Conditions: Migraine
Keywords: Episodic migraine Disability Migraine-related disability Work productivity Erenumab AIMOVIG
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 29
Healthy volunteers: no

Brief summary:
To evaluate the effect of erenumab compared to placebo on disability in employed subjects with episodic migraine (EM) who have previously failed 1 or more migraine preventive treatments.

Detailed description:
Migraine prevention continues to be an area of large, unmet medical need, with existing therapies often having modest efficacy and poor tolerability. Calcitonin gene-related peptide (CGRP) has an important role in the pathophysiology of migraine. Erenumab-aooe is a fully human monoclonal antibody that targets the CGRP receptor, and interrupts its downstream effects. Erenumab has been approved for the preventive treatment of migraine in adults. The present study is a Phase IV trial that will assess the effect of erenumab on disability and work productivity in employed subjects with episodic migraine (EM) who have previously failed 1 or more migraine preventive treatments.

Arms:
arm 1: After subjects complete baseline and are found eligible, they will be enrolled and randomized in a 1:1 ratio to either erenumab or placebo. arm 2: After subjects complete baseline and are found eligible, they will be enrolled and randomized in a 1:1 ratio to either erenumab or placebo.

Interventions: intervention 1: Placebo intervention 2: Erenumab
Intervention descriptions: intervention 1: Placebo once every 4 weeks. SC injection. intervention 2: Erenumab once every 4 weeks. SC injection.

Protocol document:
Prot_000.pdf: 
Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20180060 
Date:  31 August 2020 
Page 1 of 101 
 
CONFIDENTIAL  
 
 
Title Page 
Protocol Title: 
Effect of Erenumab-aooe on Disability and Work 
Productivity in Employed Subjects With Episodic 
Migraine Who Have Previously Failed 1 or More 
Migraine Preventive Treatments 
Short Protocol Title: 
Effect of Erenumab-aooe on Disability and Work 
Productivity in Employed Subjects With Episodic 
Migraine 
Protocol Number: 
20180060 
Investigational Product: 
Erenumab-aooe (AMG 334) 
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: 
Governance Body Chair 
Key 
Sponsor 
Contact 
Name: 
 
Address: 
One Amgen Center Drive  
Thousand Oaks, CA 91320 
Telephone Number: 
 
Email Address: 
 
EudraCT Number: 
Not applicable 
NCT Number: 
NCT03912337 
Protocol Date: 
Document Version 
Date 
Original 
18 March 2019 
Amendment 1 
14 June 2019 
Amendment 2 
09 March 2020 
Amendment 3 
31 August 2020 
Version/Date: 
Data Element Standards Version 
Version 6.1 
 
This protocol was developed, reviewed, and approved in accordance with Amgen’s 
standard operating procedures. 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20180060 
Date:  31 August 2020 
Page 2 of 101 
 
CONFIDENTIAL  
 
 
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-aooe (AMG 334) 
Protocol Number:  20180060 
Date:  31 August 2020 
Page 3 of 101 
 
CONFIDENTIAL  
 
 
Investigator’s Agreement: 
I have read the attached protocol entitled, Effect of Erenumab-aooe on Disability and 
Work Productivity in Employed Subjects With Episodic Migraine Who Have Previously 
Failed 1 or More Migraine Preventive Treatments dated 31 August 2020, 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-aooe (AMG 334) 
Protocol Number:  20180060 
Date:  31 August 2020 
Page 4 of 101 
 
CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents ................................................................................................... 4 
1. 
Protocol Synopsis ................................................................................................... 9 
2. 
Study Schema and Schedule of Activities ............................................................. 16 
2.1 
Study Schema ........................................................................................... 16 
2.2 
Schedule of Activities ................................................................................ 17 
3. 
Introduction ........................................................................................................... 23 
3.1 
Study Rationale ......................................................................................... 23 
3.2 
Background ............................................................................................... 23 
3.2.1 
Disease ..................................................................................... 23 
3.2.2 
Amgen Investigational Product Background:  
Erenumab ................................................................................. 24 
3.3 
Benefit/Risk Assessment ........................................................................... 25 
4. 
Objectives, Endpoints and Hypotheses ................................................................. 27 
4.1 
Objectives and Endpoints .......................................................................... 27 
4.2 
Hypotheses ............................................................................................... 32 
5. 
Study Design ........................................................................................................ 32 
5.1 
Overall Design .......................................................................................... 32 
5.2 
Number of Subjects ................................................................................... 32 
5.2.1 
Replacement of Subjects ........................................................... 32 
5.2.2 
Number of Sites ......................................................................... 32 
5.2.2.1 
Decentralized Clinical Trials Site (DCTS) ................ 33 
5.3 
End-of-Study ............................................................................................. 33 
5.3.1 
End-of-Study Definition .............................................................. 33 
5.3.2 
Study Duration for Subjects ....................................................... 34 
5.4 
Justification for Investigational Product Dose ............................................ 34 
5.5 
Patient Input on Study Design ................................................................... 34 
6. 
Study Population .................................................................................................. 34 
6.1 
Inclusion Criteria Part 1 ............................................................................. 35 
6.2 
Exclusion Criteria Part 1 ............................................................................ 35 
6.3 
Inclusion Criteria Part 2 ............................................................................. 37 
6.4 
Exclusion Criteria Part 2 ............................................................................ 38 
6.5 
Subject Enrollment .................................................................................... 38 
6.6 
Screen Failures ......................................................................................... 39 
7. 
Treatments ........................................................................................................... 39 
7.1 
Treatment Procedures............................................................................... 40 
7.1.1 
Investigational Products ............................................................ 40 
7.1.2 
Non-investigational Products ..................................................... 40 
7.1.3 
Medical Devices ........................................................................ 40 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20180060 
Date:  31 August 2020 
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CONFIDENTIAL  
 
 
7.1.4 
Other Protocol-required Therapies ............................................ 41 
7.1.5 
Other Treatment Procedures ..................................................... 41 
7.1.6 
Product Complaints ................................................................... 41 
7.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 41 
7.2 
Method of Treatment Assignment ............................................................. 43 
7.3 
Blinding ..................................................................................................... 43 
7.3.1 
Site Personnel Access to Individual Treatment 
Assignments ............................................................................. 43 
7.3.2 
Access to Individual Subject Treatment Assignments 
by Amgen or Designees ............................................................ 44 
7.4 
Dose Modification ...................................................................................... 44 
7.4.1 
Dose-cohort Study Escalation/De-escalation and 
Stopping Rules .......................................................................... 44 
7.4.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 44 
7.4.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 44 
7.5 
Preparation/Handling/Storage/Accountability ............................................ 44 
7.6 
Treatment Compliance .............................................................................. 45 
7.7 
Treatment of Overdose ............................................................................. 45 
7.8 
Prior and Concomitant Treatment ............................................................. 45 
7.8.1 
Prior Treatment ......................................................................... 45 
7.8.2 
Concomitant Treatment ............................................................. 45 
8. 
Discontinuation Criteria ......................................................................................... 45 
8.1 
Discontinuation of Study Treatment........................................................... 46 
8.2 
Discontinuation From the Study ................................................................ 47 
8.2.1 
Reasons for Removal From Washout, Run-in or 
Invasive Procedures .................................................................. 47 
8.2.2 
Reasons for Removal From Study ............................................. 47 
8.3 
Lost to Follow-up ....................................................................................... 47 
9. 
Study Assessments and Procedures .................................................................... 48 
9.1 
General Study Periods .............................................................................. 48 
9.1.1 
Screening, Enrollment and/or Randomization ............................ 48 
9.1.1.1 
Screening Period ..................................................... 48 
9.1.1.2 
Baseline .................................................................. 49 
9.1.1.3 
Randomization ........................................................ 49 
9.1.2 
Treatment Period ....................................................................... 49 
9.1.3 
End-of-study .............................................................................. 49 
9.2 
Description of General Study Assessments and Procedures ..................... 49 
9.2.1 
General Assessments ............................................................... 49 
9.2.1.1 
Informed Consent .................................................... 49 
9.2.1.2 
Demographics ......................................................... 50 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20180060 
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CONFIDENTIAL  
 
 
9.2.1.3 
Medical History ........................................................ 50 
9.2.1.4 
Physical Measurements .......................................... 50 
9.2.1.5 
Substance Abuse History ........................................ 51 
9.2.2 
Efficacy Assessments ................................................................ 51 
9.2.2.1 
Clinical Outcome Assessments and 
Electronic Diaries (eDiaries) .................................... 51 
9.2.2.2 
Wearable Device ..................................................... 55 
9.2.3 
Safety Assessments .................................................................. 55 
9.2.3.1 
Adverse Events ....................................................... 56 
9.2.4 
Clinical Laboratory Assessments ............................................... 59 
9.2.4.1 
Pregnancy Testing .................................................. 59 
9.2.5 
Pharmacogenetic Assessments................................................. 60 
9.2.6 
Biomarkers ................................................................................ 60 
9.2.6.1 
Biomarker Development/Future Research ............... 60 
9.2.7 
Health Economics OR Medical Resource Utilization 
and Health Economics .............................................................. 61 
10. 
Statistical Considerations ...................................................................................... 61 
10.1 
Sample Size Determination ....................................................................... 61 
10.2 
Analysis Sets, Subgroups, and Covariates ................................................ 62 
10.2.1 
Analysis Sets ............................................................................. 62 
10.2.1.1 
Full Analysis Set ...................................................... 62 
10.2.1.2 
Efficacy Analysis Set ............................................... 62 
10.2.1.3 
Safety Analysis Set ................................................. 63 
10.2.2 
Covariates ................................................................................. 63 
10.2.3 
Subgroups ................................................................................. 63 
10.2.4 
Handling of Missing and Incomplete Data .................................. 63 
10.3 
Adaptive Design ........................................................................................ 63 
10.4 
Statistical Analyses ................................................................................... 64 
10.4.1 
Planned Analyses ...................................................................... 64 
10.4.2 
Methods of Analyses ................................................................. 64 
10.4.2.1 
General Considerations ........................................... 64 
10.4.2.2 
Efficacy Analyses .................................................... 65 
11. 
References ........................................................................................................... 66 
12. 
Appendices ........................................................................................................... 69 
12.1 
Appendix 1.  List of Abbreviations and Definitions of Terms ...................... 70 
12.2 
Appendix 2.  Clinical Laboratory Tests ...................................................... 74 
12.3 
Appendix 3.  Study Governance Considerations ....................................... 75 
Regulatory and Ethical Considerations ...................................................... 75 
Recruitment Procedures ............................................................................ 75 
Informed Consent Process ........................................................................ 76 
Data Protection/Subject Confidentiality ..................................................... 77 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20180060 
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CONFIDENTIAL  
 
 
Publication Policy ...................................................................................... 78 
Investigator Signatory Obligations ............................................................. 79 
Data Quality Assurance ............................................................................. 79 
Source Documents .................................................................................... 80 
Study and Site Closure.............................................................................. 81 
Compensation ........................................................................................... 82 
12.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ....................................... 83 
Definition of Adverse Event ....................................................................... 83 
Definition of Serious Adverse Event .......................................................... 84 
Definition of Adverse Device Effect ........................................................... 84 
Recording Adverse Events and Serious Adverse Events .......................... 85 
Evaluating Adverse Events and Serious Adverse Events .......................... 86 
Reporting of Serious Adverse Event .......................................................... 87 
Adverse Device Effects:  Recording, Evaluating and Reporting ................. 87 
12.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ........................................................ 91 
Definition of Females of Childbearing Potential ......................................... 91 
Collection of Pregnancy Information .......................................................... 92 
Collection of Lactation Information ............................................................ 93 
12.6 
Appendix 6.  Sample Storage and Destruction .......................................... 96 
12.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions 
and Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ................................................................................................. 98 
Criteria for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other 
Protocol-required Therapies due to Potential 
Hepatotoxicity............................................................................ 98 
Criteria for Rechallenge of Amgen Investigational Product and 
Other Protocol-required Therapies After Potential 
Hepatotoxicity............................................................................ 99 
Drug-induced Liver Injury (DILI) Reporting and Additional 
Assessments ........................................................................... 100 
 
List of Tables 
Table 2-1.  Schedule of Activities ................................................................................... 17 
Table 7-1.  Study Treatments ........................................................................................ 40 
Table 7-2.  Excluded Treatments, Medical Devices, and Procedures ............................ 42 
Table 10-1.  Sample Size Assumptions and Statistical Power for Traditional 
Sites ....................................................................................................... 62 
Table 12-1.  Analyte Listing ........................................................................................... 74 


Product:  Erenumab-aooe (AMG 334) 
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CONFIDENTIAL  
 
 
Table 12-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies due to Potential Hepatotoxicity ............................................... 99 
List of Figures 
Figure 2-1.  Study Schema ............................................................................................ 16 
Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Form .................. 88 
Figure 12-2.  Pregnancy and Lactation Notification Worksheet ...................................... 94 
 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20180060 
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CONFIDENTIAL  
 
 
1. 
Protocol Synopsis 
Protocol Title:  Effect of Erenumab-aooe on Disability and Work Productivity in 
Employed Subjects With Episodic Migraine Who Have Previously Failed 1 or More 
Migraine Preventive Treatments 
Short Protocol Title:  Effect of Erenumab-aooe on Disability and Work Productivity in 
Employed Subjects With Episodic Migraine 
Study Phase:  4 
Indication:  Preventive treatment of migraine in adults 
Rationale: 
The presence of various comorbidities in migraine patients, whether associated or 
migraine-induced, has been established by numerous studies.  These comorbidities 
contribute to migraine-related disability, impacting work and overall function 
(Lipton et al, 2013; Stewart et al, 2008).  The American Migraine Prevalence and 
Prevention (AMPP) study of patients with episodic migraine (EM) evaluated several 
domains of headache-related disability such as work, depression, and anxiety, to name 
a few, that are frequently affected by migraine.  Other studies, though smaller in scale, 
have demonstrated the impact of migraine on quality and quantity of sleep 
(Barbanti et al, 2007; Kelman and Rains, 2005). 
Closer analyses of impact of migraine on work have not only revealed absence from 
work, but also reduction in performance also known as presenteeism 
(Stewart et al, 2008).  Relevant components of decreased presenteeism include 
impaired concentration and feeling of fatigue. 
In phase 2 and 3 clinical trials, erenumab-aooe (referred to as erenumab herein) has 
demonstrated a reduction in monthly migraine days (MMD) as well as migraine-related 
disability (Dodick et al, 2018; Tepper et al, 2017; Goadsby et al, 2017b).  Separately, 
improvement in MMD and migraine-related disability have been associated with 
improvement in work productivity (Dodick et al, 2016; Lipton et al, 2013).  
Study 20180060 is being conducted to confirm the effect of erenumab on 
migraine-related disability (inclusive of aforementioned comorbidities) and work 
productivity. 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20180060 
Date:  31 August 2020 
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CONFIDENTIAL  
 
