 2005; Welch et al, 2001).   
Migraine attacks are typically treated acutely with nonspecific symptomatic agents such 
as combination analgesics containing caffeine, non-steroidal anti-inflammatory drugs, 
and migraine-specific abortive medications such as triptans.  Acute treatments are used 
to reduce the impact of attacks (ie, pain severity and duration) once a migraine begins.  
Patients experiencing frequent and/or disabling migraine attacks often require prevention 
(prophylaxis) (Silberstein et al, 2012; Evers et al, 2009) in addition to acute medications 
for breakthrough attacks.  Preventive treatments are used to reduce the frequency and 
overall severity of attacks in such individuals. 
Approximately 25to 30of the migraine population has 4 or more migraine days per 
month (Houle et al, 2013; Lipton et al, 2007), which is generally considered a threshold 
for recommending preventive therapy.  However, based on published epidemiologic 
data, only 12.4of people with migraine received any preventive therapy due in part to 
limited efficacy and significant tolerability and safety issues associated with available 
preventive therapies (Lipton et al, 2007).  Thus, migraine prophylaxis remains an area of 
unmet medical need. 
2.2.2 
Amgen Investigational Product Background:  Erenumab 
Erenumab is a human immunoglobulin G2 monoclonal antibody that is directed against 
the canonical calcitonin gene-related peptide (CGRP) receptor, blocking the action of 
CGRP.  Erenumab has an approximate molecular weight of 150 kDa and is produced in 
genetically engineered mammalian (Chinese hamster ovary) cells. 
As of the date of approval of this protocol, erenumab has been approved in over 
70 countries.  The recommended dosage is 70 mg once monthly (QM) and, in most 
countries, 140 mg QM is indicated for some patients who may benefit from a higher 
dose.  The erenumab dose being used in this study is 140 mg.  For additional 
information, refer to Section 4.3. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of erenumab 
is provided in the Investigator’s Brochure. 


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2.3 
Benefit/Risk Assessment 
Erenumab 140 mg has demonstrated a favorable benefit risk profile for prevention of 
migraine in adults in pivotal and supportive phase 2 and 3 studies.  The key benefits of 
erenumab include reduction in frequency of MMDs, reduction in acute medication use, 
reduction in the impact of migraine on physical functioning (as measured by the Migraine 
Physical Function Impact Diary), as well as improvements in a range of other 
patient-reported outcomes, favorable tolerability (over oral standard of care 
prophylactics), low treatment discontinuation rates, convenience (QM self-administered 
injections), and rapid onset of effect. 
Specifically in Study 20120296, the pivotal study of 70 mg and 140 mg erenumab 
compared with placebo in subjects with EM, there was a statistically significant greater 
mean reduction in the change in mean MMD from baseline to the last 3 months 
(months 4, 5, and 6) of the 24-week double-blind treatment phase for 70 mg and 140 mg 
erenumab compared with placebo (difference in least square mean [LSM] [95% CI] 
of -1.40 [-1.88, -0.92] for 70 mg and -1.85 [-2.33, -1.37] for 140 mg) 
(Goadsby et al, 2017).  The benefits of the 140 mg QM dose in a difficult-to-treat EM 
patient population with a history of 2 to 4 prior preventive treatment failures were further 
confirmed by a phase 3b randomized controlled trial where 30% of patients treated with 
erenumab experienced ≥ 50% reductions from their baseline MMD compared with 14% 
in the placebo group (odds ratio 2.7 [95% CI 1.4-5.2]; p = 0.002) (Reuter et al, 2018).  
Overall, the safety profile of erenumab has been favorable in clinical studies.  No 
important identified risks or important potential risks have been observed.  Furthermore, 
a limited number of adverse drug reactions (injection site reactions, constipation, and 
muscle spasms) have been identified at low frequencies ( 5%) in clinical studies.  In 
postmarketing settings, immune system disorders (hypersensitivity reactions including 
rash, angioedema, and anaphylactoid reactions); gastrointestinal disorders (constipation 
with serious complications and oral sores); and skin and subcutaneous tissue disorders 
(alopecia and rash) have been observed.   
The safety and efficacy of erenumab have not been established in migraine patients with 
major cardiovascular disease (myocardial infarction, stroke, transient ischemic attack, 
unstable angina, coronary artery bypass surgery, or other revascularization procedures 
within 12 months prior to screening), in the long-term use of erenumab, or in elderly 
patients  65 years of age. 


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In conclusion, erenumab addresses an unmet need as an effective, safe, and tolerable 
preventive treatment of migraine.  The key benefits of erenumab outweigh the risks in 
this population. 
The above benefit risk assessment supports the conduct of this clinical trial.  Reference 
should be made to the Investigator’s Brochure and Prescribing Information, where 
approved, for further data on erenumab. 
3. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the treatment benefit of 
erenumab on headache duration of at 
least moderate pain intensity 
 
Change from baseline in mean monthly 
hours of at least moderate headache pain 
intensity over months 1, 2, and 3 
Secondary 
 
To evaluate the treatment benefit of 
erenumab on functional impairment 
 
Change from baseline in mean monthly 
function domain score as measured by the 
Migraine Functional Impact Questionnaire 
(MFIQ) over months 1, 2, and 3: 
 
Impact on physical functioning 
 
Impact on usual activities 
 
Impact on emotional functioning 
 
Impact on social functioning 
 
To evaluate the treatment benefit of 
erenumab on duration of migraine pain 
of at least moderate intensity 
 
Change from baseline in mean monthly 
average duration of at least moderate pain 
intensity in migraine attacks occurring over 
months 1, 2, and 3 (migraine attacks as 
defined in Section 11.1) 
 
To evaluate the treatment benefit of 
erenumab on peak migraine pain 
intensity 
 
Change from baseline in mean monthly 
average peak migraine pain intensity as 
assessed by the 11-point Numeric Rating 
Scale (NRS) over months 1, 2, and 3 
 
 


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Objectives 
Endpoints 
Exploratory 
Main Double-blind Treatment Period (month 1 to 3) 
 
To evaluate the treatment benefit of 
erenumab on duration of oral 
triptan-treated migraine attacks 
 
Change from baseline in mean monthly 
hours of at least moderate pain intensity for 
qualifying oral triptan-treated migraine 
attacks over months 1, 2, and 3 (qualifying 
oral triptan-treated migraine attacks as 
defined in Section 11.1) 
 
To evaluate the treatment benefit of 
erenumab on duration of migraine 
pain of at least moderate intensity for 
oral triptan-treated migraine attacks 
 
Change from baseline in mean monthly 
average duration of at least moderate pain 
intensity in qualifying oral triptan-treated 
migraine attacks occurring over months 1, 2, 
and 3 (qualifying oral triptan-treated 
migraine attacks as defined in Section 
11.1) 
 
To evaluate the treatment benefit of 
erenumab on migraine symptoms 
 
Change from baseline in Migraine Symptom 
Severity Score (MSSS) total score at 
assessment time points 
 
Change from baseline in the most 
troublesome symptom at month 3 
 
Change in Patient Global Impression of 
Severity (PGI-S) total score at month 3 
 
Change from baseline in mean monthly total 
migraine freedom days (defined in 
Section 11.1) over months 1, 2, and 3 
 
To evaluate the treatment benefit of 
erenumab on interictal burden of 
migraine 
 
Change from baseline in Migraine Interictal 
Burden Scale (MIBS-4) total score at 
assessment time points 
 
Achievement of no or mild interictal burden 
as measured by the MIBS-4 at assessment 
time points 
 
To evaluate the treatment benefit of 
erenumab on functional impairment 
 
Change from baseline in headache impact 
scores as measured by the Headache 
Impact Test (HIT-6) total score at 
assessment time points 
 
Change from baseline in physical function 
domain score as measured by MFIQ at 
assessment time points 
 
Change from baseline in usual activities 
domain score as measured by MFIQ at 
assessment time points 
 
Change from baseline in social function 
domain as measured by MFIQ at 
assessment time points 


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 
Change from baseline in emotional function 
domain score as measured by MFIQ at 
assessment time points 
 
Change from baseline in overall impact on 
usual activities global item score as 
measured by MFIQ at assessment time 
points 
 
Objectives 
Endpoints 
Exploratory (Continued) 
Main Double-blind Treatment Period (month 1 to 3) (Continued) 
 
To evaluate the treatment benefit of 
erenumab on headache-related 
cognitions and beliefs 
 
Change from baseline in pain catastrophizing 
as measured by the Pain Catastrophizing 
Scale (PCS) at month 3 
 
To evaluate the treatment benefit of 
erenumab on monthly migraine days 
(MMD) 
 
Change from baseline in mean MMD over 
months 1, 2, and 3 
Following 2 endpoints will be calculated from months with at least 1 migraine attack 
 
To evaluate the treatment benefit of 
erenumab on duration of migraine 
pain of at least moderate intensity in 
months with at least 1 migraine attack 
(migraine attacks as defined in 
Section 11.1) 
 
Change from baseline in mean monthly 
average duration of at least moderate pain 
intensity per migraine attack over months 1, 2, 
and 3 
 
To evaluate the treatment benefit of 
erenumab on peak migraine pain 
intensity in months with at least 
1  migraine attack (migraine attacks 
as defined in Section 11.1) 
 
Change from baseline in mean monthly 
average peak migraine pain intensity as 
assessed by the 11-point NRS over months 1, 
2, and 3 
Exploratory Double-blind Treatment Phase (month 4) 
 
To evaluate the treatment benefit of 
erenumab on interictal burden of 
migraine 
 
Change from baseline in Migraine Interictal 
Burden Scale (MIBS-4) total score at month 4 
For the first qualifying oral triptan-treated attack (defined in Section 11.1) with complete data at 
2-hour assessment: 
 
To evaluate the treatment benefit of 
erenumab on achieving and 
sustaining pain freedom following 
treatment with an oral triptan 
 
Achievement of pain freedom at 2 hours 
post-triptan dose for the first attack at month 4  
 
Achievement of 24-hour sustained pain 
freedom post-triptan dose for the first attack at 
month 4 
 
Achievement of pain freedom at 30 and 
60 minutes post-triptan dose for the first attack 
at month 4 
 
To evaluate the treatment benefit of 
erenumab on achieving pain relief 
following treatment with an oral triptan 
 
Achievement of pain relief (defined in 
Section 11.1) at 30, 60, and 120 minutes 
post-triptan dose for the first attack at month 4 


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 
To evaluate the treatment benefit of 
erenumab on achieving freedom from 
the most bothersome symptom 
following treatment with an oral triptan 
 
Achievement of freedom from the most 
bothersome symptom at 30, 60, and 
120 minutes post-triptan dose for the first 
attack at month 4 
 
To evaluate the treatment benefit of 
erenumab on achieving relief from the 
most bothersome symptom following 
treatment with an oral triptan 
 
Achievement of relief from the most 
bothersome symptom at 30, 60, and 
120 minutes post-triptan dose for the first 
attack at month 4 
 
To evaluate the treatment benefit of 
erenumab on migraine recurrence 
following treatment with an oral triptan 
 
Migraine recurrence (defined in Section 11.1) 
during 24 hours post-triptan dose for the first 
attack at month 4 
Exploratory Double-blind Treatment Phase (month 4) - Continued 
 
To evaluate the treatment benefit of 
erenumab on use of migraine rescue 
medication following treatment with an 
oral triptan 
 
Use of migraine rescue medication within 
24 hours post-triptan dose for the first attack 
at month 4 
For the first qualifying oral triptan-only-treated attack with complete data at 2-hour 
assessment: 
 
To evaluate the treatment benefit of 
erenumab on achieving and 
sustaining pain freedom following 
treatment with oral triptan only 
 
Achievement of pain freedom at 30, 60, and 
120 minutes post-triptan dose for the first 
triptan-only-treated attack in which complete 
data is obtained (at least 2 hours timepoint) at 
month 4 
 
To evaluate the treatment benefit of 
erenumab on achieving pain relief 
following treatment with oral triptan 
only 
 
Achievement of pain relief at 30, 60, and 
120 minutes post-triptan dose for the first 
triptan-only-treated attack at month 4 
 
To evaluate the treatment benefit of 
erenumab on achieving freedom from 
the most bothersome symptom 
following treatment with oral triptan 
only 
 
Achievement of freedom from the most 
bothersome symptom at 30, 60, and 
120 minutes post-triptan dose for the first 
triptan-only-treated attack at month 4 
 
To evaluate the treatment benefit of 
erenumab on achieving relief from the 
most bothersome symptom following 
treatment with oral triptan only 
 
Achievement of relief from the most 
bothersome symptom at 30, 60, and 
120 minutes post-triptan dose for the first 
triptan-only-treated attack at month 4 
 
4. 
Study Design 
4.1 
Overall Design 
Study 20190008 is a phase 4, interventional, prospective, double-blind, randomized, 
placebo-controlled, multicenter global study, evaluating the effects of erenumab on 
aspects of migraine beyond MMD reduction in adult subjects with high-frequency 
episodic migraine (HFEM) who have previously failed at least 1 preventive treatment.  
Subjects who meet eligibility criteria will be enrolled in a run-in period (2 weeks in 
duration), during which they will record oral triptan-treated migraine attacks in an 
episode electronic diary (eDiary).  Details of what will be recorded in the eDiary are 


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provided in Section 8.2.2.  At the end of the run-in period, subjects will be eligible to 
enter the 4-week baseline period only if they have 1 or more qualifying oral 
triptan-treated migraine attacks (defined as migraine attacks of at least moderate peak 
pain intensity that are treated with an oral triptan within 2 hours of pain reaching at least 
moderate severity) and if pain freedom is not achieved within 1 hour following oral triptan 
intake for > 50% of their qualifying migraine attacks.  During the baseline period, 
subjects will keep a daily eDiary.  At the end of the baseline period, subjects who meet 
specific eligibility criteria will be able to enter the double-blind treatment period (DBTP).   
The 4-month DBTP has 2 phases: 
 
Main DBTP (M-DBTP, months 1-3) that will assess the effect of erenumab on metrics 
such as time spent in at least moderate pain, peak migraine severity, and functional 
impairment 
 
Exploratory DBTP (E-DBTP, month 4) that will assess the impact of erenumab on the 
acute response to treatment with oral triptan therapy as well as non-ictal burden 
Throughout both phases of the DBTP, investigational product will be administered every 
4 weeks (Q4W).  Data entry will follow a daily eDiary collection during the M-DBTP and 
transition to an episode eDiary during the E-DBTP. 
The overall study design is described by a study schema in Section 1.2.  The endpoints 
are defined in Section 3. 
4.2 
Number of Subjects 
Approximately 576 subjects will be enrolled in the study, with approximately 288 subjects 
per treatment group. 
Subjects in this clinical investigation shall be referred to as “subjects”.  For the sample 
size justification, see Section 9.2. 
4.2.1 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
4.2.2 
Number of Sites 
Approximately 76 investigative sites in North America and Europe will be included in the 
study.  Sites that do not enroll subjects within 3 months of site initiation may be closed. 
4.3 
Justification for Investigational Product Dose 
The erenumab dose being used in this study is in accordance with the term of its 
marketing authorization in the US and most regions of the EU.   


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The 140 mg dose has been selected as the treatment dose because it achieved 
incremental efficacy in a comparable patient population during phase 2 and 3 clinical 
studies.  In phase 3 Study 20120296 (Study to Evaluate the Efficacy and Safety of 
Erenumab in Migraine Prevention [STRIVE]) in subjects with EM, the erenumab 140 mg 
treatment arm experienced a numerically greater reduction from baseline in MMD 
compared with 70 mg (Goadsby et al, 2019).  Furthermore, in a post-hoc analysis of 
STRIVE, subjects with 2 or more prior treatment failures in the 140 mg erenumab arm 
had an average MMD reduction nearly 2-fold greater than those in the 70 mg erenumab 
arm.  The safety profile of both erenumab doses was comparable to placebo with only 
slightly greater incidence rates of constipation adverse events and influenza adverse 
events for the 140 mg dose compared with the 70 mg dose (Goadsby et al, 2019). 
4.4 
End of Study 
4.4.1 
End of Study Definition 
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study:  The end of study date is defined as the date when the last subject 
across all sites is assessed or receives an intervention for evaluation in the study (ie, last 
subject last visit), following any additional parts in the study (eg, long-term follow-up, 
additional antibody testing), as applicable.  For this study, the end of study date is the 
date when the last subject has completed the assessments for week 16. 
4.4.2 
Study Duration for Subjects 
The total study duration for subjects who successfully complete the study will be up to 
25 weeks.   
4.5 
Patient Input on Study Design 
Patient input was not collected during study design. 
5. 
Study Population 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening). 


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Eligibility criteria will be evaluated during initial screening to allow entry into the run-in 
period, after the run-in period to allow entry into the baseline period, and after the 
baseline period to allow entry into the DBTP. 
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Section 11.3). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be provided. 
5.1 
Inclusion Criteria 
Subjects are eligible to be included in the study and enter the run-in period only if all of 
the following criteria apply: 
101 
Have provided informed consent prior to initiation of any study specific 
activities/procedures. 
102 
Age ≥ 18 years upon entry into initial screening. 
103 
Documented history of migraine with or without aura according to the 
International Headache Society (IHS) International Classification of Headache 
Disorders, Third Edition (ICHD-III) for  12 months. 
104 
Have HFEM:  Defined as history of ≥ 7 to < 15 migraine days and < 15 headache 
days per month on average during the 3 months prior to screening. 
105 
History of ≥ 4 migraine attacks of at least moderate severity per month on 
average during the 3 months prior to screening. 
106 
History of treatment failure with at least 1 preventive treatment for migraine.  
Failure of preventive treatment for migraine is defined as treatment 
discontinuation due to lack of efficacy, adverse event, or general poor tolerability. 
107 
Regular use of an oral triptan (using only eletriptan, rizatriptan, sumatriptan, or 
zolmitriptan) for acute migraine treatment, and typically initiating acute treatment 
with an oral triptan on > 50% of attacks of at least moderate pain intensity.  
Regular use is defined as ≥ 4 days of oral triptan use per month during the 
3 months prior to screening. 
Subjects are eligible to enter the baseline period of the study only if they have completed 
the run-in period and the following criterion applies (based on the episode eDiary): 
108 
Have at least 1 qualifying triptan-treated migraine attack during the run-in period 
(using 1 of the specified 4 oral triptans from inclusion criteria 107) where pain 
freedom has not been achieved within the first hour from triptan intake during that 
migraine attack.  If a subject reports more than 1 qualifying oral triptan-treated 
migraine attack where for > 50% of migraine attacks during the run-in period pain 
freedom is not achieved in ≤ 1 hour following oral triptan intake during that 
migraine attack, the subject will be eligible to enter the 4-week baseline period.   


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Subjects are eligible to enter the DBTP of the study only if they have completed the 
baseline period and all of the following criteria apply (based on daily eDiary): 
109 
Must be the same migraine type as the initial screening period (ie, if a subject 
meets HFEM criteria in the 3 months prior to screening, then the subject must 
meet HFEM criteria during baseline). 
110 
Must have ≥ 4 migraine attacks of at least moderate severity during the baseline 
period. 
111 
Demonstrated at least 80% compliance with the daily eDiary during the baseline 
period. 
112 
Subject must treat qualifying migraine attacks with the same oral triptan as used 
during run-in period using 1 of the specified 4 oral triptans from inclusion 
criteria 107. 
5.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
Disease Related 
201 
Older than 50 years of age at migraine onset. 
202 
History of hemiplegic migraine, cluster headache, or other trigeminal autonomic 
cephalalgia. 
Other Medical Conditions 
203 
Currently diagnosed with fibromyalgia and/or chronic pelvic pain. 
204 
History of major psychiatric disorder (eg, schizophrenia or other psychotic 
disorders, bipolar disorder, obsessive-compulsive disorder, post-traumatic stress 
disorder), or current evidence of moderately severe depression based on a 
Patient Health Questionnaire (PHQ-9) total score of ≥ 15 at initial screening. 
205 
Has any medical contraindication to the use of an oral triptan. 
Prior/Concomitant Therapy 
206 
Previously treated with erenumab or gepants (small molecule CGRP-R 
antagonist) in a manner consistent with migraine prevention,  
OR 
Previously treated with a ligand-based anti-CGRP monoclonal antibody 
(ie, fremanezumab, galcanezumab and/or eptinezumab) in a manner consistent 
with migraine prevention that either: 
a) in the opinion of the investigator, did not offer any evidence of a therapeutic 
response  
OR 
b) was discontinued for less than 12 weeks from the date of initial screening  
OR 
c) was previously discontinued due to a known adverse drug reaction 


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207 
Currently being treated with lasmiditan and/or a gepant in the acute setting. 
208 
No therapeutic response with > 4 of the following medication categories after an 
adequate therapeutic trial: 
 Category 1:  Topiramate 
 Category 2:  Other antiepileptics (eg, divalproex sodium, sodium valproate, 
gabapentin) 
 Category 3:  Beta blockers 
 Category 4:  Tricyclic antidepressants 
 Category 5:  Other antidepressants (eg, serotonin-norepinephrine reuptake 
inhibitors, selective serotonin-reuptake inhibitors) 
 Category 6:  Calcium channel blockers (eg, verapamil, amlodipine, cinnarizine, 
lomerizine) or calcium antagonists (eg, flunarizine) 
 Category 7:  Angiotensin receptor blockers (eg, candesartan) or 
angiotensin-converting enzyme (ACE) inhibitors (eg, lisinopril) 
 Category 8:  Onabotulinum toxin 
 Category 9:  Other drugs used for migraine prevention 
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) and is based on the investigator’s 
assessment. 
The following scenarios do not constitute lack of therapeutic response: 
 Lack of sustained response to a medication 
 Failure to tolerate a therapeutic dose 
209 
Use of an excluded medication, device, or procedure (refer to Section 6.1.6 for 
the list of excluded medications, devices, or procedures and corresponding time 
period for exclusion). 
210 
Currently has a history of consistent excellent response to oral triptans, defined 
as achievement of pain freedom in ≤ 1 hour for ≥ 50% of treated attacks of at 
least moderate pain intensity during the 3 months prior to screening. 
211 
Use of triptans administered via a non-oral (eg, subcutaneous [SC] or intranasal 
delivery systems) or sublingual route at the time of screening, during the run-in 
and baseline periods, and throughout the study duration. 
Prior/Concurrent Clinical Study Experience 
212 
Currently receiving treatment in another investigational device or drug study, or 
less than 30 days or 5 half-lives (whichever is longer) since ending treatment on 
another investigational device or drug study(ies).  Other investigational 
procedures while participating in this study are excluded. 
Other Exclusions 
213 
Female subject who are pregnant or breastfeeding or who plan to become 
pregnant or breastfeeding while on study and for an additional 16 weeks after the 
last dose of investigational product. 