 
Objective(s)/Endpoint(s) 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the effect of erenumab 
compared to placebo on disability in 
employed subjects with episodic migraine 
(EM) who have previously failed 1 or 
more migraine preventive treatments 
 
Sum of monthly changes from baseline in 
modified Migraine Disability Assessment 
(MIDAS) total score over the 6-month 
double-blind treatment period (DBTP) 
Primary Estimand 
The primary estimand for the primary objective on migraine-related disability consists of: 
 
The target population, which includes employed subjects with EM who have previously 
failed 1 or more migraine preventive treatments  
 
The endpoint, which is the sum of monthly changes from baseline in modified MIDAS total 
score over the 6-month DBTP 
 
The intercurrent event is adherence to treatment.  The treatment effect of interest will be 
assessed for all randomized subjects enrolled from traditional sites who receive at least 
1 dose of investigational product (IP) and have a baseline value and at least 1 
post-baseline value of modified MIDAS total score, regardless of adherence to treatment 
 
The summary measure, which is the difference in means of the endpoint between the 
erenumab group and the placebo group 
The primary estimand is the difference in means between erenumab and placebo of the sum of 
monthly changes from baseline in modified MIDAS total score over the 6-month DBTP in 
employed subjects with EM who have previously failed 1 or more migraine preventive 
treatments and who are randomized, receive at least 1 dose of IP, and have a baseline value 
and at least 1 post-baseline value of modified MIDAS total score, regardless of adherence to 
treatment. 
Secondary 
 
To evaluate the effect of erenumab 
compared to placebo on monthly migraine 
days (MMD) in employed subjects with 
EM who have previously failed 1 or more 
migraine preventive treatments 
 
Change from baseline in mean MMD over 
months 4, 5, and 6 of the 6-month DBTP 
The estimand for the secondary objective on MMD consists of: 
 
The target population, which includes employed subjects with EM who have previously 
failed 1 or more migraine preventive treatments  
 
The endpoint, which is the change from baseline in mean MMD over months 4, 5, and 6 of 
the 6-month DBTP 
 
The intercurrent event is adherence to treatment.  The treatment effect of interest will be 
assessed for all randomized subjects enrolled from traditional sites who receive at least 
1 dose of IP and have a baseline value and at least 1 post-baseline value of MMD, 
regardless of adherence to treatment. 
 
The summary measure, which is the difference between the mean of the endpoint for the 
erenumab group and the placebo group 


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CONFIDENTIAL  
 
 
Objectives 
Endpoints 
Secondary (Continued) 
The estimand is the difference in means between erenumab and placebo of the change from 
baseline in mean MMD over months 4, 5, and 6 of the 6-month DBTP in employed subjects 
with EM who have previously failed 1 or more migraine preventive treatments and who are 
randomized, receive at least 1 dose of IP, and have a baseline value and at least 1 post-
baseline value of MMD, regardless of adherence to treatment.  
 
To evaluate the effect of erenumab 
compared to placebo on work impairment 
in employed subjects with EM who have 
previously failed 1 or more migraine 
preventive treatments 
 
Change from baseline in mean monthly 
percent work impairment over months 4, 
5, and 6 of the 6-month DBTP, as 
measured by the Work Productivity and 
Activity Impairment Questionnaire 
(WPAI):  Migraine V2.0 
(WPAI questions 2, 4, and 5) 
Note:  the monthly percent work 
impairment equals to the arithmetic mean 
of the observed weekly percent work 
impairment over the monthly interval. 
The estimand for the secondary objective on work impairment consists of: 
 
The target population, which includes employed subjects with EM who have previously 
failed 1 or more migraine preventive treatments  
 
The endpoint, which is the change from baseline in mean monthly percent work impairment 
over months 4, 5, and 6 of the 6-month DBTP 
 
The intercurrent event is adherence to treatment.  The treatment effect of interest will be 
assessed for all randomized subjects enrolled from traditional sites who receive at least 
1 dose of IP and have a baseline value and at least 1 post-baseline value of monthly 
percent work impairment, regardless of adherence to treatment. 
 
The summary measure, which is the difference in means of the endpoint between the 
erenumab group and the placebo group 
The estimand is the difference in means between erenumab and placebo of the change from 
baseline in mean monthly percent work impairment over months 4, 5, and 6 of the 6-month 
DBTP in employed subjects with EM who have previously failed 1 or more migraine preventive 
treatments and who are randomized, receive at least 1 dose of IP, and have a baseline value 
and at least 1 post-baseline value of monthly percent work impairment, regardless of 
adherence to treatment. 
 
To evaluate the effect of erenumab 
compared to placebo on physical function, 
usual activities, and social function in 
employed subjects with EM who have 
previously failed 1 or more migraine 
preventive treatments 
 
Change from baseline in mean physical 
function domain score over months 4, 5, 
and 6 of the 6-month DBTP, as measured 
by Migraine Functional Impact 
Questionnaire (MFIQ) 
 
Change from baseline in mean usual 
activities domain score over months 4, 5, 
and 6 of the 6-month DBTP, as measured 
by MFIQ 
 
Change from baseline in mean social 
function domain score over months 4, 5, 
and 6 of the 6-month DBTP, as measured 
by MFIQ 


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CONFIDENTIAL  
 
 
Objectives 
Endpoints 
Secondary (Continued) 
The estimand for the secondary objective on function (physical, usual activities, and social) 
consists of: 
 
The target population, which includes employed subjects with EM who have previously 
failed 1 or more migraine preventive treatments  
 
The endpoints include: 
1) the change from baseline in mean physical function domain score over months 4, 5, 
and 6 of the 6-month DBTP, as measured by MFIQ 
2) the change from baseline in mean usual activities domain score over months 4, 5, and 
6 of the 6-month DBTP, as measured by MFIQ 
3) the change from baseline in mean social function domain score over months 4, 5, and 
6 of the 6-month DBTP, as measured by MFIQ 
 
The intercurrent event is adherence to treatment.  The treatment effect of interest will be 
assessed for all randomized subjects enrolled from traditional sites who receive at least 
1 dose of IP and have a baseline value and at least 1 post-baseline value of the respective 
MFIQ domain score, regardless of adherence to treatment. 
 
The summary measure, which is the difference in means of the respective endpoint 
between the erenumab group and the placebo group 
 
Hypotheses 
The primary clinical hypothesis is that preventive treatment with monthly injections of 
erenumab is superior to placebo in reducing disability in employed subjects with EM who 
have previously failed 1 or more migraine preventive treatments. 
Overall Design 
Study 20180060 is a phase 4, 24-week, prospective, double-blind, randomized, 
placebo-controlled, multicenter study in the United States (US), evaluating the effect of 
erenumab on disability and work productivity in employed patients with EM who have 
previously failed 1 or more migraine preventive treatments.  Subjects will enter initial 
screening (up to 21 days) to determine if they meet Eligibility Criteria Part 1.  If Part 1 
eligibility criteria are met, subjects will enter baseline (28 days).  After subjects complete 
baseline and are found eligible based on Eligibility Criteria Part 2, they will be enrolled 
and randomized in a 1:1 ratio to either erenumab 140 mg or placebo.  Randomization 
will be performed separately within traditional sites and decentralized clinical trial site 
(DCTS).  For DCTS, please refer to (Section 5.2.2.1).  Subjects will then enter a 
24-week DBTP which will conclude with an end-of-study visit at week 24. 
Number of Subjects 
Approximately 240 subjects from traditional sites will be enrolled in the study, 120 per 
treatment group.  Up to an additional 100 subjects (50 per treatment group) will be 


Product:  Erenumab-aooe (AMG 334) 
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CONFIDENTIAL  
 
 
enrolled to pilot DCTS, a clinical trial operating model that enables remote participation 
in clinical trials (Section 5.2.2.1). 
Summary of Subject Eligibility Criteria 
Key inclusion criteria include: 
 
 18 years of age 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 
 
Has EM defined as history of  4 and  15 migraine days and  15 headache days 
per month on average during the 3 months prior to initial screening and during 
baseline 
 
Employed  20 hours/week upon entry into initial screening, stable for at least 
3 months in the same job and has not specified willful termination of employment 
throughout the duration of the study.  Employment is defined as work outside the 
home, self-employed, or work from home. 
 
Has  4 hours of lost productive time in the past month prior to initial screening 
(determined by the subject) and during baseline (assessed by electronic Diary 
[eDiary] device).  Lost productive time is due to headache/migraine and/or 
related symptoms. 
 
Has total disability score of  10 as assessed by MIDAS (3-month recall) at initial 
screening and total disability score of  3 by modified MIDAS (1-month recall) on day 
1 (prior to randomization) 
 
History of treatment failure with at least 1 preventive treatment category for migraine 
(see exclusion criterion 214 for treatment category definition).  Failure of preventive 
treatment category for migraine is defined as treatment discontinuation due to lack of 
efficacy, adverse event, or general poor tolerability. 
Key exclusion criteria include: 
 
Previously treated with any agent (monoclonal antibody or small molecule) targeting 
the calcitonin gene-related peptide (CGRP) pathway (ligand or receptor) in 
preventive settings 
 
History of cluster headache, hemiplegic migraine, or other trigeminal autonomic 
cephalalgia 
 
Evidence of substance-related disorders (eg, abuse, misuse, or addiction), addictive 
disorders (eg, pathological gambling), or "recreational use" of illicit drugs within 
12 months prior to initial screening, based on medical records, patient self-report, or 
positive urine drug test performed during screening (with the exception of prescribed 
medications such as opioids or barbiturates that may result in a positive urine drug 
test) 
 
Taken an opioid and/or opioid-containing analgesic ≥ 4 days during the 1 month prior 
to initial screening or  4 days during baseline for any indication 
 
Taken a butalbital and/or butalbital-containing analgesic ≥ 4 days during the 1 month 
prior to initial screening or > 4 days during baseline for any indication 


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CONFIDENTIAL  
 
 
For a full list of eligibility criteria, please refer to Section 6.1 to Section 6.4. 
Treatments 
Investigational product (erenumab [140 mg] or placebo) in prefilled syringes (PFS) will 
be administered by study staff or subject (refer to Table 7-1) every 4 weeks during the 
24-week treatment period.  Subjects participating in the study as part of the DCTS will 
self-inject the IP in PFS at their own physical location (eg, home) under the observation 
of the investigator/member of the study team via videoconference, after being trained on 
day 1 by the qualified study personnel on self-injections. 
Procedures 
After signing informed consent, subjects will enter the screening period.  The screening 
period is up to 7 weeks and is composed of an initial screening up to 3 weeks (21 days) 
followed by a 4-week (28 days) baseline.  At the day 1 visit, eligible subjects will be 
enrolled and randomized into the 24-week (6-month) DBTP and will begin to receive IP 
subcutaneously (SC) every 4 weeks.  Subjects will use an eDiary everyday throughout 
the baseline period and DBTP to report information about their migraine and 
nonmigraine headaches, other migraine-related symptomatology, medication taken, and 
complete other clinical outcome assessments (COAs).  Subjects will have a wearable 
device on the wrist to monitor physical activity and sleep and will continuously wear the 
device throughout the study except when recharging or medically/professionally 
contraindicated (see Section 9.2.2.2).  Subjects will have scheduled monthly study visits 
throughout the study. 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 9.2 and the Schedule of Activities in Section 2.2. 
Statistical Considerations 
The final analysis will be performed when the last subject completes the study or 
discontinues the study. 
Formal statistical hypothesis testing will be performed for subjects enrolled from 
traditional sites.  Statistical analyses for the DCTS will be considered exploratory. 
Under the assumption of missing at random (MAR), the primary and 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.  The least-square estimate for each 
treatment group, the treatment difference, 95% CI, and p-value will be reported.   


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Primary and secondary endpoints for the erenumab 140 mg group versus placebo will 
be tested using a sequential testing procedure to maintain a family-wise type 1 error rate 
α = 0.05.  The order of the endpoints to be tested is prespecified below.  If any test is not 
significant at the α = 0.05 level, no further testing will be performed. 
1. Primary endpoint:  total monthly change from baseline in migraine-related 
disability over the 6-month DBTP, as measured by monthly modified MIDAS 
2. Secondary endpoint:  change from baseline in mean MMD over months 4, 5, 
and 6 of the 6-month DBTP 
3. Secondary endpoint:  change from baseline in mean monthly average percent 
overall work impairment over months 4, 5, and 6 of the 6-month DBTP, as 
measured by WPAI (questions 2, 4, and 5) 
4. Secondary endpoint:  change from baseline in mean physical function domain 
score over months 4, 5, and 6 of the 6-month DBTP, as measured by MFIQ 
5. Secondary endpoint:  change from baseline in mean usual activities domain 
score over months 4, 5, and 6 of the 6-month DBTP, as measured by MFIQ 
6. Secondary endpoint:  change from baseline in mean social function domain 
score over months 4, 5, and 6 of the 6-month DBTP, as measured by MFIQ 
Multiple imputation (MI) with the assumption of missing not at random (MNAR) will be 
used as a sensitivity analysis to handle missing data at each assessment time point for 
the primary and secondary endpoints, using the analysis of covariance (ANCOVA) 
model including treatment group and baseline value. 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor Name: Amgen, Inc 


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CONFIDENTIAL  
 
 
2. 
Study Schema and Schedule of Activities 
2.1 
Study Schema 
Figure 2-1.  Study Schema 
Baseline
(Eligibility Criteria Part 2)
Double-blind Treatment Period (DBTP)
Initial Screening
(Eligibility Criteria Part 1)
Placebo
End of Study
Erenumab 140 mg 
Randomization
Day 1
Wk 24
Wk 20
Wk 16
Wk 12
Wk 8
Wk 4
= Investigational Product Administration
Screening
Up to 3 wks
4 wks
 


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2.2 
Schedule of Activities 
Table 2-1.  Schedule of Activities 
Procedure 
Screening Period 
Double-blind Treatment Period (weeks)b 
Notes 
Initial 
Screeninga 
Baseline 
D -28 to D -1 
D1 
Wk 4 
Wk 8 Wk 12 Wk 16 Wk 20 
Wk 24/  
EOSc 
GENERAL ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Eligibility Criteria Part 1 
X 
 
 
 
 
 
 
 
 
For a list of criteria, see  
Sections 6.1 and 6.2. 
3-month MIDAS 
X 
 
 
 
 
 
 
 
 
3-month recall; paper formatd 
Employment status 
X 
X  
X 
X 
X 
X 
X 
X 
X 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
COVID-19 impact 
assessment 
 
Weekly 
 
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 
 
 
 
 
 
 
 
 
 


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CONFIDENTIAL  
 
 
Page 1 of 5 
Footnotes after last page of table. 
Table 2-1.  Schedule of Activities 
Procedure 
Screening Period 
Double-blind Treatment Period (weeks)b 
Notes 
Initial 
Screeninga 
Baseline 
D -28 to D -1 
D1 Wk 4 Wk 8 Wk 12 Wk 16 Wk 20 
Wk 24/  
EOSc 
GENERAL ASSESSMENTS (continued) 
Prior migraine 
preventive medication 
history 
X 
 
 
 
 
 
 
 
 
 
Substance use 
X 
 
X 
 
 
 
 
 
 
Evidence of substance-related disorders (eg, 
abuse, misuse, or addiction), addictive disorders 
(eg, pathological gambling), or "recreational 
use" of illicit drugs within 12 months prior to 
initial screening and baseline, based on medical 
records, patient self-report, or positive urine 
drug test performed at initial screening (with the 
exception of prescribed medications such as 
opioids or barbiturates that may result in a 
positive urine drug test) 
Prior/Concomitant 
therapies review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(as early as 120 days prior to initial screening) 
Eligibility Criteria Part 2 
 
 
X 
 
 
 
 
 
 
For a list of criteria, see  
Section 6.3 and 6.4. 
 