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214 
Female subjects of childbearing potential unwilling to use protocol specified 
method of contraception, see Appendix 5 (Section 11.5) during treatment and for 
an additional 16 weeks after the last dose of investigational product.   
215 
Female subjects of childbearing potential with a positive pregnancy test 
assessed at screening by a highly sensitive urine or serum pregnancy test. 
216 
Subject has known sensitivity to any of the products or components to be 
administered during dosing. 
217 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures (eg, clinical 
outcome assessments) to the best of the subject and investigator’s knowledge. 
218 
History or evidence of any other clinically significant disorder, condition, or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures or completion. 
5.3 
Subject Enrollment 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form, and all other 
subject information and/or recruitment material, if applicable (see Section 11.3). 
The subject must personally sign and date the IRB/IEC and Amgen approved informed 
consent before commencement of study-specific procedures. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment case report form (CRF). 
Each subject who enters into the screening period for the study (screening period starts 
when the subject signs and dates the informed consent form) receives a unique subject 
identification number before any study-related activities/procedures are performed.  The 
subject identification number will be assigned via interactive response technology (IRT).  
This number will be used to identify the subject throughout the clinical study and must be 
used on all study documentation related to that subject. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.  This number will not necessarily be the same as the randomization number 
assigned for the study. 


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5.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
criteria, medical history, prior therapies, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened once if the condition that led to screen failure is expected to be transient.  
Refer to Section 8.1.1. 
5.5 
Run-in and Baseline Periods 
Subjects enrolled in the study will complete the run-in period and baseline period prior to 
treatment assignment/randomization described in Section 6.4.1.  To qualify for the 
baseline period, subjects must have at least 1 qualifying oral triptan-treated migraine 
attack (defined in Section 11.1) during the run-in period and meet inclusion criterion 108.  
Upon completion of the baseline period, subjects must meet inclusion criteria 109 to 112 
to qualify for treatment assignment/randomization. 
Subjects who do not meet the eligibility criteria for the run-in or baseline periods will 
discontinue the study. 
6. 
Treatments 
Study treatment is defined as any investigational product(s), non-investigational 
product(s), placebo, or medical device(s) intended to be administered to a study subject 
according to the study protocol. 
Note that in several countries, investigational product and non-investigational product 
are referred to as investigational medicinal product and non-investigational medicinal 
product, respectively. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of each treatment shown in Table 6-1 below. 


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6.1 
Treatment(s) Administered 
6.1.1 
Investigational Products 
Table 6-1.  Study Treatments 
Study Treatment 
Name 
Amgen Investigational Product:a 
Aimovig (erenumab) 
Placebo 
Dosage 
Formulation 
Erenumab will be supplied as a 
70 mg/mL solution formulated with 
sodium acetate, sucrose, and 
polysorbate 80. 
Placebo will be presented in 
identical containers and 
stored/packaged the same as 
erenumab. 
Unit Dose 
Strength(s)/ 
Dosage Level(s) 
and Dosage 
Frequency 
140 mg once every 4 weeks 
(2 consecutive injections of 70 mg) 
Placebo once every 4 weeks 
(2 consecutive injections) 
Route of 
Administration 
SC injection 
SC injection 
Accountability 
The quantity, start date, injection site, and box number(s) of IP are to be 
recorded on each subject’s CRF. 
Dosing 
Instructions 
Treatment doses to be administered at study visits after all scheduled 
assessments by authorized investigational site study staff.  The 140-mg 
dose is administered as 2 consecutive SC injections of 70 mg each.  The 
anatomical sites for administration of IP are the upper arm, upper thigh, 
or abdomen.  
Device 
PFS 
CRF = case report form; IP = investigational product; PFS = prefilled syringe; SC = subcutaneous. 
a  Erenumab will be manufactured and packaged by Amgen and distributed using Amgen clinical study drug 
distribution procedures. 
6.1.2 
Medical Devices 
The investigational medical device provided by Amgen for use in this study is the 
prefilled syringe (PFS) (Table 6-1).  The investigational product PFS is a single-use, 
disposable, handheld manual injection device for fixed dose SC injection of 70 mg/mL in 
a 1-mL deliverable volume.  It will be administered as 2 consecutive SC injections for 
140 mg/mL dosing.  Additional details are provided in the IPIM. 
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard care. 
Non-investigational medical devices (eg, syringes, sterile needles), that are 
commercially available are not usually provided or reimbursed by Amgen (except, for 
example, if required by local regulation).  The investigator will be responsible for 
obtaining supplies of these devices.  


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6.1.3 
Other Protocol-required Therapies 
There are no other protocol-required therapies in this study. 
6.1.4 
Other Treatment Procedures 
There are no other treatment procedures in this study. 
6.1.5 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug, combination product, or device after it is released for distribution 
to market or clinic by either (1) Amgen or (2) distributors or partners for whom Amgen 
manufactures the material.  This includes all components distributed with the drug, such 
as packaging drug containers, delivery systems, labeling, and inserts. 
This includes any investigational product, device, or combination product provisioned 
and/or repackaged/modified by Amgen (eg, PFS).   
Any product complaint(s) associated with an investigational product, device, or 
combination product supplied by Amgen are to be reported according to the instructions 
provided in the IPIM. 
6.1.6 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
Excluded treatments, medical devices, and procedures are provided in Table 6-2. 


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Table 6-2.  Excluded Treatments, Medical Devices, and Procedures 
Prohibited Medications 
Time Period for Exclusion 
Use of concomitant oral migraine preventive medications, 
including the following:a 
 
Antiepileptics (eg, divalproex sodium, sodium 
valproate, topiramate, carbamazepine, levetiracetam) 
 
Angiotensin receptor blockers (eg, candesartan) or 
ACE inhibitors (eg, lisinopril) 
 
Beta blockers  
 
Calcium channel blockers (eg, verapamil, amlodipine, 
cinnarizine) or calcium antagonists (eg, flunarizine) 
 
Tricyclic antidepressants 
 
Other antidepressants (eg, serotonin-norepinephrine 
reuptake inhibitors, selective serotonin-reuptake 
inhibitors) 
 
Other drugs or supplements used for migraine 
prevention (eg, clonidine, guanfacine, methysergide, 
cyproheptadine, pizotifen, butterbur, feverfew, 
magnesium [ 500 mg/day], riboflavin [ 400 mg/day], 
coenzyme Q10). 
2 months before the start of the 
screening period and throughout 
the study 
Frequent use of an allowed acute medication for migraine 
in a pattern that would categorize prevention of migraine 
attacks (ie, in the absence of aura or headache)a 
2 months before the start of the 
screening period and throughout 
the study 
Use of the following acute medications for the acute 
treatment of migraine:a 
Opioid and/or opioid containing analgesics 
 Long-acting formulations, more than 4 days 
 Short acting more than 15 days 
2 months before the start of the 
screening period and throughout 
the study 
All anti-CGRP monoclonal antibodies other than 
erenumab study supply are expected to have been 
discontinued 12 weeks before start of screening and are 
prohibited to be taken from 12 weeks before screening 
throughout the study.   
12 weeks before the start of 
screening and throughout the 
study 
Lasmiditan and gepants 
From the start of the screening 
period and throughout the study 
Investigational medications  
30 days or 5 half-lives (whichever 
is longer) before the start of the 
screening period and throughout 
the study 
Onabotulinum toxin (in the head and/or neck region) 
4 months before the start of the 
screening period and throughout 
the study 
Page 1 of 2 
Footnotes defined on next page of table 


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Table 6-2.  Excluded Treatments, Medical Devices, and Procedures 
Prohibited Procedures or Devices 
Time Period for Exclusion 
CBD-containing products with systemic absorption  
6 months before the start of the 
screening period and throughout 
the study 
For any indication 
Infusion Therapy (eg, steroids, valproate sodium, 
dihydroergotamine)  
Note: infusion therapy may be allowed during DBTP if 
medically justified 
3 months before the start of the 
screening period and throughout 
the study 
For any indication 
Devices (eg, neuromodulation devices) or procedures 
(eg, nerve blocks, trigger-point injections, and 
acupuncture), depending on anatomic region and impact. 
3 months before the start of the 
screening period and throughout 
the study 
Cognitive Behavioral Therapy, Biofeedback, and 
Psychotherapy 
Note:  Subjects on a stable, maintenance phase of these 
therapies for migraine will be allowed to participate.   
Note:  Stable, maintenance phase of CBT is defined as 
 6 weekly or biweekly sessions administered by 
adequately trained psychologists and only “booster” 
sessions at a monthly, bimonthly, or quarterly frequency at 
least 3 months before the start of the screening period 
3 months before the start of the 
screening period and throughout 
the study 
Page 2 of 2 
ACE = angiotensin-converting-enzyme; CBD = cannabidiol; CBT = cognitive behavioral therapy; 
CGRP = canonical calcitonin gene related peptide; DBTP = double-blind treatment period.  
a Participants currently taking a medication which can exert migraine prevention effect, but is used for a 
non-migraine indication, can be allowed into the study if the medication has been stable for at least 
1 month prior to screening and will remain so throughout the study.  This allowance is limited to 
1 "migraine preventative" medication for a non-migraine indication. 
6.2 
Dose Modification 
6.2.1 
Dose-cohort Study Escalation/De-escalation and Stopping Rules 
There will be no dose changes or dose stopping rules as part of this study. 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
Dose adjustments, delays, or withholding are not permitted. 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules 
No samples assessing hepatotoxicity will be collected in this study. 


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6.3 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product and/or device during the study are provided in the 
IPIM. 
6.4 
Measures to Minimize Bias:  Randomization and Blinding 
6.4.1 
Method of Treatment Assignment 
Subjects will be randomized in a 1:1 allocation ratio to either erenumab or placebo in a 
double-blind manner after meeting all the post-baseline randomization requirements 
described in Section 5.5. 
The randomization number will be assigned by the IRT.  The randomization number is 
different than the subject identification number and will not be used by the site as a 
subject identifier. 
The randomization date is to be documented in the subject’s medical record and on the 
enrollment CRF. 
6.4.2 
Blinding 
This is a double-blind study.  Treatment assignment will be blinded to all subjects, site 
personnel, and Amgen as described below. 
6.4.2.1 
Site Personnel Access to Individual Treatment Assignments 
A subject’s treatment assignment is to only be unblinded by the investigator when 
knowledge of the treatment is essential for the further management of the subject on this 
study or may potentially impact the safety of the subject.  Unblinding at the study site for 
any other reason will be considered a protocol deviation.  It is encouraged that the 
Amgen Trial Manager be notified before the blind is broken unless the investigator 
believes that identification of the study treatment is required for a medical emergency.  If 
this is not possible, the Amgen Trial Manager must be notified within 24 hours after 
breaking the blind.  The date and reason that the blind was broken must be recorded in 
the source documentation. 
6.4.2.2 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
Blinded individuals will not have access to unblinded information until the study is 
formally unblinded.  Unblinding and potentially unblinding information is not to be 
distributed to the study team, investigators, or subjects prior to the study being formally 
unblinded except as specified (eg, Section 6.4.2.1). 


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6.5 
Treatment Compliance 
Administration of investigational product will be conducted by authorized investigational 
site study staff on scheduled visits.   
Noncompliance is to be documented in the medical file/source documentation and will 
be reflected in the electronic CRF.  Noncompliant subjects are to be re-educated on the 
importance of adhering to the investigational product administration schedule and 
reminded that repeated cycles of noncompliance could be a reason for discontinuation of 
study treatment. 
6.6 
Treatment of Overdose 
Overdose with this product has not been reported.  No specific antidote exists.  In the 
case of an overdose, the subject should be treated symptomatically, and supportive 
measures implemented as necessary. 
6.7 
Prior and Concomitant Treatment 
6.7.1 
Prior Treatment 
For prior migraine preventive medications, which are required to have ended 2 months 
prior to screening (6 month prior to screening in case of cannabidiol [CBD]-containing 
products) per Table 6-2, therapy name, indication, dose, unit, frequency, start and stop 
dates will be collected in the prior migraine preventive medication CRF.   
For all other prior therapies that were being taken/used within 120 days prior to 
screening through the signing of the informed consent, therapy name and start and stop 
dates will be collected in the concomitant medication CRF. 
6.7.2 
Concomitant Treatment 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.1.6. 
Concomitant therapies are to be collected from signing of the informed consent form 
through the end of study visit. 
7. 
Discontinuation Criteria 
Subjects have the right to withdraw from investigational product, protocol procedures, or 
the study as a whole at any time and for any reason without prejudice to their future 
medical care by the physician or at the institution. 


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The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, device, protocol procedures, or the study as a whole at any time prior to study 
completion for the reasons listed in Sections 7.1, 7.2.1, and 7.2.2. 
7.1 
Discontinuation of Study Treatment 
Subjects can decline to continue receiving investigational product at any time during the 
study but continue participation in the study.  If this occurs, the investigator is to discuss 
with the subject the appropriate processes for discontinuation from investigational 
product and must discuss with the subject the possibilities for continuation of the 
Schedule of Activities (see Table 1-1) including different options of follow-up (eg, in 
person, by phone/mail, through family/friends, in correspondence/communication with 
other treating physicians, from the review of medical records) and collection of data, 
including endpoints, adverse events, and device-related events, as applicable and must 
document this decision in the subject’s medical records.  Subjects who have 
discontinued investigational product should not be automatically removed from the 
study.  Whenever safe and feasible, it is imperative that subjects remain on-study to 
ensure safety surveillance and/or collection of outcome data. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by a separate protocol or as provided for by the local country’s regulatory mechanism, 
based on parameters consistent with Section 11.3. 
Reasons for early removal from protocol-required investigational product(s) or 
procedural assessments may include any of the following: 
 
Decision by sponsor 
 
Lost to follow-up 
 
Death 
 
Adverse event 
 
Subject request 
 
Ineligibility determined 
 
Protocol deviation 
 
Non-compliance 
 
Pregnancy or breastfeeding 
7.2 
Discontinuation From the Study 
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 


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will be included in the analysis of the study, and where permitted, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study, and must document the 
subject’s decision to withdraw in the subject’s medical records.  
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly 
(see Section 11.6 for further details).  Refer to the Schedule of Activities (Table 1-1) for 
data to be collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
7.2.1 
Reasons for Removal From Washout Period, Run-in Period, or 
Invasive Procedures 
Not applicable to this study. 
7.2.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
Decision by sponsor 
 
Withdrawal of consent from study 
 
Death 
 
Lost to follow-up 
7.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
 
The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or is able to 
continue in the study. 
 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where possible, 
3 telephone calls and, if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods).  These contact attempts are to be 
documented in the subject’s medical record. 
 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
 
For subjects who are lost to follow-up, the investigator can search publicly available 
records where permitted to ascertain survival status.  This ensures that the data 
set(s) produced as an outcome of the study is/are as comprehensive as possible. 


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8. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Table 1-1).  
As protocol waivers or exemptions are not allowed if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the subject is to continue or 
discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
8.1 
General Study Periods 
8.1.1 
Screening Period 
Informed consent must be obtained before completing any screening procedure.  After 
the subject has signed the informed consent form, the site will register the subject in IRT 
and screen the subject to assess eligibility for participation.  The screening period is up 
to 9 weeks, which consists of an initial screening up to 3 weeks (21 days), a 2-week 
run-in period (14 days, but no more than 18 days), and a 4-week (28 days, but no more 
than 35 days) baseline period. 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, (see Section 5.4) as applicable. 
If a subject has not met all eligibility criteria at the end of the screening period, the 
subject will be registered as a screen fail.  Screen fail subjects may be eligible for 
rescreening 1 time if the condition that led to screen failure is expected to be transient. 
Rescreen subjects must first be registered as screen failures in IRT and subsequently 
registered as rescreens.  Once the subject is registered as rescreened, a new 9-week 
screening window will begin.  Subjects will retain the same subject identification number 
assigned at the original screening.  If the rescreening period begins more than 30 days 
after the original signing of the informed consent form, all screening procedures, 
including informed consent, must be repeated. 
8.1.2 
Run-in Period 
The run-in period is 2 weeks (but can be extended to a maximum of 18 days, if needed) 
and starts when the subject has met all the eligibility criteria in the initial screening period 


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(refer to Section 5.1 and Section 5.2).  The run-in period ends when the subject does not 
meet the additional eligibility criterion at the end of the period (inclusion criterion 108) or 
when subject meets inclusion criterion 108 and enters the baseline period. 
8.1.3 
Baseline Period 
The baseline period starts when the subject has met all initial eligibility criteria (refer to 
Section 5.1 and Section 5.2), has completed the run-in period, and has met 
inclusion criterion 108.  The baseline period ends when the subject does not meet all the 
additional eligibility criteria (inclusion criteria 109 through 112) and is screen failed or 
when subject meets all eligibility criteria and is enrolled and randomized.  The total 
duration of the baseline period must be at least 28 days and no more than 35 days.   
8.1.4 
Treatment Period 
Visits will occur per the Schedule of Activities (Table 1-1).  The date of the first dose of 
investigational product is defined as day 1.  All subsequent doses and study visits will be 
scheduled based on the day 1 date.  Study visits after day 1 may be completed 
within ± 3 days of the scheduled visit.  All study procedures for a given study visit are to 
be completed on the same day.  Investigational product is to be administered Q4W as 
the last procedure during each visit that it is required.   
Subjects who discontinue investigational product are encouraged to remain in the study 
and complete all remaining procedures and study visits. 
8.1.5 
End of Study 
The end-of-study visit occurs at week 16 or 4 weeks after last dose of investigational 
product for subjects who discontinue the study.  If a subject discontinues treatment or 
the study prior to week 12, the week 12 assessments should be conducted for their early 
termination visit.  Assessments will be performed at the end-of-study visit as per 
Schedule of Activities (Table 1-1). 
8.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
time points. 
8.2.1 
General Assessments  
8.2.1.1 
Informed Consent 
All subjects must sign and personally date the IRB/IEC approved informed consent 
before any study-specific procedures are performed. 