Page 2 of 5 
Footnotes after last page of table. 


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CONFIDENTIAL  
 
 
Table 2-1.  Schedule of Activities 
Procedure 
Screening Period 
Double-blind Treatment Period (weeks)b 
Notes 
Initial 
Screeninga 
Baseline 
D -28 to D -1 
Day 1 Wk 4 Wk 8 Wk 12 Wk 16 Wk 20 
Wk 24/  
EOSc 
SAFETY ASSESSMENTS 
Adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Serious adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse device effects 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Product complaints 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
LOCAL LABORATORY ASSESSMENTS 
Urine pregnancy test 
(FOCP only) 
X 
 
X 
X 
X 
X 
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. 
Positive urine drug testing that may be 
reasonably linked to use of an allowable 
over-the-counter medication may require 
retesting before eligibility can be 
considered. In such instances, Amgen 
medical monitor must be consulted prior to 
retesting or determining eligibility. 
Page 3 of 5 
Footnotes after last page of table. 


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CONFIDENTIAL  
 
 
Table 2-1.  Schedule of Activities 
Procedure 
Screening Period 
Double-blind Treatment Period (weeks)b 
Notes 
Initial 
Screeninga 
Baseline 
D -28 to D -1 
Day 1  Wk 4 Wk 8 Wk 12 Wk 16 Wk 20 
Wk 24/  
EOSc 
(OPTIONAL) BIOMARKER AND PHARMACOGENETIC ASSESSMENTS 
Biomarker 
development, blood 
 
 
X 
 
 
 
 
 
 
 
Pharmacogenetic 
studiese 
 
 
X 
 
 
 
 
 
 
 
HEALTH ECONOMIC ASSESSMENTS 
HRU Questionnaire 
(24-week recall) 
 
 
X 
 
 
 
 
 
X 
The HRU questionnaire will have a 24-week 
recall of prior utilization.  For early 
termination visits, questionnaire assessed at 
the EOS visit before week 24 should only 
include HRU recalled since the previous 
assessment to avoid collecting duplicate 
information. 
CLINICAL OUTCOME ASSESSMENTS 
eDiary 
 
Daily 
 
Modified MIDAS 
 
 
X 
X 
X 
X 
X 
X 
X 
1-month recall;  
Assessment on Day 1 should be completed 
prior to randomization 
WPAI 
 
Weekly 
 
Page 4 of 5 
Footnotes after last page of table. 
 


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CONFIDENTIAL  
 
 
Table 2-1.  Schedule of Activities 
Procedure 
Screening Period 
Double-blind Treatment Period (weeks)b 
Notes 
Initial 
Screeninga 
Baseline 
D -28 to D -1 
Day 1 
Wk 4 
Wk 8 Wk 12 Wk 16 Wk 20 
Wk 24/  
EOSc 
CLINICAL OUTCOME ASSESSMENTS (continued) 
MFIQ 
 
 
X 
X 
X 
X 
X 
X 
X 
 
PHQ-9 
X 
 
X 
X 
 
X 
 
 
X 
Assessment during initial screening is 
to fulfill eligibility criteria; 
Paper format during screeningd 
GAD-7 
 
 
X 
X 
 
X 
 
 
X 
 
PSQI 
 
 
X 
X 
 
X 
 
 
X 
 
ESS 
 
 
X 
X 
 
X 
 
 
X 
 
Patient satisfaction at 
work 
 
 
X 
X 
 
X 
 
 
X 
 
PVT 
 
 
X 
X 
 
X 
 
 
X 
PVT should be collected after 
randomization on Day 1.  PVT will not 
be completed by subjects 
participating as part of DCTS. 
STUDY-RELATED DEVICE ASSIGNMENT 
Assign eDiary device 
 
X 
 
 
 
 
 
 
 
 
Assign wearable device 
 
X 
 
 
 
 
 
 
 
See Section 9.2.2.2. 
STUDY TREATMENT  
IP administration 
 
 
X 
X 
X 
X 
X 
X 
 
 
Page 5 of 5 
DCTS = decentralized clinical trial site; ESS = Epworth Sleepiness Scale; GAD-7 = Generalized Anxiety Disorder 7-item Scale; Hep = hepatitis; HRU = Health 
Resource Utilization; IP = investigational product; MFIQ = Migraine Functional Impact Questionnaire; MIDAS = Migraine Disability Assessment; PHQ-9 = Patient 


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Health Questionnaire; PSQI = Pittsburgh Sleep Quality Index; PVT = Psychomotor Vigilance Test; Wk = week; WPAI = Work Productivity and Activity Impairment 
Questionnaire 
a The initial screening period is up to 3 weeks (21 days) before the baseline period begins. 
b Each study visit during the double-blind treatment period (DBTP) has a window of ± 3 consecutive calendar days.  The baseline period has a window of + 7 
consecutive calendar days; the day 1 visit must occur 28 to 35 days after the week -4 visit date.  All study visit target dates are to be calculated from the day 1 visit 
date.  All study procedures for a given study visit are to be completed on the same day. 
c A subject who discontinues the study during the DBTP (before week 24) will complete the assessments of the week 24/EOS visit. 
d Format of these questionnaires will be electronic for the DCTS (within DCTS hand-held device). 
e 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. 
 


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CONFIDENTIAL  
 
 
3. 
Introduction 
3.1 
Study Rationale 
The presence of various comorbidities in migraine patients, whether associated or 
migraine-induced, has been established by numerous studies.  These comorbidities 
contribute to migraine-related disability, impacting work and overall function 
(Lipton et al, 2013; Stewart et al, 2008).  The American Migraine Prevalence and 
Prevention (AMPP) study of patients with episodic migraine (EM) evaluated several 
domains of headache-related disability such as work, depression, and anxiety, to name 
a few, that are frequently affected by migraine.  Other studies, though smaller in scale, 
have demonstrated the impact of migraine on quality and quantity of sleep 
(Barbanti et al, 2007; Kelman and Rains, 2005). 
Closer analyses of impact of migraine on work have not only revealed absence from 
work, but also reduction in performance also known as presenteeism 
(Stewart et al, 2008).  Relevant components of decreased presenteeism include 
impaired concentration and feeling of fatigue. 
In phase 2 and 3 clinical trials, erenumab-aooe (referred to as erenumab herein) has 
demonstrated a reduction in monthly migraine days (MMD) as well as migraine-related 
disability (Dodick et al, 2018; Tepper et al, 2017; Goadsby et al, 2017b).  Separately, 
improvement in MMD and migraine-related disability have been associated with 
improvement in work productivity (Dodick et al, 2016; Lipton et al, 2013).  
Study 20180060 is being conducted to confirm the effect of erenumab on 
migraine-related disability (inclusive of aforementioned comorbidities) and work 
productivity. 
Given that this study’s focus is on work productivity, the rationale for selecting 
EM as the target population is as follows.  CM has a higher burden of disability 
and therefore unemployment and under-employment are more prevalent.  
Additionally, the prior AMPP study referenced above, focused on EM in order to 
be able to evaluate multiple domains related to work. 
3.2 
Background 
3.2.1 
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 


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CONFIDENTIAL  
 
 
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).  Depending on the headache frequency, 
migraine is divided into 2 broad forms:  EM and chronic migraine (CM) according to 
International Classification of Headache Disorders, third edition (ICHD-III).  Episodic 
migraine is defined as migraine with fewer than 14 headache days per month, while CM 
has 15 or more headache days per month (where at least 8 of those days are migraine 
days).  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 somewhat arbitrarily distinguished based on migraine 
headache frequency, numerous lines of evidence support that they are a continuum of 
the same disorder.  Not only are clinical symptomologies and functional impairments 
very similar, but functional imaging results demonstrating involvement of similar brain 
regions support a common underlying pathophysiology (Aurora and Wilkinson, 2007; 
Afridi et al, 2005; Aurora et al, 2005; Welch et al, 2001).  Regardless of classification as 
EM or CM, migraine has life altering impact beyond physical symptoms and debilitation.  
Migraine-related disability has social, psychological, and economical implications 
(Lipton et al, 2013; Lipton et al, 2007).  The AMPP and Chronic Migraine Epidemiology 
and Outcomes (CaMEO) studies demonstrated the impact of migraine-related disability 
on various elements of daily function as well as work productivity  
(Lipton et al, 2013; Lipton et al, 2007).   
Only approximately 12% of patients with migraine receive any preventive therapy due to 
limited efficacy and significant tolerability and safety issues with available preventive 
therapies.  Migraine prevention is an area of large unmet medical need. 
3.2.2 
Amgen Investigational Product Background:  Erenumab 
Erenumab is a human immunoglobulin G2 (IgG2) monoclonal antibody that is directed 
against the canonical calcitonin gene-related peptide (CGRP) receptor complex and 
inhibits the action of CGRP.  Calcitonin gene-related peptide belongs to the calcitonin 
family of peptides and is expressed in both the central and peripheral nervous systems.  
It is prominently involved in the pathophysiology of migraine through nociceptive 
modulation, in the trigeminovascular system (Goadsby et al, 2002; Tajti et al, 1999).  
Nonclinical studies with erenumab demonstrated that it binds to and antagonizes both 


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CONFIDENTIAL  
 
 
human and cynomolgus monkey CGRP receptors with high affinity and potency.  
Erenumab has been developed for the prevention of migraine in adults based on the 
observed long serum half-life in humans (28 days), clinical data demonstrating that small 
molecule CGRP receptor antagonists are effective in acute migraine reversal 
(Ho et al, 2008a; Ho et al, 2008b), prevention (Ho et al, 2014), and the strong rationale 
for CGRP’s association with migraine pathophysiology (Goadsby et al, 2017a; 
Sun et al, 2016; Bellamy et al, 2006; Sarchielli et al, 2006; Juhasz et al, 2005; 
Petersen et al, 2005; Lassen et al, 2002; Tajti et al, 1999; Gallai et al, 1995; 
Goadsby et al, 1990; Goadsby et al, 1988). 
As of the date of approval of this protocol, erenumab 70 mg and 140 mg subcutaneously 
(SC) every 4 weeks (Q4W) or once monthly (QM) have been approved in the US, 
Europe, Australia, and Switzerland for the prevention of migraine in adults with additional 
ongoing approvals globally.  As of the date of approval of this protocol, erenumab 
70 mg and 140 mg subcutaneously (SQ), every 4 weeks (Q4W) or once monthly 
(QM) have been approved in more than 60 countries including US, EU, and 
Australia.  
A detailed description of the chemistry, pharmacology, efficacy, and safety of erenumab 
can be found in the Investigator’s Brochure. 
3.3 
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 for prevention of migraine headaches in adults consist of 
confirmatory results that include reduction in mean MMDs, reduction in acute medication 
use, and favorable tolerability and low treatment discontinuation rate, as well as 
supportive results that include convenience, and improvements in clinical outcome 
assessments (COA) (Migraine Physical Function Impact Diary [MPFID], Migraine 
Disability Assessment [MIDAS], and Headache Impact Test-6 [HIT-6]). 
Overall, the safety profile of erenumab has been favorable in clinical trials.  A limited 
number of adverse drug reactions (injection site reactions, constipation, muscle spasm, 
and pruritis) have been identified at low frequencies ( 5%) in clinical trials.  In 
post-marketing settings, hypersensitivity reactions (including rash, angioedema, and 
anaphylactoid reactions) and constipation with serious complications have been 
reported.  In conclusion, erenumab 140 mg addresses an unmet need as an effective, 


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CONFIDENTIAL  
 
 
safe, and tolerable preventive treatment of migraine.  The key benefits of erenumab 
outweigh the risks in this population. 
Reference should be made to the Investigator’s Brochure and Prescribing Information, 
where Aimovig is approved, for further data on erenumab. 


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4. 
Objectives, Endpoints and Hypotheses 
4.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the effect of erenumab 
compared to placebo on disability in 
employed subjects with episodic migraine 
(EM) who have previously failed 1 or 
more migraine preventive treatments 
 
Sum of monthly changes from baseline in 
modified Migraine Disability Assessment 
(MIDAS) total score over the 6-month 
double-blind treatment period (DBTP) 
Primary Estimand 
The primary estimand for the primary objective on migraine-related disability consists of: 
 
The target population, which includes employed subjects with EM who have previously 
failed 1 or more migraine preventive treatments  
 
The endpoint, which is the sum of monthly changes from baseline in modified MIDAS total 
score over the 6-month DBTP 
 
The intercurrent event is adherence to treatment.  The treatment effect of interest will be 
assessed for all randomized subjects enrolled from traditional sites who receive at least 
1 dose of investigational product (IP) and have a baseline value and at least 1 
post-baseline value of modified MIDAS total score, regardless of adherence to treatment 
 
The summary measure, which is the difference in means of the endpoint between the 
erenumab group and the placebo group 
The primary estimand is the difference in means between erenumab and placebo of the sum of 
monthly changes from baseline in modified MIDAS total score over the 6-month DBTP in 
employed subjects with EM who have previously failed 1 or more migraine preventive 
treatments and who are randomized, receive at least 1 dose of IP, and have a baseline value 
and at least 1 post-baseline value of modified MIDAS total score, regardless of adherence to 
treatment. 
Secondary 
 
To evaluate the effect of erenumab 
compared to placebo on monthly migraine 
days (MMD) in employed subjects with 
EM who have previously failed 1 or more 
migraine preventive treatments 
 
Change from baseline in mean MMD over 
months 4, 5, and 6 of the 6-month DBTP 


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CONFIDENTIAL  
 
 
Objectives 
Endpoints 
Secondary (Continued) 
The estimand for the secondary objective on MMD consists of: 
 
The target population, which includes employed subjects with EM who have previously 
failed 1 or more migraine preventive treatments  
 
The endpoint, which is the change from baseline in mean MMD over months 4, 5, and 6 of 
the 6-month DBTP 
 
The intercurrent event is adherence to treatment.  The treatment effect of interest will be 
assessed for all randomized subjects enrolled from traditional sites who receive at least 
1 dose of IP and have a baseline value and at least 1 post-baseline value of MMD, 
regardless of adherence to treatment. 
 