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8.2.1.2 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness.  
8.2.1.3 
Medical History 
The investigator or designee will collect a complete medical history that started within 
120 days prior to screening.  Medical history will include information on the subject's 
concurrent medical conditions.  In addition to the medical history, migraine history must 
date back to the original diagnosis.  The current severity will be collected for each 
condition that has not resolved. 
Targeted medical history is to be recorded in the neurologic medical history CRF, 
headache and migraine frequency medical history CRF, cardiovascular medical history 
CRF, cardiac risk factors medical history CRF, and gastrointestinal medical history CRF. 
8.2.1.4 
Physical Measurements 
Height (in centimeters) and weight (in kilograms) should be measured without shoes. 
8.2.1.5 
Substance Use History  
Obtain information about any prior history of diagnosed substance-related disorders. 
8.2.2 
Efficacy Assessments 
The clinical outcome assessments will be collected by subjects using a handheld device 
with an eDiary.  The handheld device will have both the episode eDiary and the daily 
eDiary, which will be accessible by the subject during specified periods of the study.  
Study site staff will assign and provide a handheld device with the eDiary to the subject 
at the run-in visit (after confirming the subject’s eligibility to enter the run-in period).  
During the run-in period, only the episode eDiary will be available to the subject.  The 
study site staff will train the subject on how to use the handheld device (eg, turning 
on/off, charging, navigating screens, transmitting data, contacting the help desk for 
technical assistance) and complete the episodic eDiary questions.  The subject will be 
instructed to interact with the episode eDiary for oral triptan-treated migraine attacks and 
to bring the handheld device to the baseline visit.  At the baseline visit, the investigator 
will confirm if inclusion criterion 108 has been met based on the run-in eligibility report.  
The episode eDiary will be made available to the subject again during study weeks 13 
to 16 (month 4) of the DBTP.  The episode eDiary will collect the following clinical 


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outcome assessments for oral triptan-related migraine attacks at the subject’s own 
physical location (eg, home): 
 
Date and time of start of each headache 
 
Date and time of end of each headache  
 
Worst pain severity per headache day 
 
Pain features and additional symptoms of migraine attack 
 
The most bothersome symptom (ie, nausea, vomiting, photophobia, or 
phonophobia) and the severity following treatment with oral triptan  
 
Use of oral triptan (triptan name and dosing) 
Once the subject has completed the run-in period and is considered eligible to enter the 
baseline period, the subject will be instructed to interact with the daily eDiary every day 
and to bring the device to site during every study visit.  The daily eDiary will collect the 
following clinical outcome assessments every day at the subject’s own physical location 
(eg, home): 
 
Date and time of start of each headache (ie, migraine or nonmigraine headache) 
 
Date and time of end of each headache  
 
Worst pain severity per headache day 
 
Pain features (eg, 1-sided, throbbing, worsens with exercise/physical activity) 
 
Symptoms (eg, aura, nausea, vomiting, photophobia, phonophobia) 
 
Use of acute medications (medication name/type [from pre-entered list], date of 
dosing) 
At the day 1 visit prior to randomization, the investigator will use the information 
collected during the baseline period by the subject’s daily eDiary to review all data 
entered and confirm the relevant inclusion criteria (inclusion 109 through 112) are met.   
The handheld device will also be used for the completion of the following 
patient-reported outcome measures: 
 
Migraine Functional Impact Questionnaire (MFIQ) 
 
Migraine Symptom Severity Score (MSSS) 
 
Change in most troublesome symptom 
 
Patient Global Impression of Severity (PGI-S) 
 
Migraine Interictal Burden Scale (MIBS-4) 
 
Headache Impact Test (HIT-6) 
 
Pain Catastrophizing Scale (PCS) 


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8.2.2.1.1 
Migraine Functional Impact Questionnaire (MFIQ) 
The MFIQ is a self-administered 26-item instrument measuring the impact of migraine on 
broader functioning (ie, Physical, Usual Activities, Social, and Emotional).  It has 
4 domains:  Impact on Physical Functioning (5 items), Impact on Usual Activities 
(10 items), Impact on Social Functioning (5 items), and Impact on Emotional Functioning 
(5 items).  In addition, there is 1 stand-alone global item assessing the overall impact on 
usual activities.  Subjects respond to items using a 5-point scale assigned scores from 
1 to 5, with 5 representing the greatest burden.  The scores are calculated as the sum of 
the item responses and the sum is rescaled to a 0 to 100 scale, with higher scores 
representing greater burden.  The recall period is the past 7 days. 
8.2.2.1.2 
Migraine Symptom Severity Scale (MSSS) 
The MSSS is a 7-item questionnaire that assesses frequency of pain and other 
symptoms associated with migraines.  Responses are as follows: “never,” “rarely,” “less 
than half the time,” “half the time or more,” and “all or nearly all of the time”.  The 
responses are given a value from 1 to 3 as follows and summed:  Never = 0, Rarely = 1, 
Less Than Half the Time = 2, Half the Time or More = 3, and All or Nearly All of the 
Time = 3.  The MSSS score is the sum of the 7 items and has a range from 0 to 21.  It is 
reported as a mean for the group of interest. 
8.2.2.1.3 
Change in Most Troublesome Symptom 
The change in most troublesome symptom will be measured by a 7-point Likert-type 
scale.  It will be a single question asking the patients to rate how their most troublesome 
“non-headache pain” symptom (during and between migraine attacks) has changed 
since the start of the study on a scale of 1 (Very Much Improved) to 7 (Very Much 
Worse).   
8.2.2.1.4 
Patient Global Impression of Severity (PGI-S) 
The PGI-S is a single question that rates the severity of the patient’s condition at the 
time of assessment, relative to the patient’s experience prior to treatment.  It is a 7-point 
scale that ranks severity of illness using 1 of the following response categories:  
1 = Normal, not at all ill, 2 = Borderline ill, 3 = Mildly ill; 4 = Moderately ill, 5 = Markedly 
ill, 6 = Severely ill, and 7 = Most extremely ill. 
8.2.2.1.5 
Migraine Interictal Burden Scale (MIBS-4) 
The MIBS-4 measures interictal migraine-related burden with 4 questions that assess 
impairment in work or school, impairment in family and social life, difficulty making plans 


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or commitments, and emotional/affective and cognitive distress.  Each of the 4 questions 
is responded to using 1 of 6 response categories: “Don’t know/NA” (Score = 0), “Never” 
(Score = 0), “Rarely” (Score = 1), “Some of the time” (Score = 2), “Much of the time” 
(Score = 3) or “Most or all of the time” (Score = 3).  Each question is multiplied with its 
score and summed up to produce total score ranges from 0 to 12.  The MIBS-4 total 
scores are categorized into 4 level of interictal burden: None (0), Mild (1 to 2), 
Moderate (3 to 4) and Severe (5 or higher). 
8.2.2.1.6 
Headache Impact Test (HIT-6) 
The HIT-6 is a short-form self-administered questionnaire based on the Internet-HIT 
question pool.  The HIT-6 was developed as a global measure of adverse headache 
impact to assess headache severity in the previous month and change in a subject's 
clinical status over a short period of time.  Six questions cover severe pain, limitation of 
daily activity (household, work, school and social), wanting to lie down when headache is 
experienced, feeling too tired to work or do daily activities because of headache, feeling 
"fed up" or irritated because of headache, and headache limiting ability to concentrate or 
work on daily activities.  Each of the 6 questions is responded to using 1 of 5 response 
categories: "never," "rarely," "sometimes," "very often," or "always".  
For each HIT-6 item, 6, 8, 10, 11, or 13 points, respectively, are assigned to the 
response provided.  These points are summed to produce a total HIT-6 score that 
ranges from 36 to 78.  HIT-6 scores are categorized into 4 grades, representing little or 
no impact (49 or less), some impact (50 to 55), substantial impact (56 to 59), and severe 
impact (60 to 78) due to headache.  No recall period is specified for the first 3 items.  
The recall period is the past 4 weeks for the last 3 items. 
8.2.2.1.7 
Pain Catastrophizing Scale (PCS) 
The PCS is a 13-item self-report measure designed to convey a subject’s characteristic 
level of pain-related, catastrophic thinking during painful experiences 
(Sullivan et al, 1995).  The measure consists of 3 subscales, which are Rumination 
(4 items), Magnification (3 items), and Helplessness (6 items).  Participants are asked to 
recall a painful experience and to rate the extent to which the thoughts and emotions 
listed in each item had occurred.  For each item, subjects are requested to provide a 
response in a 5-point Likert scale (0 “not at all,” 1 “to a slight degree,” 2 “to a moderate 
degree,” 3 “to a great degree,” 4 “all the time”).  Higher scores in PCS indicate higher 
levels of catastrophizing and both the original PCS and its headache version have been 
well validated across both experimental studies as well as clinical samples.  Both 


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versions of the PCS have demonstrated strong internal consistency and test-retest 
reliability (Sullivan et al, 1995; Osman et al, 1997; Holroyd et al, 2007). 
8.2.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
see (Table 1-1). 
8.2.4 
Adverse Events and Serious Adverse Events  
8.2.4.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
8.2.4.1.1 
Adverse Events 
The adverse event grading scale to be used for this study will be the Common 
Terminology Criteria for Adverse Events (CTCAE) and is described in Section 11.4. 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of investigational 
product through the end of study are reported using the Event CRF. 
8.2.4.1.2 
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 end of study are reported using the Event CRF. 
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee within 24 hours of the investigator’s knowledge of the event, as indicated in 
Section 11.4.  The investigator will submit any updated serious adverse event data to the 
sponsor within 24 hours of it being available. 
The criteria for grade 4 in the CTCAE grading scale differs from the regulatory criteria for 
serious adverse events.  The investigator is to determine whether these grade 4 
abnormalities are serious adverse events based on the definition of serious adverse 
events as per Appendix 4 (Section 11.4). 
8.2.4.1.3 
Serious Adverse Events After the Protocol-required Reporting 
Period 
After End of Study, there is no requirement to actively monitor study subjects after the 
study has ended with regards to study subjects treated by the investigator. However, if 
the investigator becomes aware of serious adverse events suspected to be related to 
investigational product, then these serious adverse events will be reported to Amgen 
within 24 hours following the investigator’s awareness of the event. 


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Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases and handled accordingly based 
on relationship to investigational product.  If further safety related data is needed to fulfill 
any regulatory reporting requirements for a reportable event, then additional information 
may need to be collected from the subject’s records after the subject ends the study. 
The method of recording, evaluating, and assessing causality of adverse events, 
adverse device effects, and serious adverse events and the procedures for completing 
and transmitting serious adverse event reports are provided in Section 11.4. 
8.2.4.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the subject is the 
preferred method to inquire about adverse event occurrence. 
8.2.4.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is required to 
proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 7.3).  
Further information on follow-up procedures is given in Section 11.4. 
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Event CRF. 
8.2.4.4 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 


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investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy and forwarded 
to investigators as necessary. 
An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB/IEC, if appropriate according to local requirements. 
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities.  Aggregate 
analyses may also be unblinded by the Safety Assessment Team, as appropriate.  
Investigators will receive notification of related serious adverse events reports sent to 
regulatory authorities in accordance with local requirements. 
8.2.4.5 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and 
signal management processes. 
8.2.4.6 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects and female partners of 
male subjects will be collected after the start of study treatment and until 16 weeks after 
the last dose of investigational product. 
If a pregnancy is reported, the investigator is to inform Amgen within 24 hours of learning 
of the pregnancy and/or lactation and is to follow the procedures outlined in 
Section 11.5.  Amgen Global Patient Safety will follow-up with the investigator regarding 
additional information that may be requested. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, and ectopic pregnancy) are considered serious adverse events. 
Further details regarding pregnancy and lactation are provided in Section 11.5. 


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8.2.4.7 
Adverse Device Effects 
In order to fulfill regulatory reporting obligations worldwide, the investigator is 
responsible for the detection and documentation of any adverse device effects that occur 
during the study with such devices.  
An adverse device effect is any adverse event related to the use of a combination 
product or medical device.  Adverse device effects include adverse events resulting from 
insufficient or inadequate instructions for use, adverse events resulting from any 
malfunction of the device, or adverse events resulting from use error or from intentional 
misuse of the device. 
All adverse device effects are to be reported as adverse events following the same 
reporting periods and procedures. 
Product complaints are described in Section 6.1.5. 
Further details regarding adverse device effects can be found in Section 11.4. 
8.2.5 
Clinical Laboratory Assessments 
Refer to Section 11.2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Table 1-1) for the timing and frequency.  
The investigator is responsible for reviewing laboratory test results and recording any 
clinically relevant changes occurring during the study in the Event CRF.   
All protocol-required laboratory assessments, as defined in Section 11.2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities 
(Table 1-1).  
Pregnancy Testing 
A urine pregnancy test should be completed for females of childbearing potential as per 
the Schedule of Activities (Table 1-1).   
Note:  Females who have undergone a bilateral tubal ligation/occlusion should have 
pregnancy testing per protocol requirements.  (If a female subject, or the partner of a 
male subject, becomes pregnant it must be reported on the Pregnancy Notification 
Form, see Figure 11-3).  Refer to Section 11.5 for contraceptive requirements.  
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 


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8.2.6 
Pharmacogenetic Assessments 
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed.  These optional pharmacogenetic analyses focus on 
inherited genetic variations to evaluate their possible correlation to the disease and/or 
responsiveness to the therapies used in this study.  The goals of the optional studies 
include the use of genetic markers to help in the investigation of migraines and/or to 
identify subjects who may have positive or negative response to erenumab.  No 
additional samples are collected for this part of the study.  For subjects who consent to 
this/these analysis/analyses, DNA may be extracted from the cell pellet collected in the 
plasma tube used for the biomarker development sample. 
The final disposition of samples is described in Section 11.6.  
8.2.7 
Biomarkers  
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention. 
8.2.7.1 
Biomarker Development/Future Research 
Biomarker Development refers to using samples collected for Biomarker Discovery for 
future research after the study ends. 
Biomarker development can be useful in developing markers to identify disease 
subtypes, guide therapy, and/or predict disease severity.   
If consent is provided by subjects, biomarker discovery samples collected at the time 
points specified in the Schedule of Activities will be retained for future biomarker 
development as described in Appendix 6 (Section 11.6).  
Amgen or another third-party manufacturer may attempt to develop test(s) designed to 
identify subjects most likely to respond positively or negatively to erenumab to 
investigate and further understand migraines. 
9. 
Statistical Considerations 
9.1 
Statistical Hypotheses 
The primary hypothesis is that preventive treatment with monthly administration of 
erenumab is superior to placebo in reducing duration of moderate or severe headache 
pain in subjects with HFEM who have previously failed at least 1 migraine preventive 
treatment. 


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9.2 
Sample Size Determination 
A total sample size of 576 subjects (288 subjects per group including 10% dropouts) 
provides at least a 90% power for the primary efficacy hypothesis.  The statistical power 
for secondary efficacy hypotheses ranges from 81% to > 99% (Table 9-1).   
Table 9-1.  Sample Size Assumptions and Statistical Powers for Primary and 
Secondary Efficacy Endpoints for a Total Sample Size of 576 Subjects Including a 
10% Attrition Rate due to Dropout 
Hypothesis 
Assumed 
Treatment 
Effect 
(Common SD) 
Power  
Primary: 
Change from baseline in mean monthly hours of at 
least moderate headache pain intensity over 
months 1, 2, and 3 
-16.7 (50) 
96% 
Secondary:  Change from baseline in mean monthly 
MFIQ physical function domain score over months 1, 
2, and 3 
-9.2 (18.0) 
> 99% 
MFIQ usual activities domain score over months 1, 
2, and 3 
-7.5 (19) 
> 99% 
MFIQ emotional function domain score over 
months 1, 2, and 3 
-11.5 (22) 
> 99% 
MFIQ social function domain score over months 1, 
2, and 3 
-6.9 (20) 
97% 
Average duration of at least moderate migraine pain 
intensity in migraine attacks occurring over 
months 1, 2, and 3a 
-2.0 (8) 
81% 
Average peak migraine pain intensity over months 1, 
2, and 3 
-0.11 (0.44) 
81% 
MFIQ = Migraine Functional Impact Questionnaire. 
Note:  All power calculations are based on a 2-sided significance level of 0.05.  The assumed treatment 
effects and common standard deviations are derived or chosen from a subset of placebo-treated and 
erenumab-140 mg-treated subjects in erenumab Study 20120296 with high-frequency episodic migraine 
(ie, 7 to 14 monthly migraine days) and having at least 4 moderate-to-severe migraine attacks at baseline.   
a If a subject did not have any migraine attacks in a given month, the duration of at least moderate migraine 
pain intensity was counted as 0. 
9.3 
Analysis Sets, Subgroups, and Covariates 
9.3.1 
Analysis Sets 
9.3.1.1 
Full Analysis Set  
The full analysis set consists of all subjects who were randomized in the study.  Analysis 
of disposition, demographic and baseline characteristics, and important protocol 
deviations will utilize this analysis set. 


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9.3.1.2 
Efficacy Analysis Set 
The respective efficacy analysis set consists of a subset of subjects from full analysis set 
who receive at least 1 dose of investigational product and have a baseline value and at 
least 1 post baseline value for the endpoint of interest.  Subjects will be analyzed 
according to their randomized treatment, regardless of the treatment received.  Primary 
analysis of the efficacy endpoints will utilize the respective efficacy analysis set. 
9.3.1.3 
Safety Analysis Set 
The respective safety analysis set will consist of all randomized subjects who received at 
least 1 dose of investigational product.  Subjects will be analyzed according to the 
randomized treatment unless a subject has received the incorrect dose during the entire 
DBTP.  Analysis for safety endpoints and summary of investigational product 
administration will utilize the respective safety analysis set. 
9.3.2 
Covariates 
Model-adjusted analyses of efficacy endpoints will include the corresponding baseline 
value for the endpoint being analyzed, if applicable. 
9.3.3 
Subgroups 
The primary and secondary endpoints will be analyzed in the following subgroups:  
 
Number of prior treatment failures (1, 2, and 3 or more treatment failures) 
 
Medication overuse status at baseline (yes vs no) 
The subgroups will be re-examined for appropriateness and may be re-categorized (due 
to small sample size, for example, if there are < 10% of subjects within a subgroup) 
before unblinding.   
9.3.4 
Handling of Missing and Incomplete Data 
Subjects may miss specific data points for a variety of reasons.  In general, data could 
be missing due to a subject’s early withdrawal from the study, a missed visit, or inability 
to evaluate an endpoint at a time point.  For this study, efficacy endpoints will be 
collected via eDiary and subjects could miss entering several days of data in each 
monthly interval.  The general procedures outlined below describe how missing data will 
be handled. 
For the endpoints derived from daily diary during month 1 to 3, if at least 14 days of 
eDiary are collected in the monthly interval, then the monthly frequency measurements 
(eg, migraine days, headache days) will be prorated based on the number of days with 
available information. 


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Missing items in each clinical outcome assessment questionnaire will be handled based 
on the scoring algorithm for each assessment. 
Missing data after above methods will either be handled by the linear mixed effects 
model under missing-at-random assumption or imputed as non-responders for binary 
endpoint. 
Missing data in safety data will not be imputed. 
9.4 
Statistical Analyses 
The statistical analysis plan (SAP) will be developed and finalized before database lock.  
Below is a summary of the timing and methods for the planned statistical analyses.  To 
preserve study integrity, the final analysis will be conducted and reported following the 
end of study, as defined in Section 4.4.1. 
9.4.1 
Planned Analyses 
9.4.1.1 
Primary Analysis 
The primary analysis (or final analysis since there is only 1 milestone analysis for this 
study) will occur after all subjects have completed their week 16 visit (or discontinued 
from the study).  The DBTP treatment assignment will be unblinded and all efficacy and 
safety analyses will be conducted and reported by the DBTP treatment group. 
9.4.2 
Methods of Analyses 
9.4.2.1 
General Considerations 
Summary statistics will be computed by treatment group and visit.  For continuous 
endpoints, the following descriptive statistics will be computed:  number of observations, 
means, medians, standard deviations, standard errors, first and third quartiles, 
minimums and maximums, and 2-sided 95% CIs of the means (CIs will be provided for 
efficacy endpoints only).  For categorical endpoints, the summaries will contain the 
number and percentage of subjects in each category. 
The primary analysis method utilizing a repeated measures linear mixed effects model 
will include all observed data regardless of treatment adherence. 
A sequential testing procedure will be used to maintain the family-wise type 1 error 
α = 0.05 between the primary and secondary endpoints following the prespecified order 
below.  An endpoint will only be tested for statistical significance if the endpoint tested in 
the previous step is statistically significant at 2-sided significance level of 0.05. 
1. Primary endpoint: change from baseline in mean monthly hours of at least moderate 
headache pain intensity over months 1, 2, and 3 


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2. Secondary endpoints:  change from baseline in mean monthly function domain score 
over months 1, 2, and 3, as measured by the MFIQ using the Hochberg procedure 
 
Impact on physical functioning 
 
Impact on usual activities 
 
Impact on emotional functioning 
 
Impact on social functioning 
3. Secondary endpoint:  change from baseline in mean monthly average duration of at 
least moderate pain intensity in migraine attacks occuring over months 1, 2, and 3 
(migraine attacks as defined in Section 11.1) 
4. Secondary endpoint:  change from baseline in mean monthly average peak migraine 
pain intensity over months 1, 2, and 3, as assessed by the 11-point NRS 
9.4.2.2 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
The primary endpoint will be analyzed using a linear mixed effects model 
including treatment group, baseline value, scheduled visit, and the interaction 
of treatment group with scheduled visit, without any imputation for missing 
data. 
Secondary 
The secondary endpoints will be analyzed using a linear mixed effects model 
including treatment group, baseline value, scheduled visit, and the interaction 
of treatment group with scheduled visit, without any imputation for missing 
data. 
Exploratory 
Detailed primary analysis method for exploratory endpoints will be described 
in the SAP.   
 