The summary measure, which is the difference between the mean of the endpoint for the 
erenumab group and the placebo group 
The estimand is the difference in means between erenumab and placebo of the change from 
baseline in mean MMD over months 4, 5, and 6 of the 6-month DBTP in employed subjects 
with EM who have previously failed 1 or more migraine preventive treatments and who are 
randomized, receive at least 1 dose of IP, and have a baseline value and at least 1 
post-baseline value of MMD, regardless of adherence to treatment.  
 
To evaluate the effect of erenumab 
compared to placebo on work impairment 
in employed subjects with EM who have 
previously failed 1 or more migraine 
preventive treatments 
 
Change from baseline in mean monthly 
percent work impairment over months 4, 
5, and 6 of the 6-month DBTP, as 
measured by the Work Productivity and 
Activity Impairment Questionnaire 
(WPAI):  Migraine V2.0 
(WPAI questions 2, 4, and 5) 
Note:  the monthly percent work 
impairment equals to the arithmetic mean 
of the observed weekly percent work 
impairment over the monthly interval. 
The estimand for the secondary objective on work impairment consists of: 
 
The target population, which includes employed subjects with EM who have previously 
failed 1 or more migraine preventive treatments  
 
The endpoint, which is the change from baseline in mean monthly percent work impairment 
over months 4, 5, and 6 of the 6-month DBTP 
 
The intercurrent event is adherence to treatment.  The treatment effect of interest will be 
assessed for all randomized subjects enrolled from traditional sites who receive at least 
1 dose of IP and have a baseline value and at least 1 post-baseline value of monthly 
percent work impairment, regardless of adherence to treatment. 
 
The summary measure, which is the difference in means of the endpoint between the 
erenumab group and the placebo group 


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Objectives 
Endpoints 
Secondary (Continued) 
The estimand is the difference in means between erenumab and placebo of the change from 
baseline in mean monthly percent work impairment over months 4, 5, and 6 of the 6-month 
DBTP in employed subjects with EM who have previously failed 1 or more migraine preventive 
treatments and who are randomized, receive at least 1 dose of IP, and have a baseline value 
and at least 1 post-baseline value of monthly percent work impairment, regardless of 
adherence to treatment. 
 
To evaluate the effect of erenumab 
compared to placebo on physical function, 
usual activities, and social function in 
employed subjects with EM who have 
previously failed 1 or more migraine 
preventive treatments 
 
Change from baseline in mean physical 
function domain score over months 4, 5, 
and 6 of the 6-month DBTP, as measured 
by Migraine Functional Impact 
Questionnaire (MFIQ) 
 
Change from baseline in mean usual 
activities domain score over months 4, 5, 
and 6 of the 6-month DBTP, as measured 
by MFIQ 
 
Change from baseline in mean social 
function domain score over months 4, 5, 
and 6 of the 6-month DBTP, as measured 
by MFIQ 
The estimand for the secondary objective on function (physical, usual activities, and social) 
consists of: 
 
The target population, which includes employed subjects with EM who have previously 
failed 1 or more migraine preventive treatments  
 
The endpoints include: 
1) the change from baseline in mean physical function domain score over months 4, 5, 
and 6 of the 6-month DBTP, as measured by MFIQ 
2) the change from baseline in mean usual activities domain score over months 4, 5, and 
6 of the 6-month DBTP, as measured by MFIQ 
3) the change from baseline in mean social function domain score over months 4, 5, and 
6 of the 6-month DBTP, as measured by MFIQ 
 
The intercurrent event is adherence to treatment.  The treatment effect of interest will be 
assessed for all randomized subjects enrolled from traditional sites who receive at least 
1 dose of IP and have a baseline value and at least 1 post-baseline value of the respective 
MFIQ domain score, regardless of adherence to treatment. 
 
The summary measure, which is the difference in means of the respective endpoint 
between the erenumab group and the placebo group 


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Objectives 
Endpoints 
Exploratory 
 
To evaluate the effect of erenumab 
compared to placebo on work impairment 
in employed subjects with EM who have 
previously failed 1 or more migraine 
preventive treatments 
 
Change from baseline in monthly average 
percent overall work impairment at each 
monthly assessment time point during the 
6-month DBTP, as measured by the 
WPAI (questions 2, 4, and 5) 
 
To evaluate the effect of erenumab 
compared to placebo on MMD in 
employed subjects with EM who have 
previously failed 1 or more migraine 
preventive treatments 
 
Change from baseline in MMD at each 
monthly assessment time points during 
the 6-month DBTP 
 
To evaluate the effect of erenumab 
compared to placebo on function and 
quality of life in employed subjects with 
EM or who have previously failed 1 or 
more migraine preventive treatments 
 
Change from baseline in mean emotional 
function domain score over months 4, 5, 
and 6 of the 6-month DBTP, as measured 
by MFIQ 
 
Change from baseline in mean overall 
impact on usual activities global item 
score over months 4, 5, and 6 of the 
6-month DBTP, as measured by MFIQ 
 
Change from baseline in MFIQ domain 
scores of function (physical, usual 
activities, social, and emotional) and 
overall impact on usual activities global 
item score at each monthly assessment 
time point during the 6-month DBTP 
 
Change from baseline in depression at 
months 1, 3, and 6 of the 6-month DBTP, 
as measured by the Patient Health 
Questionnaire (PHQ-9) total score 
 
Change from baseline in anxiety at 
months 1, 3, and 6 of the 6-month DBTP, 
as measured by Generalized Anxiety 
Disorder 7-item Scale (GAD-7) total score 
 
Change from baseline in insomnia at 
months 1, 3, and 6 of the 6-month DBTP, 
as measured by the Pittsburgh Sleep 
Quality Index (PSQI) total score 


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Objectives 
Endpoints 
Exploratory (Continued) 
 
 
Change from baseline in excessive 
daytime sleepiness at months 1, 3, and 6 
of the 6-month DBTP, as measured by 
the Epworth Sleepiness Scale (ESS) total 
score 
 
Change from baseline in monthly average 
activity level during and between migraine 
days at each monthly assessment time 
point during the 6-month DBTP, as 
measured by a wearable 
 
Change from baseline in patient 
satisfaction at work at months 1, 3, and 6 
of the 6-month DBTP, as measured by 
the questions in Section 9.2.2.1.8 
 
To describe the effect of erenumab on 
migraine-related health resource 
utilization (HRU) in employed subjects 
with EM who have previously failed 1 or 
more migraine preventive treatments 
 
Occurrence of at least 1 migraine-related 
hospitalization or outpatient HRU during 
the 6-month DBTP 
 
Occurrence of at least 1 migraine-related 
hospitalization during the 6-month DBTP 
 
Occurrence of at least 1 migraine-related 
outpatient HRU during the 6-month DBTP 
 
Occurrence of at least 1 migraine-related 
outpatient emergency room visit during 
the 6-month DBTP 
 
Occurrence of at least 1 migraine-related 
outpatient urgent care visit during the 
6-month DBTP 
 
Occurrence of at least 1 migraine-related 
outpatient clinic visit during the 6-month 
DBTP 
 
To evaluate the effect of erenumab 
compared to placebo on attention in 
employed subjects with EM who have 
previously failed 1 or more migraine 
preventive treatments 
 
Change from baseline in mean reaction 
time at months 1, 3, and 6 of the 6-month 
DBTP, as measured by the Psychomotor 
Vigilance Test (PVT)  
 
Change from baseline in number of 
lapses and errors at months 1, 3, and 6 of 
the 6-month DBTP, as measured by PVT 
 


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4.2 
Hypotheses 
The primary clinical hypothesis is that preventive treatment with monthly injections of 
erenumab is superior to placebo in reducing disability in employed subjects with EM who 
have previously failed 1 or more migraine preventive treatments. 
5. 
Study Design 
5.1 
Overall Design 
Study 20180060 is a phase 4, 24-week, prospective, double-blind, randomized, 
placebo-controlled, multicenter study in the US, evaluating the effect of erenumab on 
disability and work productivity in employed patients with EM who have previously failed 
1 or more migraine preventive treatments.  Subjects will enter initial screening (up to 
21 days) to determine if they meet Eligibility Criteria Part 1.  If Part 1 eligibility criteria are 
met, subjects will enter the baseline (28 days).  After subjects complete the baseline and 
are found eligible based on Eligibility Criteria Part 2, they will be enrolled and 
randomized in a 1:1 ratio to either erenumab 140 mg or placebo.  Randomization will be 
performed separately within traditional sites and the decentralized clinical trial site 
(DCTS).  For the DCTS, please refer to Section 5.2.2.1.  Subjects will then enter a 
24-week DBTP which will conclude with an end-of-study visit at week 24. 
The overall study design is described by a study schema in Section 2.1.  The endpoints 
are defined in Section 4.1. 
5.2 
Number of Subjects 
Approximately 240 subjects from traditional sites will be enrolled in the study, 120 per 
treatment group.  Up to an additional 100 subjects (50 per treatment group) will be 
enrolled to pilot DCTS, a clinical trial operating model that enables remote participation 
in clinical trials (Section 5.2.2.1). 
Subjects in this clinical investigation shall be referred to as “subjects”.  For the sample 
size justification, see Section 10.1. 
5.2.1 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
5.2.2 
Number of Sites 
Approximately 31 investigative sites (30 traditional sites plus 1 DCTS) in the US will be 
included in the study.  Sites that do not enroll subjects within 3 months of site initiation 
may be closed. 


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5.2.2.1 
Decentralized Clinical Trials Site (DCTS) 
The DCTS is a remote study model that integrates telemedicine technology into the 
clinical research process and supports management of research activities, including data 
collection.  As part of this model, study visits are completed using the DCTS technology 
platform.  This 21 Code of Federal Regulations (CFR) Part 11 compliant software 
interface facilitates recruitment, enrollment, and study data collection within a single 
cloud-based technology.  It connects subjects to their investigators and study team 
through a study-issued smartphone. 
Decentralizing research studies from traditional site-based centers, making them 
“site-less,” aims to eliminate barriers to participation including inaccessibility due to 
geography and the inconvenience of traveling to site visits.  A DCTS complies with all 
regulatory requirements applicable to study investigators, as delineated in 21 CFR 312 
and International Council for Harmonisation (ICH) E6 (R2).  As such, it does not assume 
any Sponsor or Contract Research Organization (CRO) obligations. 
5.3 
End-of-Study 
5.3.1 
End-of-Study Definition 
Primary Completion:  The primary completion date is 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), whether the study concluded as planned in the protocol or was 
terminated early. 
The primary completion date is the date when the last subject has completed the 
assessments for week 24 (month 6) or discontinues study. 
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), as 
applicable.  For this study, the end-of-study date is the same as the primary completion 
date. 


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5.3.2 
Study Duration for Subjects 
The total study duration for subjects who successfully complete the study will be up to 
31 weeks. 
5.4 
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.  The 140 mg dose has been selected as the 
treatment dose because it has demonstrated greater efficacy in phase 2 and 3 clinical 
trials.  In the Study to Evaluate the Efficacy and Safety of Erenumab in Migraine 
Prevention (STRIVE) study of EM patients (phase 3; 20120296), erenumab 140 mg 
treatment arm experienced statistically significant reduction from baseline in MMD as 
compared with 70 mg and placebo (Goadsby et al, 2017b).  Furthermore, in a post-hoc 
analysis of STRIVE, patients with ≥ 2 prior treatment failures in the 140 mg erenumab 
arm had an average MMD reduction nearly twice as much as those in the 70 mg 
erenumab arm (Goadsby et al, 2017c).  In the phase 3b LIBERTY study (A Study 
Evaluating the Effectiveness of AMG 334 Injection in Preventing Migraines in Adults 
Having Failed Other Therapies) of EM patients who had failed 2 to 4 prophylactic 
migraine treatments and were treated with either erenumab 140 mg or placebo, 
30% demonstrated a 50% or greater reduction in their individual baseline MMD 
(primary endpoint) compared with placebo.  Also, erenumab 140 mg reduced MMD as 
compared with placebo (secondary endpoint) (Reuter et al, 2018).   
5.5 
Patient Input on Study Design 
Patient input was not collected during study design. 
6. 
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).   
Eligibility criteria will be evaluated during initial screening (Part 1) and determines 
eligibility for subjects to enter baseline.  Additional (Part 2) eligibility criteria will be 
evaluated on day 1 (pre-enrollment) for those who successfully met eligibility criteria 
during initial screening and completed the 4-week (28 days) baseline for entry into the 
double-blind treatment period. 
Before any study-specific activities/procedures, the appropriate informed consent must 
be obtained (see Section 12.3).   


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Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be provided. 
6.1 
Inclusion Criteria Part 1 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
101 
Provided informed consent prior to initiation of any study-specific 
activities/procedures 
102 
 18 years of age upon entry into initial screening 
103 
Documented history of migraine with or without aura according to the 
International Headache Society (IHS) ICHD-III for  12 months 
104 
Has EM defined as history of  4 and  15 migraine days and  15 headache 
days per month on average during the 3 months prior to initial screening 
(see Section 12.1 for definition of headache/migraine days)  
106 
Has  4 hours of lost productive time due to headache/migraine and/or related 
symptoms in the past month prior to initial screening as determined by 
subject. 
107 
Has total disability score of  10 as assessed by MIDAS (3-month recall) at initial 
screening 
108 
History of treatment failure with at least 1 preventive treatment category for 
migraine (see exclusion criterion 214 for treatment category definition).  Failure of 
preventive treatment category for migraine is defined as treatment 
discontinuation due to lack of efficacy, adverse event, or general poor tolerability. 
115 
Employed  20 hours/week upon entry into initial screening, stable for at least 
3 months in the same job and has not specified willful termination of 
employment throughout the duration of the study.  Employment is defined by 
work outside the home, self-employed, or works from home. 
6.2 
Exclusion Criteria Part 1 
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 cluster headache, hemiplegic migraine, or other trigeminal autonomic 
cephalalgia 
Other Medical Conditions 
203 
Currently diagnosed with fibromyalgia and/or chronic pelvic pain 
204 
History of major psychiatric disorder (such as schizophrenia or other psychotic 
disorders, bipolar disorder, obsessive-compulsive disorder, post-traumatic stress 
disorder), or current evidence of moderately severe depression based on a 
PHQ-9 total score of  15 at initial screening 
205 
Malignancy, except non-melanoma skin cancers, cervical, or breast ductal 
carcinoma in situ, within the last 5 years 


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206 
Known human immunodeficiency virus (HIV) infection 
207 
Known hepatic disease or evidence of acute or chronic hepatitis B or hepatitis C  
231 
Evidence of substance-related disorders (eg, abuse, misuse, or addiction), 
addictive disorders (eg, pathological gambling), or "recreational use" of illicit 
drugs within 12 months prior to screening, based on medical records, patient 
self-report, or positive urine drug test performed during initial screening (with the 
exception of prescribed medications such as opioids or barbiturates that may 
result in a positive urine drug test) 
211 
Known hypersensitivity to any of the products or components to be administered 
during dosing 
236 
Taken an opioid and/or opioid-containing analgesic ≥ 4 days during the 1 month 
prior to initial screening for any indication 
237 
Taken a butalbital and/or butalbital-containing analgesic ≥ 4 days during the 
1 month prior to initial screening for any indication 
Prior Therapy 
234 
Previously treated with any agent (monoclonal antibody or small molecule) 
targeting the CGRP pathway (ligand or receptor) in preventive settings 
214 
No therapeutic response in preventive treatment of migraine after an adequate 
therapeutic trial with ≥ 3 of the following medication categories: 
 
Category 1:  Topiramate 
 
Category 2:  Other antiepileptics (eg, divalproex sodium, sodium 
valproate, carbamazepine, levetiracetam) 
 
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:  Botulinum 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 


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Concomitant Therapy 
215 
Use of an excluded medication/device or procedure (refer to Section 7.1.7 for the 
list of excluded medications, devices, or procedures and corresponding time 
period for exclusion) 
Prior/Concurrent Clinical Study Experience 
235 
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 
217 
Female subject is pregnant or breastfeeding or planning to become pregnant or 
breastfeed during treatment and for an additional 16 weeks after the last dose of 
IP 
218 
Female subject of childbearing potential is unwilling to use an acceptable method 
of effective contraception during treatment and for an additional 16 weeks after 
the last dose of IP.  Refer to Section 12.5 for additional contraceptive information. 
219 
Female subject of childbearing potential has a positive pregnancy test assessed 
at screening by a urine pregnancy test 
220 
Likely to be unavailable or unable to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject and investigator’s knowledge 
221 
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 
222 
Related to investigational study site staff or investigator 
6.3 
Inclusion Criteria Part 2 
Subjects will be assessed at the end of the baseline period and prior to enrollment into 
DBTP. 
Based on information collected through the electronic diary (eDiary) during baseline, the 
following requirements must be met: 
109 
Has EM defined as  4 and  15 migraine days and  15 headache days during 
baseline (see Section 12.1 for definition of headache/migraine days)  
110 
Employed  20 hours/week upon entry into baseline and has not specified willful 
termination of employment throughout the duration of the study.  Employment is 
defined by work outside the home, self-employed, or works from home. 
111 
Has  4 hours of lost productive time due to headache/migraine and/or related 
symptoms in the past month during baseline as assessed on Day 1 by eDiary 
device (prior to randomization) 
112 
Has total disability score of  3 as assessed by modified MIDAS (1-month recall) 
during baseline as assessed on Day 1 (prior to randomization) 


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114 
Demonstrated at least 75% compliance with the eDiary and had at least 3 WPAI 
measurements during baseline  
6.4 
Exclusion Criteria Part 2 
Subjects are excluded from the study if after baseline any of the following criteria apply: 
223 
Change in the regimen of current migraine preventive treatment or a concomitant 
medication that may have migraine prevention effects during baseline 
224 
Taken an opioid and/or opioid-containing analgesic ≥ 4 days during baseline for 
any indication 
225 
Taken a butalbital and/or butalbital-containing analgesic ≥ 4 days during baseline 
for any indication 
226 
Development of unstable or clinically significant medical condition that, in the 
opinion of the investigator, would pose a risk to subject safety or interfere with 
the study evaluation, procedures, or completion 
227 
Evidence of substance-related disorders (eg, abuse, misuse, or addiction), 
addictive disorders (eg, pathological gambling), or "recreational use" of illicit 
drugs at baseline based on medical records or patient self-report 
228 
Female subject is pregnant or planning to become pregnant during treatment and 
for an additional 16 weeks after the last dose of IP 
229 
Female subject of childbearing potential has a positive pregnancy test assessed 
at day 1 by a urine pregnancy test 
230 
Likely to be unavailable or unable to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject and investigator’s knowledge 
6.5 
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 12.3). 
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/source documentation and in/on the enrollment case report 
form (CRF). 
Upon completion of baseline period procedures, the subject is evaluated by the 
investigator, and if the subject meets all additional (Part 2) eligibility (inclusion: 
109 through 114; exclusion: 223 through 230) criteria he/she is subsequently enrolled 


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and randomized to a treatment regimen.  Subjects who do not meet additional eligibility 
criteria will be considered screen failures. 
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 be the same as the randomization number assigned 
for the study. 
6.6 
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, 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 9.1.1. 
7. 
Treatments 
Study treatment is defined as any IP(s), non-IP(s), placebo, or medical device(s) 
intended to be administered to a study subject according to the study protocol. 
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 7-1. 


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7.1 
Treatment Procedures 
7.1.1 
Investigational Products 
Table 7-1.  Study Treatments 
Study Treatment Name 
Amgen Investigational Producta:  
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, start time, 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 by authorized 
investigational site study staff or subject (as appropriate, with 
Sponsor approval).  Subjects enrolled by the DCTS will be 
permitted to self-inject IP in PFS at their own physical location 
(eg, home) under the observation of the investigator/member 
of the study team via videoconference, after being trained on 
day 1 by the qualified study personnel on self-injections.  
Subjects enrolled by the DCTS will be permitted to self-inject the IP 
in PFS at their own physical location (eg, home) under the 
observation of the investigator/member of the study team via 
videoconference, after being trained on day 1 by the qualified study 
personnel on self-injections.  Subjects enrolled at other sites 
may need to conduct self-injection after training by qualified 
personnel, as appropriate (eg, due to COVID-19 visit 
restrictions).  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; DCTS = decentralized clinical trial site; 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. 
7.1.2 
Non-investigational Products 
Not applicable. 
7.1.3 
Medical Devices 
The following investigational medical device(s) provided by Amgen for use in this study 
are the prefilled syringe (PFS) (Table 7-1). 


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The IP PFS is a single-use, disposable, handheld manual injection device at a fixed 
dose 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. 
A wearable device that measures physical activity and other associated parameters will 
be used throughout the study.  Any adverse events associated with the wearable device 
(eg, allergic reaction to components of the instrument) will be captured in the Events 
CRF as a procedure-related event. 
7.1.4 
Other Protocol-required Therapies 
There are no other protocol-required therapies in this study. 
7.1.5 
Other Treatment Procedures 
There are no other treatment procedures in this study. 
7.1.6 
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(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material. 
This includes any IP, device, or combination product(s) provisioned and/or 
repackaged/modified by Amgen (eg, wearable device that measures physical activity 
and sleep). 
Any product complaint(s) associated with an IP(s), devices(s), or combination product(s) 
supplied by Amgen are to be reported according to the instructions provided in the IPIM. 
7.1.7 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
Concomitant treatment with up to 2 oral migraine preventive medications is allowed 
under the following conditions:  
(1) Drug regimen (ie, formulation, frequency of use, route, dose) is stable for  
≥ 2 months prior to baseline period start 


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(2) Drug regimen is at generally accepted dose, frequency and route for its use in 
migraine 
(3) Drug regimen is not anticipated to change during baseline period or 
post-randomization (ie, during the subject’s study participation) 
Examples of such medications include: 
 
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 used for migraine prevention (eg, clonidine, guanfacine, methysergide, 
cyproheptadine, pizotifen, butterbur, feverfew, magnesium [ 500 mg/day], 
riboflavin [ 100 mg/day]) 
Table 7-2.  Excluded Treatments, Medical Devices, and Procedures 
Prohibited Medications 
Time Period for Exclusion 
Frequent use of an allowed acute medication for migraine in a 
pattern that could be considered more consistent with its use as 
a preventive 
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 for ≥ 4 days/month  
Barbiturates and/or butalbital-containing analgesics 
Opioid and/or opioid-containing analgesics, CBD-containing 
products anticipated to have a systemic effect (eg, ingested or 
inhaled products) 
1 month before 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 
Botulinum toxin (in the head and/or neck region) 
4 months before the start of the 
screening period and throughout the 
study 
Prohibited Procedures or Devices 
Time Period for Exclusion 
For any indication  
Infusion Therapy (ie, 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 


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Prohibited Medications 
Time Period for Exclusion 
For any indication  
Devices (such as stimulation devices), or procedures (such as 
nerve blocks affecting head and neck region or 
psychotherapy).  
 
3 months before the start of the 
screening period and throughout the 
study 
Cognitive Behavioral Therapy 
NOTE:  Subjects on a stable, maintenance phase of CBT for 
migraine will be allowed to participate.  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 
ACE = angiotensin-converting-enzyme; CBD = cannabidiol; CBT = cognitive behavioral therapy; NSAID = 
nonsteroidal anti-inflammatory drugs 
7.2 
Method of Treatment Assignment 
Subjects will be enrolled and randomized in a 1:1 ratio to either erenumab or placebo.  
Randomization will be performed separately within traditional sites and DCTS.   
The randomization will be performed by IRT, and the randomization number will be 
assigned by IRT and appear on the IRT randomization document.  The randomization 
number is different than the subject identification number and will not be utilized by the 
site as a subject identifier. 
The randomization date is to be documented in the subject’s medical record/source 
documentation and on the enrollment CRF. 
7.3 
Blinding 
This is a double-blind study.  Treatment assignment will be blinded to all subjects, site 
personnel, and Amgen as described below. 
7.3.1 
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 and CRF, as applicable. 


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7.3.2 
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 (eg, the formal unblinding may occur at the final analysis rather than during 
the primary analysis) except as specified (eg, Section 7.3.1). 
7.4 
Dose Modification 
7.4.1 
Dose-cohort Study Escalation/De-escalation and Stopping Rules 
There will be no dose changes or dose stopping rules as part of this study. 
7.4.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
Dose adjustments are not permitted. 
7.4.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Refer to Section 12.7 for details regarding drug-induced liver injury guidelines, as 
specified in the Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation, July 2009.  
7.5 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the IP and/or device during the study are provided in the IPIM. 
For DCTS, the Sponsor will supply the IP to the DCTS or the designee.  The IP will then 
be stored in a temperature-controlled environment until ready to be allocated.  The IP 
and all required supplies will be provided to the subjects via direct-to-patient shipments.  
Shipments will be confirmed and documented as delivered by the study staff.  The IP will 
be confirmed as received in good condition and within the acceptable temperature range 
(ie, fit for use), and instructions will be provided to the subject on the correct storage and 
use of IP.  Sharps containers for disposal of used IP syringes will be provided as well.  
Subjects will be asked to return unused IP, if any, at the completion of study 
participation, or immediately for DCTS subjects.  The site will retain all unused IP until 
returned to the Sponsor or destroyed per IP Sponsor’s instructions.  The study site will 
maintain an accurate record of all IP allocations, shipments, and returns in a drug 
accountability log. 


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7.6 
Treatment Compliance 
Administration of IP will be conducted by study staff or subject (refer to Table 7-1) on 
scheduled visits.  Subjects enrolled by the DCTS will be permitted to self-inject the IP in 
PFS at their own physical location (eg, home) under observation from the 
investigator/member of the study team via videoconference, after being trained on day 1 
by the qualified study personnel on self-injections.  Each injection will be documented. 
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 IP administration schedule and reminded that repeated 
cycles of noncompliance could be a reason for discontinuation of study treatment. 
7.7 
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. 
7.8 
Prior and Concomitant Treatment 
7.8.1 
Prior Treatment 
For prior migraine preventive medications, ending 2 months prior to start of baseline, 
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, start and stop 
dates will be collected in the concomitant medication CRF. 
7.8.2 
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 7.1.7. 
Concomitant therapies are to be collected from signing of the informed consent through 
the end-of-study visit. 
8. 
Discontinuation Criteria 
Subjects have the right to withdraw from IP and/or other protocol-required therapies, 
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 subject(s) from IP, device, 
and/or other protocol-required therapies, protocol procedures, or the study as a whole at 
any time prior to study completion for the reasons listed in Sections 8.1, 8.2.1, and 8.2.2. 
8.1 
Discontinuation of Study Treatment 
Subjects (or a legally acceptable representative) can decline to continue receiving IP 
and/or other protocol-required therapies or procedures 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 IP or other protocol-required 
therapies and must discuss with the subject the possibilities for continuation of the 
Schedule of Activities (see Section 2.2) 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/source documentation.  Subjects 
who have discontinued IP and/or other protocol-required therapies or procedures 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 IP(s) and/or other 
protocol-required therapies by a separate protocol or as provided for by the local 
country’s regulatory mechanism, based on parameters consistent with Section 12.3. 
Reasons for removal from protocol-required IP(s) or procedural assessments include 
any of the following: 
 
decision by sponsor 
 
lost to follow-up 
 
death 
 
ineligibility determined 
 
protocol deviation 
 
non-compliance  
 
adverse event 
 
subject request 
 
pregnancy 


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8.2 
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 
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/source documentation.  
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 12.6 for further details).  Refer to the Schedule of Activities (Table 2-1) for 
data to be collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
8.2.1 
Reasons for Removal From Washout, Run-in or Invasive Procedures 
Not applicable to this study. 
8.2.2 
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 
8.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to attend 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to attend 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/source documentation. 