9.4.2.3 
Safety Analyses 
9.4.2.3.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) will be used to code all 
adverse events. 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  Tables of fatal adverse events, serious adverse events, 
adverse events leading to withdrawal from investigational product or other 
protocol-required therapies, and significant treatment-emergent adverse events will also 
be provided.  Subject incidence of device-related events, if applicable, will be tabulated 
by system organ class and preferred term. 
9.4.2.3.2 
Exposure to Investigational Product 
The total length of investigational product exposure, the number of doses, and the 
proportion of subjects receiving each dose will be summarized using descriptive 
statistics. 


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9.4.2.3.3 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving therapies of interest will be summarized by 
medication category for each treatment group. 


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10. 
References 
Afridi SK, Giffin NJ, Kaube H, et alet al.  A positron emission tomographic study in 
spontaneous migraine.  Arch Neurol.  2005;62:1270-1275. 
Aurora SK, Wilkinson F.  The brain is hyperexcitable in migraine.  Cephalalgia.  
2007;27:1442-1453. 
Aurora SK, Barrodale P, Chronicle EP, Mulleners WM.  Cortical inhibition is reduced in 
chronic and episodic migraine and demonstrates a spectrum of illness.  Headache.  
2005;45:546-552. 
Buse DC, Rupnow MFT, Lipton RB.  Assessing and managing all aspects of migraine: 
migraine attacks, migraine-related functional impairment, common comorbidities, and 
quality of life.  Mayo Clin Proc.  2009; 84:422-435. 
Dodick DW, Ashina M, Brandes JL, et al.  ARISE:  A Phase 3 randomized trial of 
erenumab for episodic migraine.  Cephalagia.  2018;38:1026-1037. 
Evers S, Afra J, Frese A, et al.  EFNS guideline on the drug treatment of 
migraine--revised report of an EFNS task force.  Eur J Neurol.  2009;16:968-981. 
Goadsby PJ, Paemeleire, Broessner G, et al.  Efficacy and safety of erenumab 
(AMG334) in episodic migraine patients with prior preventive treatment failure:  A 
subgroup analysis of a randomized, double-blind, placebo-controlled study.  Cephalagia.  
2019;39(7):817-826. 
Goadsby PJ, Reuter U, Hallstrom Y, et al.  A Controlled Trial of Erenumab for Episodic 
Migraine.  N Engl J Med.  2017;377:2123-2132. 
Headache Classification Committee of the International Headache Society (IHS):  The 
International Classification of Headache Disorders, 3rd edition. (ICHD-III)  Cephalalgia.  
2018;38(1):1–211. 
Holroyd KA, Drew JB, Cottrell CK, Romanek KM, Heh V.  Impaired functioning and 
quality of life in severe migraine: the role of catastrophizing and associated symptoms.  
Cephalalgia.  2007;27:1156–1165. 
Houle TT, Turner DP, Houle TA, et al.  Rounding behavior in the reporting of headache 
frequency complicates headache chronification research.  Headache.  2013;53:908-919. 
Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF.  AMPP Advisory 
Group:  migraine prevalence, disease burden, and the need for preventive therapy.  
Neurology.  2007;68:343-349. 
Osman A, Barrios FX, Kopper BA, Hauptmann W, Jones J, O’Neill E.  Factor structure, 
reliability, and validity of the Pain Catastrophizing Scale.  J Behav Med.  
1997;20:589-605. 
Reuter U, Goadsby PJ, Lanteri-Minet M, et al.  Efficacy and tolerability of erenumab in 
patients with episodic migraine in whom two-to-four previous preventive treatments were 
unsuccessful:  a randomised, double-blind, placebo-controlled, phase 3b study.  Lancet.  
2018;392:2280-2287. 
Sakai F, Igarashi H.  Prevalence of migraine in Japan:  a nationwide survey.  
Cephalalgia.  1997;17:15-22. 
Silberstein SD.  Preventive migraine treatment.  Continuum (Minneap Minn).  2015; 21: 
973-989. 


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Silberstein SD, Holland S, Freitag F, et al.  Evidence-based guideline update:  
pharmacologic treatment for episodic migraine prevention in adults:  report of the Quality 
Standards Subcommittee of the American Academy of Neurology and the American 
Headache Society.  Neurology.  2012;78:1337-1345 
Stovner LJ, Andree C.  Prevalence of headache in Europe:  a review for the Eurolight 
project.  J Headache Pain.  2010;11:289-299. 
Sullivan MJL, Bishop SR, Pivik J.  The Pain Catastrophizing Scale: Development and 
Validation.  Psychol Assess.  1995;7:524–532. 
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;16:425-434. 
Welch KM, Nagesh V, Aurora S, Gelman N.  Periaqueductal gray matter dysfunction in 
migraine and chronic daily headache may be due to free radical damage.  J Headache 
Pain.  2001;2(Suppl 1):33-41. 


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11. 
Appendices 


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11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms 
 
Abbreviation or Term 
Definition/Explanation 
ACE 
angiotensin-converting enzyme 
CBD 
cannabidiol  
CFR 
Code of Federal Regulations 
CGRP 
calcitonin gene-related peptide 
CM 
chronic migraine 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBTP 
double-blind treatment period 
E-DBTP 
exploratory double-blind treatment period 
EDC 
electronic data capture 
eDiary 
electronic diary 
EM 
episodic migraine 
End of Study for Individual 
Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject 
End of Study (primary 
completion) 
defined as the date when the last subject is assessed or 
receives an intervention for the final collection of data for the 
primary endpoint(s), for the purposes of conducting the primary 
analysis, whether the study concluded as planned in the protocol 
or was terminated early 
End of Study (end of trial), 
EOS 
defined as the date when the last subject across all sites is 
assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit), following any additional parts in the 
study (eg, long-term follow-up), as applicable 
End of Treatment 
defined as the last assessment for the protocol-specified 
treatment phase of the study for an individual subject 
Enrollment 
defined as the day a subject has met all run-in and baseline 
period eligibility criteria and is enrolled and randomized into the 
study (subjects are randomized same day) 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
Headache 
a migraine or non-migraine headache 
Headache day 
Any calendar day in which the subject experiences a qualifying 
headache (initial onset, continuation, or recurrence of the 
headache).  A qualifying headache is defined as: 
 
a qualifying migraine headache (including an aura-only 
event that is treated with acute migraine-specific 
medication) or 
 
a qualifying non-migraine headache, which is a 
headache that lasts  30 minutes and is not a qualifying 
migraine headache or 
 
a headache of any duration for which acute headache 
treatment is administered 


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Abbreviation or Term 
Definition/Explanation 
HFEM 
high-frequency episodic migraine 
HIT-6 
Headache Impact Test-6 
HRT 
hormone replacement therapy 
ICH 
International Council for Harmonisation 
ICHD-III 
International Classification of Headache Disorders, Third Edition 
IEC 
Independent Ethics Committee 
IHS 
International Headache Society 
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Board 
IRT 
interactive response technology that is linked to a central 
computer in real time as an interface to collect and process 
information 
IUD 
intrauterine device 
IUS 
intrauterine hormonal-releasing system 
LSM 
least squares mean 
M-DBTP 
main double-blind treatment phase 
MFIQ 
Migraine Functional Impact Questionnaire 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIBS-4 
4-item Migraine Interictal Burden Scale 
Migraine attack 
An episode of any qualifying migraine headache.  The following 
rules will be used to distinguish an attack of long duration from 
2 attacks, or to distinguish between attacks and relapses: 
a. A migraine attack that is interrupted by sleep, or temporarily 
remits, and then recurs within 48 hours (ie, ≤ 48 hours 
between the start of the migraine attack to the time of the 
recurrence) will be considered as 1 attack and not 2. 
b. An attack treated successfully with medication but with 
relapse within 48 hours (ie, ≤ 48 hours between the start of 
the migraine attack to the time of the recurrence) will be 
considered as 1 attack. 


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Abbreviation or Term 
Definition/Explanation 
Migraine day 
A migraine day is defined as any calendar day in which the 
subject experiences a qualifying migraine headache (onset, 
continuation or recurrence of the migraine headache).  
A qualifying migraine headache is defined as a migraine with or 
without aura lasting for  30 minutes, and meeting at least 1 of 
the following criteria (a and/or b): 
a.  2 of the following pain features: 
 
Unilateral 
 
Throbbing 
 
Moderate to severe 
 
Exacerbated with exercise/physical activity 
b.  1 of the following associated symptoms: 
 
Nausea and/or vomiting 
 
Phonophobia and photophobia 
If the subject took a migraine-specific medication (ie, 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. 
Migraine recurrence 
return of any headache of at least moderate pain intensity in 
patients who were pain-free at 2 hours post-dose 
MMD 
monthly migraine days 
MSSS 
Migraine Symptom Severity Score 
NCT 
National Clinical Trials 
NRS 
Numeric Rating Scale 
pain relief 
reduction from moderate/severe pain to mild/no pain 
PCS 
Pain Catastrophizing Scale 
PFS 
prefilled syringes 
PGI-S 
Patient Global Impression of Severity 
PHQ-9 
Patient Health Questionnaire 
Q4W 
every 4 weeks 
QM 
once monthly 
Qualifying oral triptan-treated 
attacks (run-in 
period/month 4) 
migraine attacks of at least moderate peak pain intensity that are 
treated with an oral triptan within 2 hours of pain reaching at 
least moderate severity 
Qualifying oral 
triptan-treated attacks 
(baseline/ month 1, 2, and 
3) 
migraine attacks that are treated with an oral triptan  
Randomization 
defined as the day a subject has met all run-in and baseline 
period eligibility criteria and is enrolled and randomized into the 
study (subjects are enrolled same day) 
SAP 
statistical analysis plan 
SC 
subcutaneous(ly) 


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Abbreviation or Term 
Definition/Explanation 
Source data 
information from an original record or certified copy of the 
original record containing patient information for use in clinical 
research.  The information may include, but is not limited to, 
clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents (original records 
or certified copies).  (ICH Guideline [E6]).  Examples of source 
data include Subject identification, Randomization identification, 
and Stratification Value. 
Study day 1 
defined as the first day that protocol-specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject 
Total migraine freedom days 
Days where there is an absence of headache and aura, 
photophobia, phonophobia, and nausea/vomiting  
US 
United States 
 


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11.2 
Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 11-1 will be performed.  Additional tests may be performed at 
any time during the study as determined necessary by the investigator or required by 
local regulations.   
Table 11-1.  Analyte Listing 
Analyte 
Notes 
Urine pregnancy test 
 
Urine drug test 
 
Biomarker development 
Optional; sent to central laboratory 
Pharmacogenetic assessment 
Optional; sent to central laboratory 
 


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11.3 
Appendix 3.  Study Governance Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
 
Applicable ICH laws and regulations 
The protocol, protocol amendments, informed consent form, Investigator’s Brochure, and 
other relevant documents (eg, subject recruitment advertisements) must be submitted to 
an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) by the 
investigator and reviewed and approved by the IRB/IEC.  A copy of the written approval 
of the protocol and informed consent form must be received by Amgen before 
recruitment of subjects into the study and shipment of Amgen investigational product. 
Amgen may amend the protocol at any time.  The investigator must submit and, where 
necessary, obtain approval from the IRB/IEC for all subsequent protocol amendments 
and changes to the informed consent document.  The investigator must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
 
Obtaining annual IRB/IEC approval/renewal throughout the duration of the study.  
Copies of the investigator’s reports and the IRB/IEC continuance of approval must be 
sent to Amgen 
 
Notifying the IRB/IEC of serious adverse events occurring at the site, deviations from 
the protocol or other adverse event reports received from Amgen, in accordance with 
local procedures 
 
Overall conduct of the study at the site and adherence to requirements of Title 21 of 
the U.S. Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and all 
other applicable local regulations 
Recruitment Procedures 
Site staff will identify potential subjects from their existing patient population or may seek 
referral patients through existing professional networks or other community sources such 


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as patient advocacy groups.  Also, digital recruitment strategies may also be used.  All 
patient facing materials must be reviewed/approved by the sponsor (Amgen Inc.) and 
the local IRB/IEC. 
Informed Consent Process 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the sample 
informed consent form are to be communicated formally in writing from the Amgen Trial 
Manager to the investigator.  The written informed consent form is to be prepared in the 
language(s) of the potential patient population. 
The investigator or his/her delegated representative will explain to the subject the aims, 
methods, anticipated benefits, and potential hazards of the study before any 
protocol-specific screening procedures or any investigational product(s) is/are 
administered, and answer all questions regarding the study.   
Subjects must be informed that their participation is voluntary.  Subjects will then be 
required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act requirements, where applicable, and the [IRB/IEC] or study site.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
informed consent form. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study unless it is a local requirement.  The 
investigator shall then inform the primary care physician.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 
The acquisition of informed consent is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject and by the person who conducted the informed consent discussion.  Subject 


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withdrawal of consent or discontinuation from study treatment and/or procedures must 
also be documented in the subject’s medical records; refer to Section 7. 
Subjects must be re-consented to the most current version of the informed consent 
form(s) during their participation in the study.  
The original signed informed consent form is to be retained in accordance with 
institutional policy, and a copy of the informed consent form(s) must be provided to the 
subject.  
A subject who is rescreened is not required to sign another informed consent form if the 
rescreening occurs within 30 days from the previous informed consent form signature 
date. 
The informed consent form (ICF) will contain a separate section that addresses the use 
optional portions of this study.  The investigator or authorized designee will explain to 
each subject the objectives of the future research.  Subjects will be told that they are free 
to refuse to participate and may withdraw their specimens at any time and for any 
reason during the storage period.  A separate signature will be required to document a 
subject’s agreement to allow any remaining specimens to be used for future research.  
Subjects who decline to participate will not provide this separate signature. 
Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
Subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
On the case report form (CRF) demographics page, in addition to the unique subject 
identification number, include the age at time of enrollment. 
For serious adverse events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with local 
laws and regulations), and age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are to 
be kept in confidence by the investigator, except as described below. 


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In compliance with governmental regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.   
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
International Committee of Medical Journal Editors Recommendations for the Conduct of 
Reporting, Editing, and Publications of Scholarly Work in Medical Journals, which states:  
Authorship credit is to be based on:  (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the article 
or revising it critically for important intellectual content; (3) final approval of the version to 
be published; and (4) agreement to be accountable for all aspects of the work in 
ensuring that questions related to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved.  Authors need to meet conditions 1, 2, 3, and 4. 
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals must 
fully meet the criteria for authorship defined above.  Acquisition of funding, collection of 
data, or general supervision of the research group, alone, does not justify authorship.  All 
persons designated as authors must qualify for authorship, and all those who qualify are 


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to be listed.  Each author must have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content.  All publications (eg, manuscripts, 
abstracts, oral/slide presentations, book chapters) based on this study must be 
submitted to Amgen for review.  The Clinical Trial Agreement among the institution, 
investigator, and Amgen will detail the procedures for, and timing of, Amgen’s review of 
publications. 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
 
A recognized expert in the therapeutic area 
 
An investigator who provided significant contributions to either the design or 
interpretation of the study 
 
An investigator contributing a high number of eligible subjects 
 
Data Quality Assurance 
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, centrally or 
adjudicated data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.   
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
Clinical monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and 
that the study is being conducted in accordance with the currently approved protocol and 
any other study agreements, ICH GCP, and all applicable regulatory requirements per 
the sponsor’s monitoring plan.  


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The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research and Development 
Compliance and Audit function (or designees).  Inspection of site facilities 
(eg, pharmacy, protocol-required therapy storage areas, laboratories) and review of 
study-related records will occur to evaluate the study conduct and compliance with the 
protocol, ICH GCP, and applicable regulatory requirements. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Case report forms (CRF) must be completed in English.  TRADENAMES® (if used) for 
concomitant medications may be entered in the local language.  Consult the 
country-specific language requirements. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
Source Documents 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence.  Source documents may also include data captured in the IRT 
system (if used, such as subject ID and randomization number) and CRF entries if the 
CRF is the site of the original recording (ie, there is no other written or electronic record 
of data, such as paper questionnaires for a clinical outcome assessment). 


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Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available. 
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 
Elements to include: 
 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the [IRB/IEC] 
and Amgen 
 
Investigational product-related correspondence including [Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable 
 
Non-investigational product(s), and/or medical device(s) or combination product(s) 
documentation, as applicable 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Study and Site Closure 
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP.  
Both Amgen and the investigator reserve the right to terminate the investigator’s 
participation in the study according to the Clinical Trial Agreement.  The investigator is to 
notify the IRB/IEC in writing of the study’s completion or early termination and send a 
copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 


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Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 


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11.4 
Appendix 4.  Safety Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting 
Definition of Adverse Event 
Adverse Event Definition 
 
An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment.   
 
Note:  An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a treatment, combination 
product, medical device or procedure. 
 
Note:  Treatment-emergent adverse events will be defined in the statistical 
analysis plan (SAP). 
 
Events Meeting the Adverse Event Definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, electrocardiogram, radiological scans, vital signs 
measurements), including those that worsen from baseline, that are considered 
clinically significant in the medical and scientific judgment of the investigator 
(ie, not related to progression of underlying disease). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication.  Overdose per se will not be reported as an 
adverse event/serious adverse event unless it is an intentional overdose taken with 
possible suicidal/self-harming intent.  Such overdoses are to be reported 
regardless of sequelae. 
 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an adverse event or serious adverse event.  Such instances will be 
captured in the efficacy assessments.  However, the signs, symptoms, and/or 
clinical sequelae resulting from lack of efficacy will be reported as adverse event or 
serious adverse event if they fulfill the definition of an adverse event or serious 
adverse event.  
 


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Events NOT Meeting the Adverse Event Definition 
 
Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that 
leads to the procedure is the adverse event. 
 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
Definition of Serious Adverse Event 
A Serious Adverse Event is defined as any untoward medical occurrence that, 
meets at least 1 of the following serious criteria: 
Results in death (fatal) 
Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting.  Complications that occur during hospitalization are an adverse 
event.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the adverse event is to be considered serious.  Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not 
considered an adverse event. 
Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (eg, sprained ankle) which may interfere 
with or prevent everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 


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Definition of Adverse Device Effect 
The detection and documentation procedures for adverse device effects described in 
this protocol apply to all Amgen medical devices provided for use in the study (see 
Section 6.1.2 for the list of Amgen medical devices). 
Adverse Device Effect Definition 
An adverse device effect is any adverse event related to the use of a combination 
product or medical device.  Adverse device effects include adverse events resulting 
from insufficient or inadequate instructions for use, adverse events resulting from any 
malfunction of the device, or adverse events resulting from use error or from 
intentional misuse of the device. 
A Serious Adverse Event is defined as any untoward medical occurrence that, 
meets at least 1 of the following serious criteria: 
Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious adverse 
event reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require medical or surgical intervention to prevent 1 of 
the other outcomes listed in the above definition.  These events are typically to be 
considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 


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Recording Adverse Events and Serious Adverse Events 
Adverse Event and Serious Adverse Event Recording 
 
When an adverse event or serious adverse event occurs, it is the responsibility of 
the investigator to review all documentation (eg, hospital progress notes, 
laboratory, and diagnostics reports) related to the event. 
 
The investigator will then record all relevant adverse event/serious adverse event 
information in the Event case report form (CRF). 
 
The investigator must assign the following adverse event attributes: 
o Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms); 
o Dates of onset and resolution (if resolved); 
o Severity (or toxicity defined below); 
o Assessment of relatedness to investigational product and 
o Action taken. 
 
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record as a single event with the worst severity on the Event CRF. 
 
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to sponsor in lieu of completion of the Event CRF page. 
 
If specifically requested, the investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the 
medical records.  In this case, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records before 
submission to Amgen. 
 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious 
adverse event. 
Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The investigator will make an assessment of severity for each adverse event and 
serious adverse event reported during the study.  The assessment of severity will be 
based on: 
The Common Terminology Criteria for Adverse Events, version 4.03 which is available 
at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 


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Assessment of Causality 
 
The investigator is obligated to assess the relationship between investigational 
product, device and each occurrence of each adverse event/serious adverse 
event. 
 
Relatedness means that there are facts or reasons to support a relationship 
between investigational product and the event. 
 
The investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
 
The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 
 
For each adverse event/serious adverse event, the investigator must document in 
the medical notes that he/she has reviewed the adverse event/serious adverse 
event and has provided an assessment of causality. 
 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report.  However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the serious adverse event data. 
 
The investigator may change his/her opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated 
causality assessment. 
 
The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of Adverse Event and Serious Adverse Event 
 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 
Amgen to elucidate the nature and/or causality of the adverse event or serious 
adverse event as fully as possible.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 
care professionals. 
 
If a subject is permanently withdrawn from protocol-required therapies because of 
a serious adverse event, this information must be submitted to Amgen. 
 
If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Amgen with a copy of any post-mortem 
findings including histopathology. 
 
New or updated information will be recorded in the originally completed Event 
CRF. 
 
The investigator will submit any updated serious adverse event data to Amgen 
within 24 hours of receipt of the information. 