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 
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. 
9. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Table 2-1).  
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 (Table 2-1), is essential and required for study conduct. 
9.1 
General Study Periods 
9.1.1 
Screening, Enrollment and/or Randomization 
9.1.1.1 
Screening Period 
Informed consent must be obtained before any screening procedure or discontinuation 
of standard therapy for any disallowed therapy.  After the subject has signed the 
informed consent form, the site will register the subject in the IRT and screen the subject 
in order to assess eligibility for participation.  The screening period is up to 7 weeks, 
which consists of an initial screening up to 3 weeks (21 days) and a 4-week (28 days) 
baseline.  The screening period starts when ICF is signed and dated by the subject and 
ends when the subject completes baseline and is randomized or screen failed.   
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 6.6) as applicable. 
If a subject has not met all eligibility criteria at the end of initial screening or baseline, the 
subject will be registered as a screen fail.  Screen fail subjects may be rescreened one 
time if the condition(s) leading to ineligibility are transient and expected to improve or 
resolve in a timely manner.  
Rescreen subjects must first be registered as screen failures in IRT and subsequently 
registered as rescreens.  Once the subject is registered as a rescreen, a new screening 


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period will begin.  Subjects will retain the same subject identification number assigned at 
the original screening.  If the rescreening period begins more than 60 days after the 
original signing of the informed consent form, all screening procedures, including 
informed consent, must be repeated. 
9.1.1.2 
Baseline 
The 4-week (28 days) baseline starts when the subject has met all initial (Part 1) 
eligibility criteria (refer to Section 6.1 and Section 6.2) and enters the baseline period.  
Baseline ends when the subject screen fails or does not meet all additional (Part 2) 
eligibility criteria (inclusion: 109 through 114; exclusion:  223 through 230), or when 
subject meets all eligibility criteria and is enrolled and randomized. 
9.1.1.3 
Randomization 
Upon completion of baseline, subjects found to meet eligibility requirements will undergo 
randomization and be assigned a study treatment. 
9.1.2 
Treatment Period 
Study visits will occur per the Schedule of Activities (Table 2-1).  The date of the first 
dose of IP is defined as day 1 and must occur 28 to 35 days from the Day -28 visit.  
On-study visits after Day 1 may be completed within ± 3 days.  All subsequent doses 
and study visits will be scheduled based on the day 1 date.  Administration of 
protocol-required therapies is to be administered once every 4 weeks during each visit 
that it is required. 
Subjects who discontinue IP are encouraged to remain in the study and complete all 
remaining procedures and study visits.   
9.1.3 
End-of-study 
The end-of-study visit occurs at week 24 or 4 weeks after last dose of IP for subjects 
who discontinue study.  All assessments will be performed at the end-of-study visit as 
per Schedule of Activities (Table 2-1). 
9.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
time points. 
9.2.1 
General Assessments  
9.2.1.1 
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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Individuals recruited to the study as part of the DCTS will be provide electronic consent 
for their participation.  A secure link to the web portal will be sent via email.  Upon first 
access, the potential subject will receive a prompt to change the temporarily assigned 
password; the informed consent materials will then be presented through an electronic 
rendition of the IRB-approved consent document(s).  Individuals will be able to review 
the consent document(s) and discuss the study with the investigator and/or designated 
study team member by telephone or videoconference, who will answer questions about 
the study and assess the individual’s understanding. 
Individuals who agree to take part in the study will provide their handwritten signature 
digitally executed to an electronic record using a computer mouse, touchscreen, or 
stylus on a computer or a tablet (depending on the capability of their web browser) in the 
designated signature block.  The study team member administering the consent will 
countersign in the same manner.  A copy of the fully executed consent documents will 
be provided to the subject, and the informed consent process will be documented and 
maintained as part of source documentation in the DCTS software. 
9.2.1.2 
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. 
9.2.1.3 
Medical History 
The Investigator or designee will collect a complete medical (including 
gastrointestinal- and cardiovascular-related history), psychiatric, and surgical history that 
started or was ongoing within 120 days prior to screening.  Medical history will include 
information on the subject's concurrent medical conditions.  Record all findings on the 
medical history CRF.  In addition to the medical history above, neurological medical 
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, 
cardiovascular medical history CRF, gastrointestinal medical history CRF, and 
headache and migraine frequency medical history CRF. 
9.2.1.4 
Physical Measurements 
Height (in centimeters) and weight (in kilograms) should be measured without shoes. 


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9.2.1.5 
Substance Abuse History  
Obtain a detailed history of prior and/or concurrent use of alcohol, 
opioids/opioid-containing and butalbital/ butalbital-containing medications, prescription 
medication, recreational drugs, and any other psychoactive substance taken in the past 
12 months (ie, stimulants and depressors such as ritalin, benzodiazepines, etc). 
Obtain information about any prior history of diagnosed substance-related disorders. 
9.2.2 
Efficacy Assessments 
9.2.2.1 
Clinical Outcome Assessments and Electronic Diaries (eDiaries) 
The clinical outcome assessments (COAs) will be collected by subjects using a 
handheld device with the eDiary.  The eDiary will collect the following COAs daily at the 
subject’s own physical location (eg, home): 
 
Date and time of start of 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)  
Study site staff will assign and provide an eDiary to the subject at the baseline (day -28) 
visit (after confirming the subject’s eligibility to enter the baseline period).  The study site 
staff will train the subject on how to use the eDiary (eg, turning on/off, charging, 
navigating screens, transmitting data, contacting the help desk for technical assistance) 
and complete the questions.  The subject will be instructed to interact with the eDiary 
every day and to have the eDiary during every study visit.  At the day 1 visit prior to 
randomization, the investigator will use the subject’s eDiary to review all data entered 
during  baseline and confirm the relevant inclusion and exclusion criteria  
(inclusion:  109 through 114; exclusion:  223 through 230). 
The handheld device, which will include the eDiary, will also be used for the completion 
of the following patient-reported outcome measures: 
 
Modified MIDAS  
 
WPAI 
 
MFIQ 
 
PHQ-9 


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
GAD-7

PSQI

ESS

Patient satisfaction at work, at assessment time points during study visits
Completion of the following patient-reported outcome measure is not collected via the 
subject’s handheld device, but is required to be assessed per protocol: 

PVT (Note:  Subjects enrolled as part of the DCTS will not complete this
assessment.)
9.2.2.1.1 
Migraine Disability Assessment (MIDAS) 
The MIDAS Questionnaire is a 5-item self-administered questionnaire that sums the 
number of productive days lost in 2 settings:  the workplace and the home.  The MIDAS 
also assesses disability in family, social, and leisure activities.  The MIDAS score is the 
sum of missed days due to a headache from paid work, housework, and non-work 
(family, social, leisure) activities; and days at paid work or housework where productivity 
was reduced by at least half.  The score is categorized into 4 severity grades:  
grade I = 0 to 5 (defined as minimal or infrequent disability), grade II = 6 to 10 (mild or 
infrequent disability), grade III = 11 to 20 (moderate disability), and grade IV = 21 and 
over (severe disability).  The recall period for MIDAS is the past 3 months; the modified 
MIDAS has a 1-month recall period.  Within the full MIDAS, two other questions (A and 
B) are not scored, but were designed to provide the physician with clinically relevant
information on headache frequency and pain intensity.
9.2.2.1.2 
Work Productivity and Activity Impairment (WPAI) Questionnaire 
In the WPAI-Migraine, subjects are asked 6 questions about work and activity 
impairment due to their migraine, including hours worked and hours missed in the last 
7 days.  WPAI scores are based on 1-item (presenteeism, activity impairment), 2-items 
(absenteeism), and multiple items (overall work productivity); a score cannot be 
calculated if there is a missing response to the corresponding item.  The questionnaire 
will be collected weekly. 
9.2.2.1.3 
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 


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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. 
9.2.2.1.4 
Patient Health Questionnaire (PHQ-9) 
The Patient Health Questionnaire (PHQ) is a 9-question, self-administered instrument for 
screening, diagnosing, monitoring, and measuring the severity of depression.  It 
incorporates Diagnostic and Statistical Manual (of Mental Disorders) fourth edition 
(DSM-IV) depression diagnostic criteria with other leading major depressive symptoms 
into a brief self-report tool.  The tool rates the frequency of the symptoms which factors 
into the scoring severity index.  PHQ-9 scores each of the 9 DSM-IV criteria as “0” (not 
at all) to “3” (nearly every day).  The score is calculated as the sum of the item 
responses and corresponds to one of the 5 severity categories:   
Minimal or None = 0 to 4, Mild = 5 to 9, Moderate = 10 to 14,  
Moderately Severe = 15 to 19, and Severe = 20 to 27. 
Question 9 on the PHQ-9 screens for the presence and duration of suicide ideation. 
9.2.2.1.5 
Generalized Anxiety Disorder 7-item Scale Questionnaire (GAD-7) 
The GAD-7 is a self-administered 7-item instrument that uses some of the Diagnostic 
and Statistical Manual (of Mental Disorders) fifth edition (DSM-V) criteria for general 
anxiety disorder (GAD) to identify probable cases of GAD along with measuring anxiety 
symptom severity.  Responders are asked to rate the frequency of anxiety symptoms in 
the last 2 weeks on a Likert scale ranging from 0 (not at all) to 3 (nearly every day).  
Items are summed to provide a total score.  Score interpretation is as follows:   
1 to 4 minimal symptoms, 5 to 9 mild symptoms, 10 to 14 moderate symptoms, and  
15 to 21 severe symptoms.  Changes of 5 points or more are clinically meaningful. 
9.2.2.1.6 
Pittsburgh Sleep Quality Index (PSQI) 
The PSQI is a self-reported questionnaire that assesses sleep quality over a 1-month 
time interval.  The measure consists of 19 individual items, creating 7 components that 
produce 1 global score.  The 7 components are subjective sleep quality, sleep latency, 
sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, 
and daytime dysfunction. 


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9.2.2.1.7 
Epworth Sleepiness Scale (ESS) 
The ESS is a self-administered questionnaire with 8 questions designed to assess 
daytime sleepiness.  Respondents are asked to rate, on a 4-point scale (0 to 3), their 
usual chances of dozing off or falling asleep while engaged in 8 different activities.  Most 
people engage in those activities at least occasionally, although not necessarily every 
day.  The ESS score (the sum of 8 item scores, 0 to 3) can range from 0 to 24 with 
higher ESS scores indicating higher average sleep propensity (ASP) in daily life, or 
“daytime sleepiness”.  Score interpretation is as follows:  0 to 5 Lower Normal Daytime 
Sleepiness, 6 to 10 Higher Normal Daytime Sleepiness, 11 to 12 Mild Excessive 
Daytime Sleepiness, 13 to 15 Moderate Excessive Daytime Sleepiness, and 
16 to 24 Severe Excessive Daytime Sleepiness.   
9.2.2.1.8 
Patient Satisfaction at Work 
To better understand impact of depression, anxiety, sleepiness, and inability to 
concentrate on work productivity, subjects will be asked to complete the following 
questions via the handheld device:  
 
How much does your depressed mood, as a result of your migraines, impact your 
ability to function at work?   Scale, 0 = no impact and 10 = severely impacts 
 
How much does your anxiety, as a result of your migraines, impact your ability to 
function at work?   Scale, 0 = no impact and 10 = severely impacts 
 
How much does your sleepiness, as a result of your migraines, impact your 
ability to function at work? Scale, 0 = no impact and 10 = severely impacts 
 
How much does your inability to concentrate, as a result of your migraines, 
impact your ability to function at work? Scale, 0 = no impact and 10 = severely 
impacts 
 
How would you rate your overall satisfaction with your productivity at work? 
Scale, 0 = as dissatisfied as you can imagine and 10 = as satisfied as you can 
imagine 
These questions are not part of a validated questionnaire and will be scored individually.  
The recall period is the past month. 
9.2.2.1.9 
Health Resource Utilization Questionnaire 
The questionnaire is designed to collect data on HRU.  Specifically, the aim is to capture 
frequency of migraine-related hospitalizations and outpatient visits including emergency 
department visits, urgent care visits, and other clinical visits.  The recall period for the 
HRU questionnaire is 24 weeks, and the HRU questionnaire will be administered on  
day 1, and week 24 of the DBTP.  The questionnaire assessed at the early termination 


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visit before week 24 should only include HRU recalled since the previous assessment at 
day 1 to avoid collecting duplicate information. 
HRU questionnaire is an investigator-reported outcome collected through subject 
interview and/or available medical records at study visits.  The HRU data will be entered 
in the HRU CRF. 
9.2.2.1.10 
Psychomotor Vigilance Task (PVT) 
Psychomotor Vigilance Task is a sustained-attention, reaction-timed task that measures 
the speed with which a subject responds to a visual stimulus.  The visual stimulus is a 
timer inside a rectangle against a solid background.  The test is administered on a tablet, 
and once initiated, the subject responds by touching the bottom of the screen as soon as 
the numbers appear.  The numbers are then cleared from the screen, another timer 
appears, and the subject touches the bottom of the screen to respond as previously 
done.  Subject’s reaction of touching the screen stops the timer, and the elapsed time 
from activation to deactivation, measured in milliseconds, is recorded.  Mean reaction 
time, reciprocal mean reaction time, number of lapses and errors will be calculated from 
the individual elapsed time recordings during the 10-minute session.  Subjects will be 
allowed to have a practice session to become familiar with the test. 
Subjects enrolled as part of the DCTS will not complete this assessment. 
9.2.2.2 
Wearable Device 
The wearable device is a watch-like accelerometer worn on the wrist for monitoring 
physical activity and sleep.  The device records movements and communicates the data 
to a computer.  Subjects are required to continuously wear the device every day except 
when recharging.  Subjects whose medical history or professional activity is deemed to 
contraindicate or be incompatible with a compliant wearable device use may be made 
exempt from this requirement as per Amgen’s medical monitor discretion upon 
consultation.  Amgen must be consulted about the appropriateness of such exemption 
during screening.  
9.2.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
see (Table 2-1). 


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9.2.3.1 
Adverse Events 
9.2.3.1.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
9.2.3.1.1.1 
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 12.4. 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after the first dose of IP through the 
end-of-study are reported using the Event CRF. 
9.2.3.1.1.2 
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 the 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, as indicated in Section 12.4.  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.  It is left to the investigator’s judgment to report these grade 4 
abnormalities as serious adverse events. 
9.2.3.1.1.3 
Serious Adverse Events After the Protocol-required Reporting 
Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after end-of-study.  However, these serious 
adverse events can be reported to Amgen.  Per local requirements in some countries, 
investigators are required to report serious adverse events that they become aware of 
after end-of-study.  If serious adverse events are reported, the investigator is to report 
them to Amgen within 24 hours following the investigator’s knowledge of the event. 
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 IP.  
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 12.4. 