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Reporting of Serious Adverse Event 
Adverse Device Effects:  Recording, Evaluating and Reporting 
 
Any adverse event resulting from an adverse device effect that occur during the 
study will be documented in the subject’s medical records, in accordance with the 
investigator’s normal clinical practice, and on the Event CRF page. 
 
It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by Amgen) at the time of the initial 
report and describes any corrective or remedial actions taken to prevent recurrence 
of the incident. 
 
Serious Adverse Event Reporting via Electronic Data Collection Tool 
 
The primary mechanism for reporting serious adverse event will be the electronic 
data capture (EDC) system.  
 
If the EDC system is unavailable for more than 24 hours, then the site will report 
the information to Amgen using an electronic Serious Adverse Contingency Report 
Form (see Figure 11-1) within 24 hours of the investigator’s knowledge of the 
event. 
 
The site will enter the serious adverse event data into the electronic system as 
soon as it becomes available. 
 
After the study is completed at a given site, the EDC system will be taken off-line to 
prevent the entry of new data or changes to existing data. 
 
If a site receives a report of a new serious adverse event from a study subject or 
receives updated data on a previously reported serious adverse event after the 
EDC has been taken off-line, then the site can report this information on a paper 
Serious Adverse Event Report Form (see Figure 11-2). 
 
Once the study has ended, serious adverse event(s) suspected to be related to 
investigational product will be reported to Amgen if the investigator becomes aware 
of a serious adverse event.  The investigator should use the paper-based Serious 
Adverse Event Contingency Report Form to report the event.  


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Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Form 
 


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Figure 11-2.  Sample Serious Adverse Event Report Form 
 


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11.5 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy 
and Lactation Information 
Study-specific contraception requirements for female subjects of childbearing potential 
are outlined in Section 5.2. 
Female subjects of childbearing potential must receive pregnancy prevention counseling 
and be advised of the risk to the fetus if they become pregnant during treatment and for 
16 weeks after the last dose of protocol-required therapies. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered female of childbearing potential: 
 
Premenopausal female with 1 of the following: 
o Documented hysterectomy; 
o Documented bilateral salpingectomy; or 
o Documented bilateral oophorectomy. 
Note:  Site personnel documentation from the following sources is acceptable:  
1) review of subject’s medical records; 2) subject’s medical examination; or 
3) subject’s medical history interview. 
 
Premenarchal female 
 
Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
o Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.   


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Contraception Methods for Female Subjects 
Acceptable Methods of Effective Contraception 
 
Combined (estrogen and progestogen containing) or progestogen-only hormonal 
methods given via oral, intravaginal, transdermal, injectable, or implantable route) 
 
Intrauterine device (IUD) 
 
Intrauterine hormonal-releasing system (IUS) 
 
Bilateral tubal ligation/occlusion 
 
Vasectomized partner (provided that partner is the sole sexual partner of the female 
subject of childbearing potential and that the vasectomized partner has received 
medical assessment of the surgical success) 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments; the reliability of sexual 
abstinence must be evaluated in relation to the duration of the trial and the preferred 
and usual lifestyle of the subject) 
 
Male or female condom with or without spermicide 
 
Cap, diaphragm or sponge with spermicide 
 
Double barrier method:  the male uses a condom and the female may choose either 
a cap, diaphragm, or sponge with spermicide (a female condom is not an option due 
to the risk of tearing when both partners use a condom) 
Unacceptable Methods of Birth Control for Female Subjects 
Birth control methods that are considered unacceptable in clinical trials include: 
 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
 
Withdrawal (coitus interruptus) 
 
Spermicides only 
 
Lactational amenorrhea method 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
 
Investigator will collect pregnancy information on any female subject who becomes 
pregnant while taking protocol-required therapies through 16 weeks after the last 
dose of investigational product. 
 
Information will be recorded on the Pregnancy Notification Form (see Figure 11-3).  
The form must be submitted to Amgen Global Patient Safety within 24 hours of 
learning of a subject’s pregnancy.  (Note: Sites are not required to provide any 
information on the Pregnancy Notification Form that violates the country or regions 
local privacy laws). 


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 
After obtaining the female subject’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy and infant 
health information and complete the pregnancy questionnaire for any female subject 
who becomes pregnant while taking protocol-required therapies through 16 weeks 
of the study drug.  This information will be forwarded to Amgen Global Patient 
Safety.  Generally, infant follow-up will be conducted up to 12 months after the birth 
of the child (if applicable). 
 
Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.  
 
While pregnancy itself is not considered to be an adverse event or serious adverse 
event, any pregnancy complication or report of a congenital anomaly or 
developmental delay, fetal death, or suspected adverse reactions in the neonate will 
be reported as an adverse event or serious adverse event.  Note that an elective 
termination with no information on a fetal congenital malformation or maternal 
complication is generally not considered an adverse event, but still must be reported 
to Amgen as a pregnancy exposure case. 
 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a serious adverse event. 
 
Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Section 11.4.  While the 
investigator is not obligated to actively seek this information in former study 
subjects, he or she may learn of a serious adverse event through spontaneous 
reporting.  
 
Any female subject who becomes pregnant while participating will discontinue study 
treatment (see Section 7.1 for details). 
Male Subjects With Partners Who Become Pregnant 
 
In the event a male subject fathers a child during treatment, and for an additional 
16 weeks after discontinuing protocol-required therapies, the information will be 
recorded on the Pregnancy Notification Form.  The form (see Figure 11-3) must be 
submitted to Amgen Global Patient Safety within 24 hours of the site’s awareness of 
the pregnancy.  (Note: Sites are not required to provide any information on the 
Pregnancy Notification Form that violates the country or regions local privacy laws). 
 
The investigator will attempt to obtain a signed authorization for release of 
pregnancy and infant health information directly from the pregnant female partner to 
obtain additional pregnancy information. 
 
After obtaining the female partner’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy outcome and 
infant health information on the pregnant partner and her baby and complete the 
pregnancy questionnaires.  This information will be forwarded to Amgen Global 
Patient Safety. 


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 
Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable).  
 
Any termination of the pregnancy will be reported to Amgen Global Patient Safety 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
Collection of Lactation Information 
 
Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 16 weeks after the last dose of 
investigational product. 
 
Information will be recorded on the Lactation Notification Form (see below) and 
submitted to Amgen Global Patient Safety within 24 hours of the investigator’s 
knowledge of event. 
 
Study treatment will be discontinued if female subject breastfeeds during the study 
as described in exclusion criterion 213. 
 
With the female subjects signed authorization for release of mother and infant 
health information, the investigator will collect mother and infant health information 
and complete the lactation questionnaire on any female subject who breastfeeds 
while taking protocol-required therapies through 16 weeks after discontinuing 
protocol-required therapies. 


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Figure 11-3.  Pregnancy and Lactation Notification Forms 
 


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11.6 
Appendix 6.  Sample Storage and Destruction 
Any blood (biomarker or pharmacogenetic) sample collected according to the Schedule 
of Activities (Table 1-1) can be analyzed for any of the tests outlined in the protocol and 
for any tests necessary to minimize risks to study subjects.  This includes testing to 
ensure analytical methods produce reliable and valid data throughout the course of the 
study.  This can also include, but is not limited to, investigation of unexpected results, 
incurred sample reanalysis, and analyses for method transfer and comparability. 
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality. 
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand 
migraines, the dose response and/or prediction of response to erenumab, and 
characterize aspects of the molecule (eg, mechanism of action/target, metabolites). 
Results from this analysis are to be documented and maintained, but are not necessarily 
reported as part of this study.  Samples can be retained for up to 20 years. 
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of pharmacogenetic, biomarker development or other 
exploratory studies are not placed in the subject’s medical record and are not to be 
made available to the subject, members of the family, the personal physician, or other 
third parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood samples and any other components from the cells can be located and destroyed. 
Samples will be destroyed once all protocol-defined procedures are completed.  
However, information collected from samples prior to the request for destruction, will be 
retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 


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longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  
See Section 11.3 for subject confidentiality. 


Product:  Erenumab 
Protocol Number:  20190008 
Date:  29 June 2022 
Page 1 of 9 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Superseded Amendment 1 
Protocol Title:  Comprehensive Assessment of Erenumab Efficacy in Subjects 
With High Frequency Episodic Migraine With at Least 1 Previously Failed 
Preventive Treatment:  a Global, Double blind, Placebo controlled Phase 4 Study 
 
Amgen Protocol Number:  Erenumab, 20190008 
EudraCT Number:  2019-003646-33 
 
Amendment Date: 
29 June 2022 
 
Rationale: 
This protocol is being amended to clarify terminology used in secondary endpoint within 
statistics section in the protocol. 
 


Product:  Erenumab 
Protocol Number:  20190008 
Date:  25 April 2022 
Page 1 of 48 
 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0   
 
Amendment 1 
Protocol Title: Comprehensive Assessment of Erenumab Efficacy in Subjects With 
High Frequency Episodic Migraine With at Least 1 Previously Failed Preventive 
Treatment:  a Global, Double blind, Placebo-controlled Phase 4 Study 
Amgen Protocol Number Erenumab 20190008 
EudraCT Number:  2019-003646-33 
 
Amendment Date: 
25 April 2022 
Rationale: 
This protocol is being amended to:  
 
Update the secondary and exploratory objectives and endpoints language in the 
objectives and endpoints sections 
 
Update overall design language to incorporate the qualifying oral triptan-treated 
migraine attack definition; to update the eligibility criteria for the end of the run-in 
period 
 
Update the key inclusion and exclusion criteria language of the summary of subject 
eligibility criteria in the synopsis  
 
Update schedule of activities (SoA) language in the following rows:  
Prior/concomitant therapies review, Serious adverse events, Urine pregnancy test, 
Urine drug testing, Pharmacogenetic studies, Episode (electronic diary) eDiary, 
Change in most troublesome symptom, and footnotes 
 
Update the Amgen investigational product background language for erenumab to 
clarify that the number of countries erenumab has been approved are over 
70-countries; to clarify that the recommended dose in most countries is 70 mg once 
monthly (QM), and 140 mg QM, as indicated, for some patients   
 
Update benefit/risk assessment section to clarify that immune system disorders, 
gastrointestinal disorders, and skin and subcutaneous tissue disorders have been 
observed in in postmarketing settings in addition to hypersensitivity reactions 
 
Update the number of North America and Europe investigative sites from 60 to 76 in 
the number of sites section 


Product:  Erenumab 
Protocol Number:  20190008 
Date:  25 April 2022 
Page 2 of 48 
 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0   
 
 
Remove the primary completion date definition in end of study definition section  
 
Update language in the Inclusion and exclusion criterion sections 
 
Update table 6-2 in Section 6.1.6 to notify that opioids and/or opioids containing 
analgesics of different acting formulations (ie, long acting or short acting), 
anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies, and cannabidiol 
(CBD)-containing products with systemic absorption are prohibited medications each 
with their respective time period for exclusion; to add a footnote to clarify that certain 
medications with migraine preventative effects, but are used for non-migraine 
indications, are allowed under restrictive use  
 
Update prior treatment language in Section 6.7.1 to clarify that prior migraine 
preventative medications containing CBD need to be discontinued 6 months before 
start of screening  
 
Add language in screening period section to clarify that a 2 week and 4 week run-in 
and baseline periods can’t be extended for more than 18 days and 35 days, 
respectively; similar language was used in the run-in period section  
 
Update the pain catastrophizing scale (PCS) language  
 
Update subgroup language to clarify that primary and secondary endpoints will be 
analyzed in the subgroups number of prior treatment failures, and in the medication 
overuse status at baseline  
 
Update the statistical analysis methods language for the primary, secondary, and 
exploratory endpoints in the efficacy analysis section 
 
Administrative and editorial changes (including grammatical, typographical, and 
formatting) have been made throughout the protocol. 
 

SAP_001.pdf: 
Product:  Erenumab (AMG 334) 
Protocol Number:  20190008 
Date:  15 November 2023 
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Statistical Analysis Plan 
Protocol Title: 
Comprehensive Assessment of Erenumab Efficacy in 
Subjects With High Frequency Episodic Migraine With at 
Least 1 Previously Failed Preventive Treatment: a 
Global, Double-blind, Placebo-controlled Phase 4 Study 
Short Protocol Title: 
Erenumab – Comprehensive Assessment of Efficacy in 
(High-Frequency) Episodic Migraine (EMBRACE) 
Protocol Number: 
20190008 
EudraCT Number: 
2019-003646-33 
Authors: 
 
Sponsor: 
Amgen, Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
SAP Date: 
Document Version 
Date 
Original (v1.0) 
08 March 2021 
Amendment 1 (v2.0) 
15 November 2023 
NCT Number: NCT04252742
This NCT number has been applied to the document 
for purposes of posting on Clinicaltrials.gov


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Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
08MAR2021 
NA 
Amendment 1 (v2.0) 
02NOV2023 
Section 1:  
 
updated the protocol version and date 
Section 2.1: 
 
updated the secondary and 
exploratory endpoints regarding 
duration of migraine attack to align 
with the latest protocol 
 
specified endpoints assessed for the 
first qualifying oral triptan-treated 
attack with complete data at 2-hour 
assessment 
 
added endpoints assessed for the first 
qualifying oral triptan-only-treated 
attack with complete data at 2-hour 
assessment 
Section 2.2: 
 
updated the primary clinical 
hypothesis to align with the latest 
protocol 
Section 3.1: 
 
updated the study design to align with 
the latest protocol 
Section 5.1.1: 
 
added Gepants and Ditans to acute 
headache medication 
 
updated the criteria of combination 
acute headache medication overuse 
 
updated the definition of migraine-free 
day 
 
updated the definition of diary day 
 
updated the definition of headache 
pain intensity (3-level) 
 
updated the definition of monthly 
migraine day 
 
updated the definition of monthly 
hours of at least moderate headache 
pain intensity 
 
updated the definition of monthly 
hours of at least moderate headache 
pain intensity of qualifying oral triptan 
treated migraine attacks 
 
updated the term to monthly average 
duration of at least moderate pain 
intensity in migraine attacks 


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 
added the definition of monthly 
average duration of at least moderate 
pain intensity in qualifying oral triptan 
treated migraine attacks 
Section 5.1.3: 
 
updated the definition of most 
troublesome symptom 
Section 5.5: 
 
added definition of on study 
Section 5.7: 
 
corrected the option in eCRF to 
adverse event 
Section 6.2: 
 
updated the definition of M-DBTP 
efficacy analyses set 
Section 5.1.3: 
 
corrected the PRO name to MIBS-4 
Section 9.6.2: 
 
updated sort order for adverse event 
tables 
Table 3-1: 
 
updated the hypothesis and footnote 
to align with the latest protocol 
Table 9-3:  
 
removed covariates in the endpoint 
achievement of pain freedom at 2 
hours post-triptan dose for the first 
attack at month 4 
 
added summary and analysis method 
for use of migraine rescue medication 
within 24 hours post-triptan dose for 
the first attack at month 4 
 
added summary and analysis method 
for change from baseline in the most 
troublesome symptom at month 3 in 
footnote c 
 
removed use of migraine rescue 
medication within 24 hours 
post-triptan dose for the first attack at 
month 4 in footnote d 
 


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Table of Contents  
1. 
Introduction ............................................................................................................. 7 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 7 
2.1 
Objectives and Endpoints ............................................................................ 7 
2.2 
Hypotheses and/or Estimations ................................................................... 9 
3. 
Study Overview .................................................................................................... 10 
3.1 
Study Design ............................................................................................. 10 
3.2 
Sample Size .............................................................................................. 10 
4. 
Covariates and Subgroups ................................................................................... 11 
4.1 
Planned Covariates ................................................................................... 11 
4.2 
Subgroups ................................................................................................. 12 
5. 
Definitions ............................................................................................................. 12 
5.1 
Definition of Terms Included in Study Endpoints ....................................... 12 
5.1.1 
Efficacy Endpoints Based on Daily Diary Data 
Collection During M-DBTP ........................................................ 12 
5.1.2 
Efficacy Endpoints Based on Episodic Diary Data 
Collection During E-DBTP ......................................................... 17 
5.1.3 
Efficacy Endpoints Based on Monthly Data Collection ............... 19 
5.1.4 
Safety Endpoints ....................................................................... 20 
5.2 
Study Dates .............................................................................................. 21 
5.3 
Study Points of Reference ......................................................................... 21 
5.4 
Study Time Intervals ................................................................................. 22 
5.4.1 
Monthly Intervals for Efficacy Endpoints Derived From 
Daily Diary Collection ................................................................ 22 
5.4.2 
Monthly Interval for Efficacy Endpoints Derived From 
Episodic Diary Collection ........................................................... 23 
5.4.3 
Analysis Visits for Endpoints Derived Based on 
Monthly Data Collection ............................................................ 23 
5.5 
Subject Disposition .................................................................................... 24 
5.6 
Arithmetic Calculations .............................................................................. 25 
5.7 
Disease Characteristics ............................................................................. 25 
6. 
Analysis Sets ........................................................................................................ 26 
6.1 
Full Analysis Set........................................................................................ 26 
6.2 
M-DBTP Efficacy Analyses Set ................................................................. 26 
6.3 
E-DBTP Efficacy Analysis Set  .................................................................. 26 
6.4 
Safety Analysis Set ................................................................................... 26 
7. 
Planned Analyses ................................................................................................. 26 
8. 
Data Screening and Acceptance ........................................................................... 26 
8.1 
General Principles ..................................................................................... 26 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 27 


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8.3 
Handling of Missing and Incomplete Data ................................................. 27 
8.4 
Detection of Bias ....................................................................................... 28 
8.5 
Outliers ..................................................................................................... 28 
8.6 
Distributional Characteristics ..................................................................... 29 
8.7 
Validation of Statistical Analyses ............................................................... 29 
9. 
Statistical Methods of Analysis.............................................................................. 29 
9.1 
General Considerations ............................................................................. 29 
9.2 
Subject Accountability ............................................................................... 30 
9.3 
Important Protocol Deviations ................................................................... 30 
9.4 
Demographic and Baseline Characteristics ............................................... 30 
9.5 
Efficacy Analyses ...................................................................................... 31 
9.5.1 
Analyses of Primary and Secondary Efficacy 
Endpoints  ................................................................................. 34 
9.5.2 
M-DBTP Analyses of Exploratory Efficacy Endpoints ................ 35 
9.5.3 
E-DBTP Analyses of Exploratory Efficacy Endpoints ................. 35 
9.6 
Safety Analyses ........................................................................................ 36 
9.6.1 
Analyses of Safety Endpoints .................................................... 36 
9.6.2 
Adverse Events ......................................................................... 36 
9.6.3 
Exposure to Investigational Product .......................................... 37 
9.6.4 
Exposure to Concomitant Medication ........................................ 37 
9.7 
Other Analyses ......................................................................................... 37 
10. 
Changes From Protocol-specified Analyses.......................................................... 37 
11. 
Literature Citations / References ........................................................................... 38 
12. 
Data Not Covered by This Plan............................................................................. 38 
13. 
Appendices ........................................................................................................... 39 
 
List of Tables 
Table 5-1.  Monthly Intervals for Efficacy Endpoints Derived From Daily Diary 
Data Collection ....................................................................................... 23 
Table 5-2.  Monthly Interval for Efficacy Endpoints Derived From Episodic 
Diary Data .............................................................................................. 23 
Table 5-3.  MIBS-4 Analysis Visit Windows ................................................................... 24 
Table 5-4.  MFIQ, MSSS and HIT-6 Analysis Visit Windows .......................................... 24 
Table 5-5.  PGI-S, MTS and PCS Analysis Visit Windows ............................................. 24 
Table 9-1.  Primary Efficacy Endpoint Summary Table .................................................. 32 
Table 9-2.  Secondary Efficacy Endpoint Summary Table ............................................. 32 
Table 9-3.  Exploratory Efficacy Endpoint Summary Table ............................................ 33 
 


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List of Appendices 
Appendix A.  Reference Values/Toxicity Grades ........................................................... 40 
 


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List of Abbreviations 
 
Abbreviation 
Explanation 
ANCOVA 
Analysis of covariance 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CI 
Confidence Interval 
DBTP 
Double-blind treatment period 
E-DBTP 
Exploratory double-blind treatment period 
EAS 
Efficacy analysis set 
eDiary 
Electronic diary 
EM 
Episodic migraine 
FAS 
Full analysis set 
HFEM 
High-frequency episodic migraine 
HIT-6 
Headache Impact Test-6 
ICH 
International Council for Harmonisation 
IP 
Investigational product 
LSM 
Least squares mean 
M-DBTP 
Main double-blind treatment phase 
MFIQ 
Migraine Functional Impact Questionnaire 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIBS-4 
4-item Migraine Interictal Burden Scale 
MMD 
Monthly migraine day 
MO 
Medication overuse 
MTS 
Most troublesome symptom 
MSSS 
Migraine Symptom Severity Score 
NCT 
National Clinical Trials 
NRS 
Numeric Rating Scale 
PCS 
Pain Catastrophizing Scale 
PGI-S 
Patient Global Impression of Severity 
Q4W 
Every 4 weeks 
SAP 
Statistical analysis plan 
SAS 
Safety analysis set 
 