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9.2.3.1.2 
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. 
For subjects enrolled as part of the DCTS, AEs are first reported to the investigator/study 
team or are identified by the study team during interactions with the subjects either via 
telephone or videoconferencing encounters.  Additionally, AEs may be identified from lab 
reports or other records. 
The investigator evaluates a potential event using information provided by the subject to 
determine if it meets the definition of an AE or an SAE.  A course of action is prescribed 
if necessary and documentation is recorded in the DCTS software as source 
documentation.  The appropriate medical intervention, therapeutic intervention, and/or 
support measures are instituted as necessary (ie, rescue medication administered,  
911 called, emergency services utilized, mobile study personnel sent to subject’s home).  
Follow-up and assessment of the AE/SAE until stabilized or resolved is completed per 
protocol (see Section 9.2.3.1.3 below).  
Provision of study-issued smartphone allows subjects to contact the study team to report 
potential AEs at any time.  Subjects can also request timely secure video or telephone 
conference with the investigator and/or designated members of the study team. 
9.2.3.1.3 
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 8.3).  
Further information on follow-up procedures is given in Section 12.4. 
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. 


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9.2.3.1.4 
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 
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 (SUSAR) 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. 
9.2.3.1.5 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects will be collected after the 
start of study treatment and through 16 weeks after last dose of IP. 
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 12.5.  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, ectopic pregnancy) are considered serious adverse events. 


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Further details regarding pregnancy and lactation are provided in Section 12.5. 
9.2.3.1.6 
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 7.1.6. 
Further details regarding adverse device effects can be found in Section 12.4. 
9.2.3.1.7 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and 
signal management processes. 
9.2.4 
Clinical Laboratory Assessments 
Refer to Section 12.2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Table 2-1) 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 12.2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities 
(Table 2-1).  
Subjects enrolled as part of the DCTS may be requested to have their blood sample 
collected by an in-home phlebotomist with the exception of urine pregnancy test and 
urine drug testing, which may be self-collected.  
9.2.4.1 
Pregnancy Testing 
A urine pregnancy test should be completed for females of childbearing potential as per 
the Schedule of Activities (Table 2-1). 


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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 
Worksheet, see Figure 12-2).  Refer to Section 12.5 for contraceptive requirements.  
Additional pregnancy testing should be performed at monthly intervals during treatment 
with protocol-required therapies and at the end-of-study visit. 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 
9.2.5 
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 AMG 334.  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 will be described in Section 12.6. 
9.2.6 
Biomarkers 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention. 
9.2.6.1 
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 Section 12.6.  No additional samples will be collected for 
biomarker development/future research. 


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Amgen or another third-party manufacturer may attempt to develop test(s) designed to 
identify subjects most likely to respond positively or negatively to AMG 334 to investigate 
and further understand migraines. 
9.2.7 
Health Economics OR Medical Resource Utilization and Health 
Economics 
Health resource utilization data, associated with migraine-related medical encounters, 
will be collected in the CRF by the investigator and study-site personnel for all subjects 
throughout the study.  Protocol-mandated procedures, tests, and encounters are 
excluded.  
The data collected may be used to conduct exploratory economic analyses and will 
include: 
 
number of medical care encounters, including surgeries, and other selected 
procedures (inpatient and outpatient) 
 
duration of hospitalization (total days or length of stay) 
 
outpatient medical encounters (including physician or emergency room visits, and 
urgent care visits). 
10. 
Statistical Considerations 
10.1 
Sample Size Determination 
The total sample size of 240 subjects (120 subjects per treatment group) enrolled from 
traditional sites will provide at least a 94% power for the primary efficacy hypothesis.  
The statistical power for secondary efficacy hypotheses ranges from 88% to 99%.  This 
sample size is not inflated for dropouts since subjects who drop out early during the 
6-month DBTP are likely to have at least 1 post-baseline measurement and therefore will 
still be included in the analysis based on the primary estimand utilizing a repeated 
measures linear mixed model approach.  Table 10-1 provides sample size assumptions 
and resulting statistical power for each hypothesis. 


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Table 10-1.  Sample Size Assumptions and Statistical Power for Traditional Sites 
Hypothesis 
Assumed Treatment Effect 
(Erenumab – Placebo) 
Assumed Common 
Standard Deviation 
Power for 
Sample Size of 
240 Subjects 
Primary:  modified MIDAS 
total score 
-20 
43 
94% 
Secondary:  
 
 
 
 
MMD 
-2.0 
3.4 
> 99% 
 
Work productivity 
impairment (WPAI) 
-10.0 
23.1 
91% 
 
MFIQ physical 
function 
-7.6 
16.2 
95% 
 
MFIQ usual activities 
-6.1 
14.9 
88% 
 
MFIQ social function 
-6.8 
15.6 
91% 
MFIQ = Migraine Functional Impact Questionnaire; MIDAS = Migraine Disability Assessment; 
MMD = monthly migraine days; WPAI = Work Productivity and Activity Impairment. 
Note:  All power calculations are based on a 2-sided significance level of 0.05 and not adjusted to reflect the 
sequential testing procedure.  The assumed treatment effects and common standard deviations for 
modified MIDAS, MMD, and MFIQ hypotheses are derived from a subset of subjects in erenumab 
Study 20120296 satisfying the key entry criteria of the current study.  The assumed treatment effect and 
common standard deviation for the work impairment hypothesis is derived from the LIBERTY study.   
In addition, a total sample size of 100 subjects (50 per treatment group) will be enrolled 
as part of the DCTS for pilot purposes. 
10.2 
Analysis Sets, Subgroups, and Covariates 
10.2.1 
Analysis Sets 
All analyses will be performed by the traditional sites separately from DCTS.  Therefore, 
respective analysis sets will be defined for traditional sites and DCTS. 
10.2.1.1 
Full Analysis Set 
The respective full analysis set (FAS) consists of all subjects who were randomized in 
the study through traditional study sites or DCTS.  Analysis of disposition, demographic 
and baseline characteristics, and important protocol deviations will utilize the respective 
FAS.   
10.2.1.2 
Efficacy Analysis Set 
The respective efficacy analysis set (EAS) consists of a subset of subjects from 
traditional study sites or DCTS who receive at least 1 dose of IP 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 EAS. 


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10.2.1.3 
Safety Analysis Set 
The respective safety analysis set (SAS) will consist of all randomized subjects from 
traditional study sites or DCTS who received at least 1 dose of IP.  Subjects will be 
analyzed according to the randomized treatment unless a subject has received the 
incorrect treatment during the entire DBTP.  Analysis for safety endpoints and summary 
of IP administration will utilize the respective SAS.  
10.2.2 
Covariates 
All model-adjusted analyses of efficacy endpoints will include the corresponding baseline 
value for the endpoint being analyzed. 
10.2.3 
Subgroups 
The primary and secondary endpoints will be summarized in the subgroups defined by 
number of prior treatment failures (1, 2, and 3 or more treatment failures) for the 
traditional sites only. 
10.2.4 
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 what will be done for 
missing data in efficacy. 
For the endpoints derived from daily, if at least 14 days of eDiary are collected in the 
monthly interval, then the monthly frequency measurements (eg, migraine days) will be 
prorated based on the number of days with available information. 
Missing items in each COA questionnaire will be handled based on the scoring algorithm 
for each COA. 
Missing data after above methods will either be handled by the linear mixed effects 
model as the primary analysis method or the sensitivity analysis method detailed in 
Section 10.4.2.2. 
Missing data in safety data will not be imputed. 
10.3 
Adaptive Design 
Not applicable. 


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10.4 
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 5.3.1. 
10.4.1 
Planned Analyses 
Primary Analysis 
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 24 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. 
10.4.2 
Methods of Analyses 
10.4.2.1 
General Considerations 
All analyses will be conducted separately for subjects enrolled from traditional sites and 
subjects from DCTS.  Formal statistical hypothesis testing for the primary and secondary 
endpoints will be performed for subjects enrolled from traditional sites only.  Subject 
characteristics for both traditional sites and DCTS will be summarized descriptively. 
Summary statistics by each treatment group will be tabulated at each assessment time 
point if applicable.  For continuous endpoints, the descriptive statistics include:  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 order of modified 
MIDAS, MMD, WPAI, MFIQ physical function, MFIQ usual activity, and MFIQ social 
function endpoints.  An endpoint will only be tested if the endpoint tested in the previous 
step is statistically significant at 2-sided significance level of 0.05. 


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10.4.2.2 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Under the assumption of missing at random (MAR), 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. 
Multiple imputation (MI) with the assumption of missing not at random 
(MNAR) will be used as a sensitivity analysis to handle missing data at each 
assessment time point, using the analysis of covariance (ANCOVA) model 
including treatment group and baseline value.   
Secondary 
Under the assumption of MAR, 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. 
MI with the assumption of MNAR will be used as a sensitivity analysis to 
handle missing data at each assessment time point, using the ANCOVA 
model including treatment group and baseline value.   
Exploratory 
Detailed primary analysis method for exploratory endpoints will be described 
in the SAP.  No sensitivity analysis will be performed for exploratory 
endpoints. 
 
10.4.2.2.1 
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 or by preferred term in descending order of frequency.  
Tables of fatal adverse events, serious adverse events, adverse events leading to 
withdrawal from IP, adverse device effects, 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. 
10.4.2.2.2 
Exposure to Investigational Product 
The total length of IP exposure, the number of doses, and the proportion of subjects 
receiving each dose will be summarized using descriptive statistics. 
10.4.2.2.3 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving acute headache medications will be 
summarized by the medication category for each treatment group. 


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11. 
References 
Amgen, Inc.  Erenumab-aooe Investigator’s Brochure.  Thousand Oaks, CA. 
Afridi SK, Giffin NJ, Kaube H, et 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. 
Barbanti P, Fabbrini G, Aurilia C, Vanacore N, Cruccu G.  A case-control study on 
excessive daytime sleepiness in episodic migraine.  Cephalalgia.  2007;27:1115-1119. 
Bellamy JL, Cady RK, Durham PL.  Salivary levels of CGRP and VIP in rhinosinusitis 
and migraine patients.  Headache.  2006;46:24-33. 
Dodick DW, Ashina M, Brandes JL, et al.  ARISE:  A Phase 3 randomized trial of 
erenumab for episodic migraine.  Cephalagia.  2018;38:1026-1037. 
Dodick DW, Loder EW, Manack Adams A, et al.  Assessing Barriers to Chronic Migraine 
Consultation, Diagnosis, and Treatment: Results From the Chronic Migraine 
Epidemiology and Outcomes (CaMEO) Study.  Headache.  2016;56:821-834. 
Gallai V, Sarchielli P, Floridi A, et al.  Vasoactive peptide levels in the plasma of young 
migraine patients with and without aura assessed both interictally and ictally.  
Cephalalgia.  1995;15:384-390. 
Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S.  
Pathophysiology of Migraine:  A Disorder of Sensory Processing.  Physiol Rev.  
2017a;97(2):553-622. 
Goadsby PJ, Reuter U, Hallstrom Y, et al.  A Controlled Trial of Erenumab for Episodic 
Migraine.  N Engl J Med.  2017b;377:2123-2132. 
Goadsby PJ, Paemeleire, Broessner G, et al.  Efficacy of Erenumab in Subjects with 
Episodic Migraine with Prior Preventive Treatment Failure(s) [18th Congress of the 
International Headache Society Oral Abstract].  Cephalagia.  2017c;37:01-24. 
Goadsby PG, Lipton RB, Ferrari MD.  Migraine—current understanding and treatment.  
N Engl J Med.  2002;364(4):257-270. 
Goadsby PJ, Edvinsson L, Ekman R.  Vasoactive peptide release in the extracerebral 
circulation of humans during migraine headache.  Ann Neurol.  1990;28:183-187. 
Goadsby PJ, Edvinsson L, Ekman R.  Release of vasoactive peptides in the 
extracerebral circulation of humans and the cat during activation of the trigeminovascular 
system.  Ann Neurol.  1988;23:193-196. 
Ho TW, Ferrari MD, Dodick DW, et al.  Efficacy and tolerability of MK 0974 
(telcagepant), a new oral antagonist of calcitonin gene related peptide receptor, 
compared with zolmitriptan for acute migraine:  a randomised, placebo controlled, 
parallel treatment trial.  Lancet.  2008a;372:2115-2123. 
Ho TW, Mannix LK, Fan X, et al.  MK 0974 Protocol 004 study group.  Randomized 
controlled trial of an oral CGRP receptor antagonist, MK 0974, in acute treatment of 
migraine.  Neurology.  2008b;70:1304-1312. 


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Ho TW, Connor KM, Zhang Y, et al. Randomized controlled trial of the CGRP receptor 
antagonist telcagepant for migraine prevention. Neurology. 2014;83:958-966. 
International Committee of Medical Journal Editors, Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals:  Writing and Editing for Biomedical 
Publication.  2013.  http://www.icmje.org/ 
Juhasz G, Zsombok T, Jakab B, Nemeth J, Szolcsanyi J, Bagdy G.  Sumatriptan causes 
parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and 
migraine headache during nitroglycerin induced migraine attack.  Cephalalgia.  
2005;25(3):179-183. 
Kelman L, Rains JC.  Headache and sleep:  examination of sleep patterns and 
complaints in a large clinical sample of migraineurs.  Headache.  2005;45:904-910. 
Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J.  CGRP may 
play a causative role in migraine.  Cephalalgia.  2002;22:54-61. 
Lipton RB, Buse DC, Serrano D, Holland S, Reed ML.  Examination of unmet treatment 
needs among persons with episodic migraine:  results of the American Migraine 
Prevalence and Prevention (AMPP) Study.  Headache.  2013;53:1300-1311. 
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. 
Petersen KA, Lassen LH, Birk S, Lesko L, Olesen J.  BIBN4096BS antagonizes human 
alpha-calcitonin gene related peptide-induced headache and extracerebral artery 
dilatation.  Clin Pharmacol Ther.  2005;77:202-213. 
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. 
Sarchielli P, Pini LA, Zanchin G, et al.  Clinical-biochemical correlates of migraine 
attacks in rizatriptan responders and non-responders.  Cephalalgia.  2006;3:257-265. 
Stewart WF, Wood GC, Razzaghi H, Reed ML, Lipton RB.  Work impact of migraine 
headaches.  J Occup Environ Med.  2008;50:736-745. 
Stovner LJ, Andree C.  Prevalence of headache in Europe:  a review for the Eurolight 
project.  J Headache Pain.  2010;11:289-299. 
Sun H, Dodick DW, Silberstein S, et al.  Safety and efficacy of AMG 334 for prevention 
of episodic migraine:  a randomised, double-blind, placebo-controlled, phase 2 trial.  
Lancet Neurol.  2016;15(4):382-390. 
Tajti J, Uddman R, Möller S, Sundler F, Edvinsson L.  Messenger molecules and 
receptor mRNA in the human trigeminal ganglion.  J Auton Nerv Syst.  1999;76:176-183. 