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1. 
Introduction  
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol superseded amendment 1 for 
study 20190008, Erenumab (AMG 334) dated 29 June 2022. The scope of this plan 
includes the primary analysis that is planned and will be executed by the Amgen Global 
Biostatistical Science department unless otherwise specified. 
2. 
Objectives, Endpoints and Hypotheses  
2.1 
Objectives and Endpoints  
 
Objectives 
Endpoints 
Primary 
 
To evaluate the treatment benefit 
of erenumab on headache 
duration of at least moderate pain 
intensity 
 
Change from baseline in mean 
monthly hours of at least 
moderate headache pain intensity 
over months 1, 2, and 3 
Secondary 
 
To evaluate the treatment benefit 
of erenumab on functional 
impairment 
 
Change from baseline in mean 
monthly function domain score as 
measured by the Migraine 
Functional Impact Questionnaire 
(MFIQ) over months 1, 2, and 3: 
      − Impact on physical functioning 
      − Impact on usual activities 
      − Impact on emotional functioning 
            − Impact on social functioning 
 
To evaluate the treatment benefit 
of erenumab on duration of 
migraine pain of at least moderate 
intensity 
 
Change from baseline in mean 
monthly average duration of at 
least moderate pain intensity in 
migraine attacks occurring over 
months 1, 2, and 3 
 
To evaluate the treatment benefit 
of erenumab on peak migraine 
pain intensity 
 
Change from baseline in mean 
monthly average peak migraine 
pain intensity as assessed by the 
11-point Numeric Rating Scale 
(NRS) over months 1, 2, and 3 
 
Exploratory 
 
Main Double-blind Treatment Period (month 1 to 3) 
 
To evaluate the treatment benefit 
of erenumab on duration of oral 
triptan-treated migraine attacks 
 
Change from baseline in mean 
monthly hours of at least 
moderate pain intensity for 
qualifying oral triptan-treated 


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migraine attacks over months 1, 
2, and 3 
 
To evaluate the treatment 
benefit of erenumab on duration 
of migraine pain of at least 
moderate intensity for oral 
triptan-treated migraine attacks 
 
Change from baseline in mean 
monthly average duration of at 
least moderate pain intensity in 
qualifying oral triptan-treated 
migraine attacks occurring 
over months 1, 2, and 3 
 
To evaluate the treatment benefit 
of erenumab on migraine 
symptoms 
 
Change from baseline in Migraine 
Symptom Severity Score (MSSS) 
total score at assessment time 
points 
 
Change from baseline in the most 
troublesome symptom (MTS) at 
month 3 
 
Change in Patient Global 
Impression of Severity (PGI-S) 
total score at month 3 
 
Change from baseline in mean 
monthly total migraine freedom 
days over months 1, 2, and 3 
 
To evaluate the treatment benefit 
of erenumab on interictal burden of 
migraine 
 
Change from baseline in Migraine 
Interictal Burden Scale (MIBS-4) 
total score at assessment time 
points 
 
Achievement of no or mild 
interictal burden as measured by 
the MIBS-4 at assessment time 
points 
 
To evaluate the treatment benefit 
of erenumab on functional 
impairment 
 
Change from baseline in 
headache impact scores as 
measured by the Headache 
Impact Test (HIT-6) total score at 
assessment time points 
 
Change from baseline in physical 
function domain score as 
measured by MFIQ at 
assessment time points 
 
Change from baseline in usual 
activities domain score as 
measured by MFIQ at 
assessment time points 
 
Change from baseline in social 
function domain as measured by 
MFIQ at assessment time points 
 
Change from baseline in 
emotional function domain score 
as measured by MFIQ at 
assessment time points 
 
Change from baseline in overall 
impact on usual activities global 


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item score as measured by MFIQ 
at assessment time points 
 
To evaluate the treatment benefit 
of erenumab on headache-related 
cognitions and beliefs 
 
Change from baseline in pain 
catastrophizing as measured by 
the Pain Catastrophizing Scale 
(PCS) at month 3 
 
To evaluate the treatment benefit 
of erenumab on monthly migraine 
days (MMD) 
 
Change from baseline in mean 
MMD over months 1, 2, and 3 
Following 2 endpoints will be calculated from months with at least 1 migraine 
attack 
 
To evaluate the treatment 
benefit of erenumab on duration 
of migraine pain of at least 
moderate intensity with at least 
1 migraine attack 
 
Change from baseline in mean 
monthly average duration of at 
least moderate pain intensity 
per migraine attack occurring 
over months 1, 2, and 3 
 
To evaluate the treatment 
benefit of erenumab on peak 
migraine pain intensity with at 
least 1 migraine attack 
 
Change from baseline in mean 
monthly average peak migraine 
pain intensity as assessed by 
the 11-point Numeric Rating 
Scale (NRS) over months 1, 2, 
and 3 
Exploratory Double-blind Treatment Phase (month 4) 
 
To evaluate the treatment benefit 
of erenumab on interictal burden of 
migraine 
 
Change from baseline in Migraine 
Interictal Burden Scale (MIBS-4) 
total score at month 4 
For the first qualifying oral triptan-treated attack with complete data at 2-hour 
assessment: 
 
To evaluate the treatment benefit 
of erenumab on achieving and 
sustaining pain freedom following 
treatment with an oral triptan 
 
Achievement of pain freedom at 2 
hours post-triptan dose for the 
first attack at month 4 
 
Achievement of 24-hour 
sustained pain freedom 
post-triptan dose for the first 
attack at month 4 
 
Achievement of pain freedom at 
30 and 60 minutes post-triptan 
dose for the first attack at month 4 
 
To evaluate the treatment benefit 
of erenumab on achieving pain 
relief following treatment with an 
oral triptan 
 
Achievement of pain relief at 30, 
60, and 120 minutes post-triptan 
dose for the first attack at month 4 
 
To evaluate the treatment benefit 
of erenumab on achieving freedom 
from the most bothersome 
symptom following treatment with 
an oral triptan 
 
Achievement of freedom from the 
most bothersome symptom at 30, 
60, and 120 minutes post-triptan 
dose for the first attack at month 4 
 
To evaluate the treatment benefit 
of erenumab on achieving relief 
from the most bothersome 
 
Achievement of relief from the 
most bothersome symptom at 30, 


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symptom following treatment with 
an oral triptan 
60, and 120 minutes post-triptan 
dose for the first attack at month 4 
 
To evaluate the treatment benefit 
of erenumab on migraine 
recurrence following treatment with 
an oral triptan 
 
Migraine recurrence within 24 
hours post-triptan dose for the 
first attack at month 4 
 
To evaluate the treatment benefit 
of erenumab on use of migraine 
rescue medication following 
treatment with an oral triptan 
 
Use of migraine rescue 
medication within 24 hours 
post-triptan dose for the first 
attack at month 4 
For the first qualifying oral triptan-only-treated attack with complete data at 
2-hour assessment: 
 
To evaluate the treatment 
benefit of erenumab on 
achieving and sustaining pain 
freedom following treatment 
with oral triptan only 
 
Achievement of pain freedom 
at 30, 60, and 120 minutes post-
triptan dose for the first triptan-
only-treated attack in which 
complete data is obtained (at 
least 2 hours timepoint) at 
month 4 
 
To evaluate the treatment 
benefit of erenumab on 
achieving pain relief following 
treatment with oral triptan only 
 
Achievement of pain relief at 
30, 60, and 120 minutes post-
triptan dose for the first triptan-
only-treated attack at month 4 
 
To evaluate the treatment 
benefit of erenumab on 
achieving freedom from the 
most bothersome symptom 
following treatment with oral 
triptan only 
 
Achievement of freedom from 
the most bothersome symptom 
at 30, 60, and 120 minutes post-
triptan dose for the first triptan-
only-treated attack at month 4 
 
To evaluate the treatment 
benefit of erenumab on 
achieving relief from the most 
bothersome symptom following 
treatment with oral triptan only 
 
Achievement of relief from the 
most bothersome symptom at 
30, 60, and 120 minutes post-
triptan dose for the first triptan-
only-treated attack at month 4 
 
2.2 
Hypotheses and/or Estimations  
The primary clinical hypothesis is that preventive treatment with monthly administration 
of erenumab is superior to placebo in reducing duration of moderate or severe 
headache pain in subjects with high-frequency episodic migraine (HFEM) who have 
previously failed at least 1 migraine preventive treatment. 
3. 
Study Overview  
3.1 
Study Design  
Study 20190008 is a phase 4, interventional, prospective, double-blind, randomized, 
placebo-controlled, multicenter global study, evaluating the effects of erenumab on 


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aspects of migraine beyond MMD reduction in adult subjects with high-frequency 
episodic migraine (HFEM) who have previously failed at least 1 preventive treatment. 
Subjects who meet eligibility criteria will be enrolled in a run-in period (2 weeks in 
duration) during which they will record oral triptan-treated migraine attacks in an episode 
electronic diary (eDiary). At the end of the run-in period, subjects will be eligible to 
enter the 4-week baseline period only if they have 1 or more qualifying oral 
triptan-treated migraine attacks (defined as migraine attacks of at least moderate 
peak pain intensity that are treated with an oral triptan within 2 hours of pain 
reaching at least moderate severity) and if pain freedom is not achieved within 
1 hour following oral triptan intake for > 50% of their qualifying migraine attacks. 
During the baseline period subjects will keep a daily eDiary. At the end of the baseline 
period, subjects who meet specific eligibility criteria will be able to enter the double-blind 
treatment period (DBTP). 
The 4-month DBTP has 2 phases: 
 
Main DBTP (M-DBTP, months 1-3) that will assess the effect of erenumab on 
metrics such as time spent in at least moderate pain, peak migraine severity, and 
functional impairment 
 
Exploratory DBTP (E-DBTP, month 4) that will assess the impact of erenumab on 
the acute response to treatment with oral triptans therapy as well as non-ictal 
burden 
Throughout both phases of the DBTP, investigational product will be administered every 
4 weeks (Q4W). Data entry will follow a daily eDiary collection during the M-DBTP and 
transition to an episode eDiary during the E-DBTP. 
3.2 
Sample Size  
A total sample size of 576 subjects (288 subjects per group including 10% dropouts) 
provides at least a 90% power for the primary efficacy hypothesis. The statistical power 
for secondary efficacy hypotheses ranges from 81% to > 99% (Table 3-1). 
Table 3-1. Sample Size Assumptions and Statistical Powers for Primary and 
Secondary Efficacy Endpoints for a Total Sample Size of 576 Subjects  
Including a 10% Attrition Rate due to Dropout 
Hypothesis 
Assumed 
Treatment 
Effect 
Power 


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(Common SD) 
Primary: 
Change from baseline in mean monthly hours of at 
least moderate headache pain intensity over months 
1, 2, and 3 
-16.7 (50) 
96% 
Secondary: Change from baseline in mean monthly 
MFIQ physical function domain score over months 
1, 2, and 3 
-9.2 (18.0) 
> 99% 
MFIQ usual activities domain score over months 1, 
2, and 3 
-7.5 (19) 
> 99% 
MFIQ emotional function domain score over months 
1, 2, and 3 
-11.5 (22) 
> 99% 
MFIQ social function domain score over months 1, 
2, and 3 
-6.9 (20) 
97% 
Average duration of at least moderate migraine pain 
intensity in migraine attacks occurring over 
months 1, 2, and 3a 
-2.0 (8) 
81% 
Average peak migraine pain intensity over months 1, 
2, and 3 
-0.11 (0.44) 
81% 
MFIQ = Migraine Functional Impact Questionnaire 
Note: All power calculations are based on a 2-sided significance level of 0.05. The assumed treatment 
effects and common standard deviations are derived or chosen from a subset of placebo-treated and 
erenumab-140mg-treated subjects in erenumab Study 20120296 with high-frequency episodic migraine 
(ie, 7 to 14 monthly migraine days) and having at least 4 moderate-to-severe migraine attacks at baseline. 
a If a subject did not have any migraine attacks in a given month, the duration of at least moderate migraine 
pain intensity was counted as 0. 
4. 
Covariates and Subgroups  
4.1 
Planned Covariates  
For efficacy endpoints of the M-DBTP, all model-adjusted analyses of efficacy endpoints 
will include the corresponding baseline value for the endpoint being analyzed. The 
baseline value is calculated based on data collected during the 4-week baseline period 
or on day 1 prior to the first dose. 
For pain freedom and pain relief related efficacy endpoints of the E-DBTP (month 4), the 
following covariates may be considered: 
 
Medication overuse status at month 3 (yes vs no)  


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 
Time to triptan intake since reaching moderate/severe pain of the first qualifying 
attack at month 4 (< 1 hour vs ≥ 1 hour) 
 
Pain intensity prior to triptan intake is severe (yes [NRS ≥ 7] vs no) of the first 
qualifying attack at month 4  
For most bothersome symptom related endpoints of the E-DBTP, the following symptom 
types may be included in the model: 
 
Nausea/Vomiting (yes vs no) 
 
Photophobia/phonophobia (yes vs no) 
4.2 
Subgroups  
The primary and secondary endpoints of the M-DBTP will be analyzed in the following 
subgroups:  
 
Number of prior treatment failures (1, 2, and 3 or more treatment failures) 
 
Medication overuse status at baseline (yes vs. no) 
Selected exploratory endpoints of the E-DBTP for the first qualifying triptan-treated 
attack may be analyzed by medication overuse status at month 3 (yes vs. no) (see 
Section 9.5.3). 
The subgroups will be re-examined for appropriateness and may be re-categorized (due 
to small sample size, for example, if there are < 10% of subjects within a subgroup) 
before unblinding. 
5. 
Definitions  
5.1 
Definition of Terms Included in Study Endpoints  
5.1.1 
Efficacy Endpoints Based on Daily Diary Data Collection During 
M-DBTP  
During the 4-week baseline period and the 12-week M-DBTP, headache start and stop 
date/time, pain feature/symptoms, acute headache medication and aura related 
information will be reported on a daily basis via optional any-time diar(ies) (available 24 
hours) and mandatory evening diary (only available once daily from 17:00 to 23:59). 
Acute Headache Medication (AHM) 
Acute headache medications collected in the eDiary are classified separately as follows: 
 
Medication Group A 
Acute headache medication 
(AHM) 
Ergotamine-Based Migraine Medications  
Triptan-Based Migraine Medications  
Gepant-Based Migraine Medications 
Ditan-Based Migraine Medications 


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Non-Opioid Acute Headache Medications 
Non-Opioid Butalbital Containing Medications  
Opioid-Containing Acute Headache Medications  
Opioid-Containing Butalbital Containing Medications  
 
 
Medication Group B 
Acute headache medication 
(AHM) 
Ergots 
Triptans 
Gepants 
Ditans 
Opiate or opioid-containing medication 
Opioid Combination-analgesic 
Non-opioid Combination-analgesic 
Simple analgesics/NSAIDs 
 
Acute Migraine-specific Medication (AMSM) 
A subset of acute headache medication consisting of triptan-based migraine medications 
and ergotamine-based migraine medications 
Medication Overuse (MO)  
Monthly acute headache medication days meeting at least one of the following criteria 
based on medication category B: 
 
≥ 10 days of triptans 
 
≥ 10 days of ergotamines 
 
≥ 10 days of opiates or opioid-containing medications or opioid 
combination-analgesics 
 
≥ 10 days of non-opioid combination-analgesics 
 
≥ 15 days of simple analgesics/NSAIDs if no other acute headache medications were 
used 
 
≥ 10 days of a combination of triptans, ergotamines, opiates or opioid-containing 
meds or opioid combination-analgesic, non-opioid combination-analgesic 
medications or simple analgesics/NSAIDs whilst not satisfying medication 
overuse criteria in any of the individual medication categories alone 


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Number of Diary 
Days  
in a Monthly Interval 
Monthly Days with Medication Use 
 
≥ 14 days 
Prorate to 28-day equivalent without rounding 
Number of observed days with medication use*28/number of 
(diary days or medication days) within each monthly interval 
 
 
 
< 14 days 
Set to missing 
Qualified Headache  
A qualified headache is defined as 
 
A headache of duration ≥ 30 minutes, or 
 
A headache with acute headache medications (migraine-specific or not) taken 
during the headache (start time and end time inclusive) with any length of 
duration, or 
 
An aura during which an acute migraine-specific medication is administered 
Headache Day 
A calendar day (00:00 to 23:59) in which the subject experiences ≥ 1 qualified headache 
Qualified Migraine Headache 
A qualified migraine headache should meet at least one of the following criteria: 
 
A headache of duration ≥ 30 minutes, and meeting ≥ 1 of the following criteria (a 
and/or b): 
a) ≥ 2 of the following pain features: 
 
Unilateral 
 
Throbbing 
 
Moderate to severe (based on the 3-level categorical pain severity) 
 
Exacerbated with exercise/physical activity 
b) ≥ 1 of the following associated symptoms: 
 
Nausea 
 
Vomiting 
 
Photophobia and phonophobia 
 
A headache during which an acute migraine-specific medication is administered 
regardless of the headache duration, pain features, and associated symptoms 
 
An aura during which an acute migraine-specific medication is administered 
Migraine Day 
A calendar day (00:00 to 23:59) in which the subject experiences ≥ 1 qualified migraine 
headache 


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Migraine-free Day 
A calendar day (00:00 to 23:59) of a diary day in which the subject does not experience 
any headache and aura, photophobia, phonophobia, and nausea/vomiting, and does 
not take any acute headache medication 
Diary Day 
A calendar day (00:00 to 23:59) with complete headache, aura, and acute headache 
medication data recorded via daily evening diary 
Information Day 
A calendar day (00:00 to 23:59) which is either a headache day or a diary day 
Migraine Attack in M-DBTP 
A migraine attack is an episode of any qualified migraine headache. The following rules 
will be used to distinguish an attack of long duration from 2 attacks, or to distinguish 
between attacks and relapses: 
 
A migraine attack that is interrupted by sleep, or temporarily remits, and then recurs 
within 48 hours (recurrence time – headache start time ≤ 48 hours) will be counted 
as 1 attack 
 
An attack treated successfully with medication but with relapse within 48 hours 
(recurrence time – headache start time ≤ 48 hours) will be counted as 1 attack 
Triptan-treated Migraine Attack in M-DBTP 
A migraine attack with triptan taken during the attack (start time and end time inclusive) 
Headache Pain Intensity (evaluated by NRS) in M-DBTP 
Worst or peak pain intensity collected on a headache ranges from 0 to 10 with a higher 
score indicating more severe pain. 
Pain intensity is reported when the headache end time is reported or in an evening diary 
on a daily basis for an ongoing headache. Therefore, there can be multiple pain intensity 
values reported for a headache that lasts for multiple days. In some circumstances, a 
headache which starts and ends on the same day may also have up to 2 pain intensity 
values reported when the headache ends after evening diary completion: 1) pain 
intensity is reported in the evening diary for the period between headache start time and 
diary completion time; 2) pain intensity is reported either in any-time diary or the next 
day’s evening diary for the period between previous diary completion time and headache 
end time. The NRS headache pain intensity will be used to assess the monthly average 
peak pain intensity. 


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Headache Pain Intensity (3-level) 
Worst or peak pain intensity collected on a headache in 3 levels (mild, moderate or 
severe) followed by the NRS pain intensity question when the preceding NRS headache 
pain intensity is reported to be ≥ 4, worst or peak pain intensity (3 levels) is set as 
mild if NRS headache pain intensity is reported to be <4. 
Duration of Headache With at Least Moderate Pain Intensity 
Duration of headache with at least moderate pain intensity (in hours and minutes) will be 
collected only when “Moderate” or “Severe” intensity is reported based on the 3-level 
headache pain intensity scale. 
Monthly Migraine Days (MMD) 
Number of migraine days during one monthly interval as defined below. 
Number of Diary Days  
in a Monthly Interval 
Monthly Migraine Days 
 
≥ 14 days 
Prorate to 28-day equivalent without rounding 
Number of observed migraine days*28/number of (diary days or 
migraine days) within each monthly interval 
 
 
 
< 14 days 
Set to missing 
Monthly Headache Days (MHD) 
Number of headache days during one monthly interval as defined below. 


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Number of Diary Days  
in a Monthly Interval 
Monthly Headache Days 
 
≥ 14 days 
Prorate to 28-day equivalent without rounding 
Number of observed headache days*28/number of information 
days 
 
Note:  An information day is either a headache day or a diary day. 
 
< 14 days 
Set to missing 
Monthly Hours of at Least Moderate Headache Pain Intensity 
Number of Diary Days  
in a Monthly Interval 
Monthly Hours of at Least Moderate Headache Pain 
Intensity 
 
≥ 14 days 
Prorate to 28-day equivalent without rounding 
Sum of hours of headaches with at least moderate pain intensity 
*28/number of (diary days or days with headache pain intensity) 
within each monthly interval 
 
< 14 days 
Set to missing 
Monthly Hours of at Least Moderate Headache Pain Intensity of Qualifying Oral 
Triptan Treated Migraine Attacks 
Number of Diary Days 
in a Monthly Interval 
Monthly Hours of at Least Moderate Headache Pain 
Intensity of Qualifying Oral Triptan Treated Migraine 
Attacks 
 
≥ 14 days 
Prorate to 28-day equivalent without rounding 
Sum of hours of at least moderate pain intensity of qualifying oral 
triptan treated migraine attacks *28/number of (diary days or 
migraine days) within each monthly interval 
 
< 14 days 
Set to missing 
Monthly Average Duration of at Least Moderate Pain Intensity in Migraine Attacks 
Number of Diary Days 
in a Monthly Interval 
Monthly Average Duration of at Least Moderate Pain 
Intensity in Migraine Attacks 
 
≥ 14 days 
Sum of all the reported duration with at least moderate headache 
pain intensity within an attack divided by number of attacks in each 
month 
If there is no migraine during the monthly interval, then the monthly 
average duration will be set to 0. 
 
< 14 days 
Set to missing 
Monthly Average Duration of at Least Moderate Pain Intensity in Qualifying Oral 
Triptan Treated Migraine Attacks 


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Number of Diary 
Days in a Monthly 
Interval 
Monthly Average Duration of at Least Moderate Pain 
Intensity in Qualifying Oral Triptan Treated Migraine 
Attacks 
 
≥ 14 days 
Sum of all the reported duration with at least moderate headache 
pain intensity within a qualifying oral triptan-treated attack 
divided by number of qualifying oral triptan-treated attacks in 
each month; 
If there is no migraine during the monthly interval, then the 
monthly average duration will be set to 0. 
 
< 14 days 
Set to missing 
Monthly Average Peak Migraine Pain Intensity 
Number of Diary Days 
in a Monthly Interval 
Monthly Average Peak Migraine Pain Intensity 
 
≥ 14 days 
Sum of observed highest pain intensity scores (NRS) per migraine 
day divided by total number of migraine days with at least one 
measure of NRS; 
If there is no migraine day with NRS during the monthly interval, then 
the monthly average peak migraine pain intensity will be set to 0. 
 
< 14 days 
Set to missing 
 
5.1.2 
Efficacy Endpoints Based on Episodic Diary Data Collection During 
E-DBTP  
During the 2-week run-in period and the 1-month E-DBTP at month 4, subjects 
experiencing a qualified triptan-treated migraine attack will report medication usage, pain 
intensity, the most bothersome symptom and corresponding severity using the episodic 
diary. A qualifying headache for reporting is a headache reaching at least moderate pain 
intensity with initial triptan intake within 2 hours and also satisfying migraine headache 
criteria (ie, a qualified triptan-treated migraine attack).  The initial triptan intake time (ie, 
time point 0) will trigger a 48-hour assessment window, during which the headache pain 
intensity, severity of the most bothersome symptom at 30, 60 and 120 minutes, 24 hours 
and 48 hours post triptan will be collected. Another 48-hour assessment window will be 
triggered if there is a new qualified triptan-treated migraine attack starts after the 
previous assessment window. 
Headache Pain Intensity (NRS) in E-DBTP 
Worst or peak pain intensity collected on a headache ranges from 0 to 10 with a higher 
score indicating more severe pain. 


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NRS Pain intensity is collected when a qualified headache reaching at least moderate 
pain intensity with triptan intake within 2 hours and for the following timed assessments 
at 30 minutes, 1-hour, 2-hour, 24-hour and 48-hour diaries.   
Migraine Rescue Medication  
Migraine rescue medication for each qualifying triptan-treated attack is defined as any 
additional acute headache medication(s) taken during the 48-hour assessment window.  
Migraine Recurrence Within 24 Hours Post-triptan  
Pain intensity NRS = 0 at any of the 30-minute, 60-minute, and 2-hour timed 
assessments and pain intensity NRS ≥ 4 at 24-hour timed assessment 
Pain Relief at timed assessment post-triptan dose  
Pain intensity NRS < 4 at the specific timed assessment (eg, 30 minutes, 60 minutes, or 
2 hours post-triptan dose). 
Pain freedom at timed assessment post-triptan dose  
Pain intensity NRS = 0 at the specific timed assessment (eg, 30 minutes, 60 minutes or 
2 hours post-triptan dose). 
Achievement of 24-hour sustained pain freedom post-triptan dose  
Pain intensity NRS = 0 at both 2-hour and 24-hour timed assessment without rescue 
medication taken post-triptan dose. 
Most Bothersome Symptom 
The most bothersome symptom can be selected among nausea, vomiting, sensitivity to 
light, or sensitivity to sound. 
Severity of Most Bothersome Symptom (4-level) 
Worst or peak severity collected on the most bothersome symptom according to 4 levels 
(none, mild, moderate or severe) 
Achievement of freedom from the most bothersome symptom at timed 
assessment post-triptan dose  
Symptom severity = none at the specific timed assessment (eg, 30 minutes, 60 minutes 
or 2 hours post-triptan dose). 
Achievement of relief from the most bothersome symptom at timed assessment 
post-triptan dose  
Reduction in symptom severity by at least one level down (eg, from severe to moderate, 
mild to none) at the specific timed assessment (eg, 30 minutes, 60 minutes or 2 hours 
post-triptan dose). 


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5.1.3 
Efficacy Endpoints Based on Monthly Data Collection  
Migraine Functional Impact Questionnaire (MFIQ)  
The MFIQ version 2.0 is a self-administered 26-item instrument measuring the impact of 
migraine on broader functioning including 4 domains: Impact on Physical Functioning 
(5 items), Impact on Usual Activities (10 items), Impact on Social Functioning (5 items), 
and Impact on Emotional Functioning (5 items). In addition, there is 1 stand-alone global 
item assessing the overall impact on usual activities. Subjects respond to items using a 
5-point scale assigned scores from 1 to 5, with 5 representing the greatest burden. Each 
domain score will be calculated as the sum of the item responses and the sum will be 
rescaled to a 0 to 100 scale, with higher scores representing greater burden.  The recall 
period is the past 7 days and will be collected monthly at day 1, weeks 4, 8 and 12. 
Migraine Symptom Severity Scale (MSSS) 
The MSSS is a 7-item questionnaire that assesses frequency of pain and other 
symptoms associated with migraines. Responses are as follows: “never”, “rarely”, “less 
than half the time”, “half the time or more”, and “all or nearly all of the time”. The 
responses are given a value from 0 to 3: Never = 0, Rarely = 1, Less Than Half the 
Time = 2, Half the Time or More = 3, and All or Nearly All of the Time = 3. The MSSS 
score is the sum of the responses to the 7 items with a range from 0 to 21. MSSS will be 
collected monthly at day 1, weeks 4, 8 and 12. 
Most Troublesome Symptom (MTS) 
The MTS will be measured by 5 questions on day 1 and the change in the MTS will be 
assessed by 2 questions at week 12. The baseline questions will be asking the subjects 
to select the most troublesome symptom during and/or between migraine headache 
attacks and to rate how often they experience the symptoms. The week 12 questions will 
be asking the subjects to rate how their previously identified most troublesome symptom 
during and/or between migraine headache attacks have changed since the start of the 
study on a scale of 1 (Very Much Improved) to 7 (Very Much Worse). Achieving 1 = Very 
Much Improved or 2 = Much Improved is considered as meaningful improvement. 
Only subjects with non-missing baseline will be considered in the analysis. As per 
questionnaire design, if a subject answer ‘No’ for question 3 at baseline, subject 
will not be considered for between migraine headache attacks analysis. 
 


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Patient Global Impression of Severity (PGI-S) 
The PGI-S is a single question that rates the severity of the subject’s condition at the 
time of assessment. It is a 7-point scale that ranks severity of illness using one of the 
following response categories: 1 = Normal, not at all ill, 2 = Borderline ill, 3 = Mildly ill; 
4 = Moderately ill, 5 = Markedly ill, 6 = Severely ill, and 7 = Most extremely ill.  PGI-S will 
be collected at day 1 and week 12. 
Migraine Interictal Burden Scale (MIBS-4) 
The MIBS-4 measures interictal migraine-related burden with 4 questions that assess 
impairment in work or school, impairment in family and social life, difficulty making plans 
or commitments, and emotional/affective and cognitive distress. Each of the 4 questions 
is responded to using 1 of 6 response categories: “Don’t know/NA” (Score = 0), “Never” 
(Score = 0), “Rarely” (Score = 1), “Some of the time” (Score = 2), “Much of the time” 
(Score = 3) or “Most or all of the time” (Score = 3). Response to each question is 
summed up to produce total score ranges from 0 to 12. The MIBS-4 total scores are 
categorized into 4 level of interictal burden: None (0), Mild (1 to 2), Moderate (3 to 4) and 
Severe (5 or higher). MIBS-4 will be collected monthly at day 1, weeks 4, 8, 12 and 16. 
Headache Impact Test (HIT-6) 
The scoring of the HIT-6 total score will be performed using the QualityMetric’s PRO 
CoRE Scoring Software. The HIT-6 total scores ranging from 36 to 78 can be 
categorized into 4 grades, representing little or no impact (49 or less), some impact (50 
to 55), substantial impact (56 to 59), and severe impact (60 to 78) due to headache. 
HIT-6 will be collected monthly at day 1, weeks 4, 8 and 12. 
Pain Catastrophizing Scale (PCS) 
The PCS is a 13-item self-report measure consists of 3 subscales, which are Rumination 
(4 items), Magnification (3 items), and Helplessness (6 items). For each item, subjects 
are requested to provide a response in a 5-point Likert scale (0 “not at all,” 1 “to a slight 
degree,” 2 “to a moderate degree,” 3 “to a great degree,” 4 “all the time”). Higher scores 
in PCS indicate higher levels of catastrophizing. Response to each item is summed up to 
get the total score ranging from 0 to 52. PCS will be collected at day 1 and week 12. 
5.1.4 
Safety Endpoints  
Serious Adverse Event (SAE) 
An event categorized as “Adverse Event” with the indicator flag “Serious” equal to “Yes” 
on the Events eCRF starting on or after signing of the informed consent and up to the 
End of Study date. 


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Treatment-emergent Adverse Event (TEAE) 
An event categorized as “Adverse Event” on the Events eCRF starting on or after first 
dose of investigational product, as determined by “Did event start before first dose of 
investigational product” equal to “No” or missing, and up to the End of Study date. 
Serious TEAE 
A TEAE with the indicator flag “Serious” equal to “Yes” on the Events eCRF. 
Treatment-emergent Adverse Device Effect 
A TEAE with the indicator flag “Is there a reasonable possibility that the event may have 
been caused by the investigational device” equal to “Yes” on the Events eCRF. 
5.2 
Study Dates  
Informed Consent Date 
The date on which subject signs the informed consent form.  
Date of Ready for Daily Diary Entry in Baseline 
The date on which an eDiary device is ready for daily diary entry after completion of 
run-in period. 
Randomization Date 
Randomization Date is defined as the date subject was allocated to a treatment group. 
Enrollment Date 
Enrollment Date is defined as the randomization date. 
First IP Dose Date 
First IP Dose Date is the date on which a subject is administered the first dose of IP 
following randomization as recorded on the IP Administration eCRF. The first IP dose 
may be the same day or after the randomization date. 
Last IP Dose Date 
Last IP Dose Date is the date on which a subject is administered the last dose of IP as 
recorded on the IP Administration eCRF. 
End of Study (EOS) Date 
End of study (EOS) date is defined as the last date on which the subject participates in 
the study as recorded on the End of Study eCRF. 


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5.3 
Study Points of Reference  
Run-in Assessment 
Run-in assessment is designed to determine the entry eligibility for baseline period. 
Baseline Assessment 
Baseline assessment for the endpoint of the interest is defined as the last non-missing 
measurement taken or the monthly interval assessed (for endpoints derived from daily 
eDiary collection during baseline period) before the first dose of investigational product. 
In cases where baseline measurements are taken on the same day as IP, it will be 
assumed that these measurements are taken prior to IP being administered. For 
subjects who are randomized but not dosed after the randomization, the baseline of the 
study is defined as the last non-missing measurement prior to or on the date of 
randomization. 
Study Day 1 
Study Day 1 is defined as the first IP dose date. For subjects who are randomized but 
not dosed after randomization, the Study Day 1 is defined as the date of randomization. 
Study Day 
Study Day is defined as the number of days from Study Day 1. 
Before Study Day 1: 
Study Day = (Date of Interest – Date of Study Day 1) 
On or after Study Day 1: 
Study Day = (Date of Interest – Date of Study Day 1) + 1 
Therefore, the day prior to Study Day 1 is -1. 
5.4 
Study Time Intervals  
5.4.1 
Monthly Intervals for Efficacy Endpoints Derived From Daily Diary 
Collection  
The (4-week) monthly intervals for efficacy endpoints derived from daily eDiary collection 
during baseline and months 1, 2, and 3 will be determined based on each subject’s 
monthly IP dosing dates. When an IP is missed or discontinued, a 28-day monthly 
interval will be used. Any eDiary data occurring after EOS date will not be included in the 
analysis. 
Applicable efficacy endpoints utilizing the monthly intervals in Table 5-1 include: 
 
Monthly migraine days (MMD) 


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 
Monthly headache hours of at least moderate pain intensity 
 
Monthly average duration of at least moderate pain intensity per migraine attack 
 
Monthly average peak migraine pain intensity 
 
Monthly migraine-free days 
 
Monthly hours of at least moderate pain intensity of triptan-treated migraine 
attacks 
Table 5-1. Monthly Intervals for Efficacy Endpoints Derived From Daily Diary Data 
Collection  
Study 
Period 
Assessment 
Timepoint 
Monthly Interval 
Start Date (Day) a 
End Date (Day) b 
Baseline 
Period 
Baseline 
Date of device ready for 
entry in baseline period  
Day prior to study day 1 
M-DBTP 
 
Week 4 (Month 1) 
Study Day 1  
Week 4 dose date – 1 
Week 8 (Month 2) 
Week 4 dose date  
Week 8 dose date – 1 
Week 12 (Month 3) 
Week 8 dose date  
Week 12 dose date – 1 
a Start Date (Day) = End date (day) of previous monthly interval + 1 if IP dose date is not available 
b End Date (Day) = Start date (day) of current monthly interval + 27 if IP dose date is not available 
 
5.4.2 
Monthly Interval for Efficacy Endpoints Derived From Episodic Diary 
Collection  
The first qualifying triptan-treated attack during the E-DBTP will be identified within the 
monthly interval defined in Table 5-2: 
Table 5-2. Monthly Interval for Efficacy Endpoints Derived From Episodic Diary 
Data  
Study Period 
Monthly Interval 
Start Date (Day)  
End Date (Day)  
E-DBTP 
Week 12 dose date 
MIN (Week 12 dose date + 27, 
EOS date) 
5.4.3 
Analysis Visits for Endpoints Derived Based on Monthly Data 
Collection  
Since the actual visit for a subject may not exactly coincide with their targeted visit date, 
the actual visit date is mapped to the analysis visit as in Table 5-3, Table 5-4, and 
Table 5-5. Any data occurred after EOS date will not be included in the analysis. 
For by-visit summaries, if more than one visit with non-missing measurement (including 
the unscheduled visits, ie, CPEVENT = ‘UNSCHED’) fall within the same visit window, 
the following rules will be applied according to the order described below for selecting 
one visit per visit window for summary: 


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1. Scheduled visit will be used regardless of the distance from the target day.  
Unscheduled visit will only be used when there is no measurement from scheduled 
visit in the visit window. 
2. The visit closest to the target day among visits of the same type (all scheduled visits 
or all unscheduled visits) will be considered for analysis. 
3. If two assessment dates are equidistant from the target date, the latter visit will be 
considered for analysis. 
Table 5-3. MIBS-4 Analysis Visit Windows  
Study Period 
Analysis Visit 
Target Day 
Visit Window (Study Day) 
Baseline Period 
Day 1 (Baseline) 
1 
Last measurement ≤ Day 1 
M-DBTP 
Week 4 (Month 1) 
29 
16 to 43 
Week 8 (Month 2) 
57 
44 to 71 
Week 12 (Month 3) 
85 
72 to 99 
E-DBTP 
Week 16 (Month 4) 
113 
100 to 127 
Table 5-4. MFIQ, MSSS and HIT-6 Analysis Visit Windows  
Study Period 
Analysis Visit 
Target Day 
Visit Window (Study Day) 
Baseline Period 
Day 1 (Baseline) 
1 
Last measurement ≤ Day 1 
M-DBTP 
Week 4 (Month 1) 
29 
16 to 43 
Week 8 (Month 2) 
57 
44 to 71 
Week 12 (Month 3) 
85 
72 to 99 
Table 5-5. PGI-S, MTS and PCS Analysis Visit Windows  
Study Period 
Analysis Visit 
Target Day 
Visit Window (Study Day) 
Baseline Period 
Day 1 (Baseline) 
1 
Last measurement ≤ Day 1 
M-DBTP 
Week 12 (Month 3) 
85 
72 to 99 
5.5 
Subject Disposition  
Randomized 
Individuals are considered randomized if they have been assigned a randomization 
number. Randomized individuals are referred to as “subjects”. 
Exposed to Investigational Product 
Subjects are defined as exposed if they receive at least one dose of investigational 
product.  
Completing Investigational Product 
Subjects are defined as completing investigational product if the primary reason for 
ending IP on End of IP eCRF is “Completed”. 


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Completing Study 
Subjects are defined as completing study if they complete the entire 16 weeks of study 
evaluation. It will be derived from the End of Study eCRF with “Completed” as the 
primary reason for ending study. 
On Study 
Subjects are defined as on study for specific study week if their end of study date 
is on or after the first day of the analysis window.  
 
5.6 
Arithmetic Calculations  
Duration of Migraine 
The number of years from the diagnosis date (DXDT) of migraine (migraine with aura or 
migraine without aura, whichever is earlier) to the date informed consent is signed. 
Observed 
Portion  
Missing 
Portion  
Duration of Migraine (Years) 
Year, Month, Day 
NA 
(Informed Consent Date – DXDT) / 365.25 
Year, Month  
Day  
[Year(Informed Consent Date) – Year(DXDT)] +  
[Month(Informed Consent Date) – Month(DXDT)] / 12 a 
Year 
Month, Day 
[Year(Informed Consent Date) – Year(DXDT)] a 
a If it equals 0, add 1/12 years (ie, 1 month) to avoid a disease duration of 0.   
Duration of IP Exposure 
Minimum (Last Dose Date + 27, EOS Date) – First Dose Date + 1 
Change From Baseline in Monthly Measurement 
Postbaseline monthly value – Baseline, as defined in Section 5.4. If the baseline or 
postbaseline value is missing, the change from baseline value will be set to missing. 
Change From Baseline in Mean Monthly Measurement Over Multiple Months 
Change from baseline in Mean Monthly Measurement is the arithmetic mean of the 
monthly change from baseline values for the months considered with observed data, if 
there is at least one observed monthly value. 
Subject Incidence of TEAEs 
The subject incidence for a given event during the study is defined as the number of 
subjects with at least one reported occurrence of the event divided by the number of 
subjects who received at least one dose of investigational product. For subjects with 
multiple occurrences of the same event, the event will only be counted once per subject. 


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5.7 
Disease Characteristics  
Treatment Failure of Prior Migraine Preventive Medications 
Treatment failure of prior migraine preventive medications is determined by “Reason for 
Stopping” as “Lack of efficacy” or “Adverse event” or “Intolerance” on the Prior Migraine 
Prophylactic Medication eCRF. 
6. 
Analysis Sets  
6.1 
Full Analysis Set  
The full analysis set consists of all subjects who were randomized in the study. Analysis 
of disposition, demographic and baseline characteristics, important protocol deviations, 
and protocol deviations related to COVID-19 control measures will utilize this analysis 
set. 
6.2 
M-DBTP Efficacy Analyses Set  
The respective efficacy analysis set for each efficacy endpoint consists of a subset of 
subjects from full analysis set who receive at least 1 dose of investigational product and 
have observed monthly hours of at least moderate headache pain intensity at 
baseline and at least 1 measurement during M-DBTP. Subjects will be analyzed 
according to their randomized treatment, regardless of treatment received. Primary 
analysis of the efficacy endpoints during M-DBTP will utilize this efficacy analysis set. 
6.3 
E-DBTP Efficacy Analysis Set   
The E-DBTP efficacy analysis set consists of a subset of subjects from full analysis set 
who receive week 12 dose. Subjects will be analyzed according to their randomized 
treatment, regardless of treatment received. Analysis of exploratory efficacy endpoints 
during E-DBTP will utilize this efficacy analysis set. 
6.4 
Safety Analysis Set  
The safety analysis set will consist of all randomized subjects who receive at least 1 
dose of investigational product. Subjects will be analyzed according to the randomized 
treatment unless a subject has received the incorrect dose during the entire DBTP, in 
which case, the subject will be analyzed according to the actual treatment received. 
Analysis for safety endpoints and summary of investigational product administration will 
utilize the safety analysis set. 
7. 
Planned Analyses  
The primary analysis (or final analysis since there is only one milestone analysis for this 
study) will occur after all subjects have completed their week-16 visit (or discontinued 


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from the study). The DBTP treatment assignment will be unblinded and all efficacy and 
safety analyses will be conducted and reported by the DBTP treatment group. 
8. 
Data Screening and Acceptance  
8.1 
General Principles  
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
8.2 
Data Handling and Electronic Transfer of Data  
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses.  This study will use the RAVE 
database as well as eDiary data which is outside of the RAVE database. 
8.3 
Handling of Missing and Incomplete Data  
Subjects may miss specific data points for a variety of reasons. In general, data could be 
missing due to a subject’s early withdrawal from the study, a missed visit, or inability to 
evaluate an endpoint at a time point. For this study, efficacy endpoints will be collected 
via eDiary and subjects could miss entering several days of data in each monthly 
interval. The general procedures outlined below describe how missing data will be 
handled. 
For the endpoints derived from the daily diary data, please refer to proration approach 
specified in Section 5.1.1 on handling missing daily diary data. Missing monthly 
measurement after proration will be handled by statistical analysis approaches listed in 
Section 9.5.  
For the endpoint derived from the episodic diary data, missing data at timed assessment 
will be handled by statistical analysis approaches listed in Section 9.5. 
Missing items in each clinical outcome assessment questionnaire will be handled based 
on the scoring algorithm for each assessment. The missing value in the algorithm 
derived measurements (eg, total score, domain scores) will be handled by statistical 
analysis approaches listed in Section 9.5. 
Missing data in safety endpoints will not be imputed except for incomplete start date of 
an AE or concomitant medication, which will be imputed as follows: 


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Missing 
Imputation 
Exception on adverse event start date 
Start date  
(AE, 
concomitant 
medication) 
Day 
01 
Default to Study Day 1 if an adverse event 
started the same year and month as Study 
Day 1 and the flag indicates that the adverse 
event started on or after the first dose of 
investigational product on the Events eCRF 
Day/Month 
01 JAN 
Default to Study Day 1 if an adverse event 
started the same year as Study Day 1 and 
the flag indicates that the adverse event 
started on or after the first dose of 
investigational product on the Events eCRF 
Day/Month/Year 
No 
imputation 
- 
 
8.4 
Detection of Bias  
This study has been designed to minimize potential bias by allocating treatment groups 
randomly, assessing endpoints and handling withdrawals without knowledge of the 
treatment. Other factors that may bias the results of the study include: 
 
important protocol deviations likely to impact the analysis and interpretation of 
the efficacy endpoints  
 
inadvertent breaking of the blind before formal unblinding  
 
investigational product dosing non-compliance  
 
the timing of and reasons for early withdrawal from treatment and from study  
The incidence of these factors may be assessed. Important protocol deviations will be 
listed and tabulated. If necessary, the incidence of other factors will be tabulated. 
The reasons for early withdrawal from treatment and from study will be tabulated. 
8.5 
Outliers  
Histograms will be examined to identify outliers in any of the continuous variables used 
in the analyses. Unexpected and/or unexplained values in categorical data will be 
identified by utilizing frequency tables. 
Outliers due to data entry errors will be assessed by the study team before final 
database lock. The validity of any questionable values or outliers will be confirmed. 
Outliers or any questionable values with confirmed validity will be included in the 
analyses. However, ad-hoc sensitivity analyses may be conducted to evaluate the 
influence of extreme values in the data. 


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8.6 
Distributional Characteristics  
Continuous endpoints of change from baseline value will be analyzed under normality 
assumption. If they deviate appreciably from normality, appropriate transformations or 
the non-parametric alternatives will be used, such as Quade test (Quade D, 1966) may 
additionally be considered. 
8.7 
Validation of Statistical Analyses  
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.  
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.  
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later. 
9. 
Statistical Methods of Analysis  
9.1 
General Considerations  
Summary statistics will be computed by treatment group and visit. For continuous 
endpoints, the following descriptive statistics will be computed: number of observations, 
means, medians, standard deviations, standard errors, first and third quartiles, 
minimums and maximums, and 2-sided 95% confidence intervals (CIs) of the means 
(CIs will be provided for efficacy endpoints only). For categorical endpoints, the 
summaries will contain the number and percentage of subjects in each category. 
For the primary and secondary endpoints, the primary analysis method utilizing a 
repeated measures linear mixed effects model will include all observed data regardless 
of treatment adherence. 
A sequential testing procedure will be used to maintain the family-wise type 1 error 
α = 0.05 between the primary and secondary endpoints following the prespecified order 
below. An endpoint will only be tested for statistical significance if the endpoint tested in 
the previous step is statistically significant at 2-sided significance level of 0.05. 
1. Primary endpoint: change from baseline in mean monthly hours of at least moderate 
headache pain intensity over months 1, 2, and 3 
2. Secondary endpoints: change from baseline in mean monthly function over months 
1, 2, and 3, as measured by the MFIQ using the Hochberg procedure 
 
Impact on physical functioning 


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 
Impact on usual activities 
 
Impact on emotional functioning 
 
Impact on social functioning 
3. Secondary endpoint: change from baseline in mean monthly average duration of at 
least moderate pain intensity in migraine attacks over months 1, 2, and 3 
4. Secondary endpoint: change from baseline in mean monthly peak migraine pain 
intensity over months 1, 2, and 3, as assessed by the 11-point NRS 
9.2 
Subject Accountability  
The disposition of all randomized (enrolled) subjects will be tabulated by randomized 
treatment group. The summary will include the number of subjects who are randomized, 
the number and percent of subjects who receive/never receive double-blind IP, who 
complete double blind IP, discontinue double-blind IP and reasons for discontinuing, who 
complete the study, and who withdraw prematurely from the study before completion of 
the study and their reasons for withdrawal. Summary of subjects who discontinue 
investigational product/study due to COVID-19 control measures will be included. 
9.3 
Important Protocol Deviations  
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to database lock.  These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the course of the study.  Eligibility deviations are defined 
in the protocol. IPDs will be summarized and listed by randomized treatment group. 
Protocol Deviations (PDs) related to COVID-19 control measures will be summarized 
separately. 
9.4 
Demographic and Baseline Characteristics  
Subject demographic and baseline characteristics will be summarized using descriptive 
statistics by randomized treatment group and overall study population using FAS. If 
multiple races have been reported for a subject, the subject will be categorized as 
multiple races as well as by combination of races. 
At baseline, the following demographic and baseline characteristics will be summarized: 
 
Age 
 
Sex 
 
Ethnicity 
 
Race 
 
Height (cm) 


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 
Weight (kg) 
 
Body mass index (BMI, kg/m2)  
 
Targeted neurological disease diagnosis at baseline 
 
Disease duration of migraine with or without aura 
 
Age at onset of migraine 
 
Summary of prior migraine preventive medication and reasons for discontinuation 
 
Acute headache medication use during baseline period: 
a) Migraine-specific 
b) Non migraine-specific 
 
Monthly migraine days during baseline period 
 
Monthly headache days during baseline period 
 
Monthly hours of at least moderate headache pain intensity 
 
Monthly average duration of at least moderate pain intensity per migraine attack 
 
Monthly average peak migraine pain intensity 
 
Monthly total migraine freedom days 
 
Monthly hours of at least moderate pain intensity for triptan-treated migraine 
attacks 
 
MFIQ domain scores of function (physical, usual activities, social, and emotional) 
 
HIT-6 total score 
 
MTS 
 
MSSS total score 
 
PGI-S score 
 
MIBS-4 total score 
 
PCS total score 
9.5 
Efficacy Analyses  
The primary and secondary efficacy analyses will utilize the M-DBTP EAS and the 
exploratory efficacy analyses will utilize the E-DBTP EAS. Subjects will be analyzed 
according to their randomized treatment group regardless of the actual treatment 
received during the study. 
Detailed efficacy analysis methods and covariates included in the models are 
summarized in the table below. 


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Table 9-1. Primary Efficacy Endpoint Summary Table  
Endpoint 
Primary Summary and Analysis Method 
Change from baseline in mean 
monthly hours of at least moderate 
headache pain intensity over months 
1, 2, and 3 
1. Summary statistics by visit using observed data at 
each visit and the calculated mean monthly hours 
of headache pain over months 1, 2, and 3 
2. Least squares means from a linear mixed effect 
model including treatment group, scheduled visit, 
interaction of treatment and scheduled visit and 
baseline value using observed data 
3. Estimate treatment difference 
(AMG 334 – Placebo) from the model in #2. 
Table 9-2. Secondary Efficacy Endpoint Summary Table  
Endpoint 
Primary Summary and Analysis Method  
Change from baseline in mean 
monthly function as measured by the 
Migraine Functional Impact 
Questionnaire (MFIQ) over months 
1, 2, and 3; 
 
Change from baseline in mean 
monthly average duration of at least 
moderate pain intensity in migraine 
attacks over months 1, 2, and 3; 
 
Change from baseline in mean 
monthly peak migraine pain intensity 
as assessed by the 11-point 
Numeric Rating Scale (NRS) over 
months 1, 2, and 3 
1. Summary statistics by visit using observed data at 
each visit, and the calculated mean monthly values 
over months 1, 2 and 3 
2. Least squares means from a linear mixed effect 
model including treatment group, scheduled visit, 
interaction of treatment and scheduled visit and 
baseline value using observed data 
3. Estimate treatment difference 
(AMG 334 – Placebo) from the model in #2 


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Table 9-3.  Exploratory Efficacy Endpoint Summary Table  
Endpoint 
Primary Summary and Analysis Method 
Change from baseline in mean MMD 
over months 1, 2, and 3a 
1. Summary statistics by visit using observed data at 
each visit and the calculated mean monthly 
migraine day over months 1, 2, and 3 
2. Least squares means from a linear mixed effect 
model including treatment group, scheduled visit, 
interaction of treatment and scheduled visit and 
baseline value using observed data 
3. Estimate treatment difference 
(AMG 334 – Placebo) from the model in #2. 
Change from baseline in pain 
catastrophizing as measured by the 
Pain Catastrophizing Scale (PCS) at 
month 3b 
1. Summary statistics using observed data at 
week 12 
2. Analysis of covariance (ANCOVA) model including 
treatment group and baseline value using 
observed data 
3. Estimate treatment difference 
(AMG 334 – Placebo) using the model in #2. 
Achievement of no or mild interictal 
burden as measured by the MIBS-4 
at assessment time pointsc 
1. Summary statistics using observed data at the 
specific month 
2. Logistic regression model including treatment 
group and baseline value will be used after 
subjects with missing outcome data are imputed as 
non-responders (NRI) 


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Endpoint 
Primary Summary and Analysis Method 
Achievement of pain freedom at 2 
hours post-triptan dose for the first 
attack at month 4d 
1. Summary statistics using observed data at the 
assessment time points 
2. Logistic regression model including treatment 
group will be used after subjects with missing 
timed assessment are imputed as non-responders 
Use of migraine rescue 
medication within 24 hours 
post-triptan dose for the first 
attack at month 4 
1. Summary statistics using observed data at the 
assessment time points 
2. Logistic regression model including treatment 
group using observed data 
a The same analyses methods will be applied to the endpoints: 
Change from baseline in mean monthly hours of at least moderate pain intensity for qualifying oral 
triptan-treated migraine attacks over months 1, 2, and 3 
Change from baseline in mean average duration of at least moderate pain intensity for qualifying oral 
triptan-treated migraine attacks occurring over months 1, 2, and 3 
Change from baseline in Migraine Symptom Severity Score (MSSS) total score at assessment time points 
Change from baseline in mean monthly total migraine freedom days over months 1, 2, and 3 
Change from baseline in Migraine Interictal Burden Scale (MIBS-4) total score at assessment time points 
(the model will include data at month 1-4) 
Change from baseline in headache impact scores as measured by the Headache Impact Test (HIT-6) total 
score at assessment time points 
Change from baseline in physical function domain score as measured by MFIQ at assessment time points 
Change from baseline in usual activities domain score as measured by MFIQ at assessment time  
points 
Change from baseline in social function domain as measured by MFIQ at assessment time points 
Change from baseline in emotional function domain score as measured by MFIQ at assessment time 
points 
Change from baseline in overall impact on usual activities global item score as measured by MFIQ at 
assessment time points 
   Change from baseline in mean monthly average duration of at least moderate pain intensity per 
migraine attack in months with at least 1 migraine attack 
   Change from baseline in mean monthly peak migraine pain intensity as assessed by the 11-point 
Numeric Rating Scale (NRS) in months with at least 1 migraine attack 
 
b The same analyses methods will be applied to the endpoints: 
Change in Patient Global Impression of Severity (PGI-S) total score at month 3 
 
c The same analyses methods will be applied to the endpoints: 
Change from baseline in the most troublesome symptom (MTS) at month 3 
 


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d The same analyses methods will be applied to the endpoints: 
Achievement of pain freedom at 30 and 60 minutes post-triptan dose for the first attack at month 4 
Achievement of pain relief at 2 hours post-triptan dose for the first attack at month 4 
Achievement of freedom from the most bothersome symptom at 30, 60, and 120 minutes post-triptan dose 
for the first attack at month 4 
Achievement of relief from the most bothersome symptom at 30, 60, and 120 minutes post-triptan dose for 
the first attack at month 4 
Achievement of 24-hour sustained pain freedom post-triptan dose for the first attack at month 4 
Migraine recurrence during 24 hours post-triptan dose for the first attack at month 4 
 
9.5.1 
Analyses of Primary and Secondary Efficacy Endpoints   
For the primary and secondary endpoints will be tested using a linear mixed model 
based on observed monthly data with appropriate contrasts for pairwise treatment 
comparisons. 
The model will include treatment, scheduled visit, treatment by visit interaction, and 
baseline value as covariates. If applicable, the first-order autoregressive covariance 
structure is assumed. Least squares means (LSMs) for each treatment group, standard 
errors, associated 95% CIs, difference of LSMs compared to placebo group, associated 
95% CIs and nominal two-sided p-values will be tabulated by visit and treatment, as well 
as for the mean monthly values over months 1, 2, and 3 of the DBTP. No sensitivity 
analyses will be performed for the primary and secondary endpoints. 
Subgroup analysis described below will be performed for the primary and secondary 
endpoints: 
1. Treatment failure of prior migraine prophylactic medications (1, 2, and 3 or more 
treatment failures) 
2. Medication overuse at baseline (yes vs. no) 
The purpose of the subgroup analyses is to explore if the treatment effect varies across 
subgroups of interest. Subgroup analyses are performed for primary and secondary 
efficacy endpoints using the same method as primary analysis method but performed 
within each interested subgroup. 
The heterogeneity of the treatment effect across the subgroups will be evaluated by 
examining the treatment-by-subgroup interaction at primary time point and an interaction 
p-value will be presented. The primary analysis model with the addition of 
treatment-by-subgroup interaction will be used. 


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9.5.2 
M-DBTP Analyses of Exploratory Efficacy Endpoints  
For exploratory efficacy endpoints during the M-DBTP, summary statistics and primary 
analysis method will be conduct in the same way as that for the primary and secondary 
endpoints. 
The continuous exploratory efficacy endpoints at each assessment time point or over 
months 1, 2, and 3 of the 3-month M-DBTP will be analyzed using the  
linear mixed effects model that includes treatment group, baseline values, scheduled 
visit, and the interaction of treatment and scheduled visit without any imputation for 
missing data. 
The efficacy endpoints for PCS total score and PGI-S score will be analyzed using 
analysis of covariance model including treatment and baseline value as covariates. The 
efficacy endpoints for MTS (achievement of “Very Much Improved” or “Much Improved”) 
and the MIBS (achievement of no or mild interictal burden) will be analyzed using logistic 
regression model with missing data imputed using NRI up to End of Study Date. No 
sensitivity analyses will be performed for the exploratory endpoints. 
9.5.3 
E-DBTP Analyses of Exploratory Efficacy Endpoints  
The dichotomous efficacy endpoints for assessing qualifying triptan-treated attacks only 
in E-DBTP will be analyzed using logistic regression model with missing data imputed as 
non-responders (NRI) up to End of Study Date. Odds ratios of treatment group and 
placebo with associated 95% CIs and p-values will be reported. The efficacy endpoint for 
Migraine Interictal Burden Scale at month 4 will be analyzed using the linear mixed 
effects model that includes treatment group, baseline values, scheduled visit, and the 
interaction of treatment and scheduled visit without any imputation for missing data.  
The following exploratory endpoints of the E-DBTP for the first qualifying triptan-treated 
attack will be analyzed by medication overuse status at month 3 (yes vs. no): 
 
Achievement of pain freedom at 2 hours post-triptan dose for the first attack at 
month 4 
 
Achievement of pain relief at 2 hours post-triptan dose for the first attack at month 4 
 
Achievement of relief from the most bothersome symptom at 30, 60, and 120 
minutes post-triptan dose for the first attack at month 4 
 
Achievement of 24-hour sustained pain freedom post-triptan dose for the first attack 
at month 4 
 
Migraine recurrence within 24 hours post-triptan dose for the first attack at month 4 
 
Use of migraine rescue medication within 24 hours post-triptan dose for the first 
attack at month 4 


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9.6 
Safety Analyses  
9.6.1 
Analyses of Safety Endpoints  
For safety endpoints, all randomized subjects who received at least one dose of IP (ie, 
Safety Analysis Set) will be analyzed based on the randomized treatment unless a 
subject has received the incorrect dose during the entire study. 
No statistical testing comparing treatment groups will be performed in the safety 
analyses. 
9.6.2 
Adverse Events  
The Medical Dictionary for Regulatory Activities (MedDRA) version 23.0 or later will be 
used to code all adverse events (AEs) to a system organ class (SOC) and a preferred 
term (PT).  All AEs will be graded using the Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.03. All AE summary tables described below will be 
summarized by treatment group using subject incidence. 
The subject incidence of AEs will be summarized for all treatment-emergent adverse 
events (TEAEs), serious AEs, AEs leading to withdrawal of investigational product, fatal 
AEs, and adverse events of interest (EOI) including 
 
Ischaemic Central Nervous System Vascular Conditions SMQ (Narrow) 
 
Ischaemic Heart Disease SMQ (Narrow and Broad) 
 
Peripheral Arterial Disease AMQ (Narrow) 
 
Hypertension SMQ (Narrow and Broad) 
 
Constipation AMQ (Narrow and Broad) 
 
Alopecias AMQ (Narrow and Broad) 
 
COVID-19 SMQ (Narrow) 
Subject incidence of all TEAEs, SAEs, AEs leading to withdrawal of investigational 
product, fatal AEs, and device related AEs will be tabulated by SOC in alphabetical order 
and PT in descending order of frequency based on the AMG 334 140 mg dose, then 
Placebo dose and then alphabetically. 
Subject incidence of EOI (standardized MedDRA queries [SMQ] and/or Amgen medical 
queries [AMQ]) will also be summarized according to their categories and PT in 
descending order of frequency. 
In addition, summarizes of all TEAEs and SAEs occurring in at least 3% of the subjects 
by PT in any treatment arm will be provided in descending order of frequency based on 


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the AMG 334 140 mg dose, then Placebo dose and then alphabetically. Summaries 
of all TEAEs and SAEs will be tabulated by SOC, PT, and grade. 
9.6.3 
Exposure to Investigational Product  
Descriptive statistics will be produced to describe the exposure to investigational product 
by treatment group. The number and percentage of subjects with dose change, reason 
for dose change and duration of exposure to IP in days will be summarized by treatment 
group. 
9.6.4 
Exposure to Concomitant Medication  
The number and proportion of subjects receiving acute headache medications will be 
summarized by acute medication category for each treatment group based on 
medication data collected in eDiary. 
9.7 
Other Analyses  
Not Applicable. 
10. 
Changes From Protocol-specified Analyses  
There are one deviation from protocol: 
 
The efficacy analysis set mentioned in protocol was changed to M-DBTP efficacy 
analysis set and E-DBTP efficacy analysis set to meet the target population of 
primary, secondary and exploratory endpoints. 
11. 
Literature Citations / References  
Holroyd KA, Drew JB, Cottrell CK, Romanek KM, Heh V. Impaired functioning and 
quality of life in severe migraine: the role of catastrophizing and associated symptoms. 
Cephalalgia. 2007;27:1156–1165. 
Sullivan MJL, Bishop SR, Pivik J. The Pain Catastrophizing Scale: Development and 
Validation. Psychol Assess. 1995;7:524–532. 
Quade, D. (1966), Rank analysis of covariance, University of North Carolina, Institute of 
Statistics Mimeo Series. No. 483 
12. 
Data Not Covered by This Plan  
There are no plans to specifically analyze or summarize the following data points.  


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13. 
Appendices  
Appendix A.  Reference Values/Toxicity Grades  
Adverse event severity and laboratory toxicity are graded based on NCI Common 
Toxicity Criteria version 4.03, which is available at the following:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickRefere
nce_5x7.pdf