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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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12. 
Appendices 


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12.1 
Appendix 1.  List of Abbreviations and Definitions of Terms 
 
Abbreviation or Term 
Definition/Explanation 
ACE 
angiotensin-converting enzyme 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AMPP 
American Migraine Prevalence and Prevention 
ASP 
average sleep propensity 
AST 
aspartate aminotransferase 
ATA 
American Telemedicine Association 
CaMEO 
Chronic Migraine Epidemiology and Outcomes 
CFR 
Code of Federal Regulations 
CGRP 
calcitonin gene-related peptide 
CM 
chronic migraine 
COA 
clinical outcome assessment 
CRF 
case report form 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBTP 
double-blind treatment period 
DCTS 
decentralized clinical trial site 
DILI 
drug-induced liver injury 
DSM-IV 
Diagnostic and Statistical Manual (of Mental Disorders) fourth 
edition 
DSM-V 
Diagnostic and Statistical Manual (of Mental Disorders) fifth 
edition 
EAS 
efficacy analysis set 
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), 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 period of the study for an individual subject 


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Abbreviation or Term 
Definition/Explanation 
Enrollment 
defined as the day a subject has met all Part 1 and Part 2 
eligibility criteria and is enrolled and randomized into the study 
(subjects are randomized same day) 
ESS 
Epworth Sleepiness Scale 
FSH 
follicle stimulating hormone 
FAS 
full analysis set 
GAD 
generalized anxiety disorder 
GAD-7 
Generalized Anxiety Disorder 7-item Scale 
GCP 
Good Clinical Practice 
Headache 
a migraine or non-migraine headache 
Headache day 
Any calendar day in which the subject experiences a qualified 
headache (initial onset, continuation, or recurrence of the 
headache).  A qualified headache is defined as: 
 
a qualified migraine headache (including an aura-only 
event that is treated with acute migraine-specific 
medication) or 
 
a qualified non-migraine headache, which is a headache 
that lasts  30 minutes and is not a qualified migraine 
headache or 
 
a headache of any duration for which acute headache 
treatment is administered 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency 
HIT-6 
Headache Impact Test-6 
HRT 
hormone replacement therapy 
HRU 
Health Resource Utilization 
ICH 
International Council for Harmonisation 
ICHD-III 
International Classification of Headache Disorders, Third Edition 
IEC 
Independent Ethics Committee 
IgG2 
immunoglobulin G2 
IHS 
International Headache Society 
INR 
international normalized ratio 
IP 
investigational product 
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
IUD 
intrauterine device 
IUS 
intrauterine hormonal-releasing system 
LIBERTY 
A Study Evaluating the Effectiveness of AMG 334 Injection in 
Preventing Migraines in Adults Having Failed Other Therapies 
MAR 
missing at random 


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Abbreviation or Term 
Definition/Explanation 
MFIQ 
Migraine Functional Impact Questionnaire 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
Modified MIDAS 
modified Migraine Disability Assessment 
MIDAS 
Migraine Disability Assessment 
Migraine day 
A migraine day is defined as any calendar day in which the 
subject experiences a qualified migraine headache (onset, 
continuation or recurrence of the migraine headache).  A 
qualified migraine headache is defined as a migraine with or 
without aura lasting for  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. 
MMD 
monthly migraine days 
MNAR 
missing not at random 
MPFID 
Migraine Physical Function Impact Diary 
NCT 
National Clinical Trials 
PFS 
prefilled syringes 
PHQ-9 
Patient Health Questionnaire 
PSQI 
Pittsburgh Sleep Quality Index 
PVT 
Psychomotor Vigilance Task 
Q4W 
every 4 weeks 
QM 
once monthly 
Randomization 
defined as the day a subject has met all Part 1 and Part 2 
eligibility criteria and is enrolled and randomized into the study 
(subjects are enrolled same day) 
SAS 
safety analysis set 
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. 
STRIVE 
Study to Evaluate the Efficacy and Safety of Erenumab in 
Migraine Prevention 
Study Day 1 
defined as the first day that protocol-specified 
IP(s)/protocol-required therapies is/are administered to the 
subject 
SUSAR 
suspected unexpected serious adverse reaction 
TBL 
total bilirubin 
ULN 
upper limit of normal 
US 
United States 
WPAI 
Work Productivity and Activity Impairment Questionnaire 
 


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12.2 
Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 12-1 will be performed by the local laboratory.  The tests 
performed by central laboratory are optional. 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
Table 12-1.  Analyte Listing 
Local Laboratory 
(Optional) Central Laboratory 
Urine pregnancy 
Urine drug testing  
Biomarker development 
Pharmacogenetic assessment  
 


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12.3 
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 IP. 
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 IP(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 (HIPAA) requirements, where applicable, and the IRB/IEC or study 
site.  
The medical record/source documentation 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/source documentation, and the informed consent form is to be signed and 
personally dated by the subject and by the person who conducted the informed consent 


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discussion.  Subject withdrawal of consent or discontinuation from study treatment 
and/or procedures must also be documented in the subject’s medical records; refer to 
Section 8. 
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.  
The informed consent form will contain a separate section that addresses the use of 
remaining mandatory samples for optional future research.  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. 
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 


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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 
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 


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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.  
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. 


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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.  
For DCTS, source documentation will be maintained in the DCTS software. 
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 
interactive response technology (IRT) (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 [COA]). 


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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, IP 
Accountability Record(s), Return of IP for Destruction Form(s), Final IP 
Reconciliation Statement, as applicable 
 
Non-IP(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 IP(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 IP(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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12.4 
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. 
 
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. 
 
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. 


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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 
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. 
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 7.1.3 for the list of Amgen medical devices). 


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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. 
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: 
 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms); 
 
Dates of onset and resolution (if resolved); 
 
Severity (or toxicity defined below); 
 
Assessment of relatedness to IP (erenumab or placebo), other 
protocol-required therapies, or Amgen medical devices (prefilled syringe 
[PFS]); and 
 
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. 


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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. 
 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between IP, device(s), 
and/or study-mandated procedure and each occurrence of each adverse 
event/serious adverse event. 
 
Relatedness means that there are facts or reasons to support a relationship 
between IP 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. 


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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. 
Reporting of Serious Adverse Event 
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 via the Safety Report Form.  
 
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 12-1) 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 12-1). 
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. 


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Date:  31 August 2020 
Page 88 of 101 
 
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Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Form 
 


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12.5 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy 
and Lactation Information 
Study-specific contraception requirements for female of childbearing potential are 
outlined in Section 6.2. 
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 
an additional 16 weeks after the last dose of IP. 
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: 
 
Documented hysterectomy; 
 
Documented bilateral salpingectomy; or 
 
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 
 
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. 
 
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. 
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) 


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 
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 IP. 
 
Information will be recorded on the Pregnancy Notification Worksheet (see 
Figure 12-2).  The worksheet 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 Worksheet that violates the 
country or regions local privacy laws). 
 
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 last 
dose of IP 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.  


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 
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 12.4.  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 8.1 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 Worksheet.  The worksheet (see 
Figure 12-2) 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 Worksheet 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. 
 
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 IP. 
 
Information will be recorded on the Lactation Notification Worksheet (see below) and 
submitted to Amgen Global Patient Safety within 24 hours of the investigator’s 
knowledge of event. 


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 
Study treatment will be discontinued if female subject breastfeeds during the study 
as described in exclusion criterion 217. 
 
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 the last dose of IP. 
Figure 12-2.  Pregnancy and Lactation Notification Worksheet 
 


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Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20180060 
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12.6 
Appendix 6.  Sample Storage and Destruction 
Any blood (biomarker or pharmacogenetic) sample collected according to the Schedule 
of Activities (Table 2-1) 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 AMG 334, 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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CONFIDENTIAL  
 
 
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 12.3 for subject confidentiality. 


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12.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and 
Follow-up Assessments and Study Treatment Rechallenge 
Guidelines 
Subjects with abnormal hepatic laboratory values  (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis (as 
described below) may meet the criteria for withholding or permanent discontinuation of 
Amgen IP or other protocol-required therapies, as specified in the Guidance for Industry 
Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, July 2009. 
Criteria for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies due to Potential 
Hepatotoxicity 
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver biomarkers (TBL, INR and transaminases) has not been 
identified.  
Important alternative causes for elevated AST/ALT and/or TBL values include, but are 
not limited to: 
 
hepatobiliary tract disease 
 
viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes 
simplex virus, varicella, toxoplasmosis, and parvovirus) 
 
right-sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia 
 
exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants and mushrooms 
 
heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, indinavir, 
atazanavir) 
 
alpha-one antitrypsin deficiency 
 
alcoholic hepatitis 
 
autoimmune hepatitis 
 
Wilson’s disease and hemochromatosis 
 
nonalcoholic fatty liver disease including steatohepatitis 
 
non-hepatic causes (eg, rhabdomyolysis, hemolysis) 
If IP(s) is/are withheld, the subject is to be followed for possible drug induced liver injury 
(DILI) according to recommendations in the last section of this appendix.  


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Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL, is discovered and the laboratory abnormalities resolve 
to normal or baseline (see next section in this appendix). 
Table 12-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required Therapies due to 
Potential Hepatotoxicity 
Analyte 
Temporary Withholding 
Permanent Discontinuation 
TBL 
 3 x ULN at any time 
 2 x ULN 
 
 
OR 
INR 
-- 
 1.5 x (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
 8 x ULN at any time 
 5 x ULN but  8 x ULN for  2 weeks 
 5 x ULN but  8 x ULN and unable to 
adhere to enhanced monitoring schedule 
 3 x ULN with clinical signs or symptoms 
that are consistent with hepatitis (such as 
right upper quadrant pain/tenderness, 
fever, nausea, vomiting, and jaundice) 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values 
 3 x ULN (when baseline was  ULN) 
 
OR 
 
ALP 
 8 x ULN at any time 
-- 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase;  
INR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject is to be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then Amgen IP and other protocol-required 
therapies, as appropriate is to be permanently discontinued.  Subjects who clearly meet 
the criteria for permanent discontinuation (as described in Table 12-2) are never to be 
rechallenged. 


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Drug-induced Liver Injury (DILI) Reporting and Additional Assessments 
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation, according to the criteria specified in the above, require 
the following: 
 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
 
The appropriate Case Report Form (CRF) (eg, Event CRF) that captures information 
necessary to facilitate the evaluation of treatment-emergent liver abnormalities is to 
be completed and sent to Amgen  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 12.4. 
Additional Clinical Assessments and Observation 
All subjects in whom IP(s) or protocol-required therapies is/are withheld (either 
permanently or conditionally) due to potential DILI as specified in Table 12-2 or who 
experience AST or ALT elevations  3 x upper limit of normal (ULN) or 2-fold increases 
above baseline values for subjects with elevated values before drug are to undergo a 
period of “close observation” until abnormalities return to normal or to the subject’s 
baseline levels.   
Assessments that are to be performed during this period include:  
 
Repeat AST, ALT, ALP, total bilirubin (TBL), and INR within 24 hours  
 
In cases of TBL  2 x ULN or INR  1.5, retesting of liver tests, TBL, and INR is to be 
performed every 24 hours until laboratory abnormalities improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the IP(s) or protocol-required therapies has/have been discontinued AND the 
subject is asymptomatic. 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL.  
The following are to be considered depending on the clinical situation: 
 
complete blood count with differential to assess for eosinophilia 
 
serum total immunoglobulin (Ig)G, anti-nuclear antibody anti-smooth muscle 
antibody, and liver kidney microsomal antibody-1 to assess for autoimmune hepatitis 
 
serum acetaminophen (paracetamol) levels 


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CONFIDENTIAL  
 
 
 
a more detailed history of:  
 
prior and/or concurrent diseases or illness 
 
exposure to environmental and/or industrial chemical agents  
 
symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
 
prior and/or concurrent use of alcohol, recreational drugs and special diets 
 
concomitant use of medications (including non-prescription medicines and herbal 
and dietary supplements), plants, and mushrooms 
 
viral serologies 
 
creatine phosphokinase, haptoglobin, lactate dehydrogenase and peripheral blood 
smear 
 
appropriate liver imaging if clinically indicated 
 
appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected 
 
hepatology consult (liver biopsy may be considered in consultation with a 
hepatologist) 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  The 
“close observation period” is to continue for a minimum of 4 weeks after discontinuation 
of all IP(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in the corresponding CRFs.  


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20180060 
 
Page 1 of 14 
Amgen Proprietary - Confidential 
Amendment 3 
Protocol Title:  Effect of Erenumab-aooe on Disability and Work Productivity in 
Employed Subjects with Episodic Migraine Who Have Previously Failed 1 or More 
Migraine Preventative Treatments 
 
Amgen Protocol Number (AMG 334/Erenumab) 20180060 
 
Amendment Date: 
31 August 2020 
 
Rationale: 
The following changes were made to the protocol, dated August 31st, 2020, due to the 
COVID-19 pandemic.  The COVID-19 pandemic has disrupted all clinical trials from an 
operational standpoint.  However more importantly, the disruptions of this pandemic and 
its suppression effects are likely impacting this Work Productivity trial endpoints.  
Because of these unexpected changes in the way we work, measures had to be taken to 
mitigate their impact and to maintain the scientific rigor of our study.  Hence, we have 
aligned on these new requirements as part of our protocol.   
 
Added weekly COVID-19 impact assessments to the schedule of activities 
 
Modified Investigational Product dosing instructions to include COVID-19 impact 
mitigation strategies 
Other changes include: 
 
Added additional rationale regarding the use of EM subject population 
 
Added clarification to additional ongoing approvals to erenumab product 
background 
 
Modification to inclusion criterion #105 to include job stability assessment  
 
Modification to inclusion criterion #106 and #111 to clarify lost productive time 
 
Modification to exclusion criterion #232 and #233 to clarify opioid and butalbital 
or analgesics taken for greater than or equal to 4 days rather than greater than 
4 days for the month prior to screening 
 
Clarification of excluded treatments described within Table 7-2 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20180060 
 
Page 2 of 14 
Amgen Proprietary - Confidential 
 
Clarified incorrect treatment rather than incorrect dose within Safety Analysis Set 
 
Updated Common Terminology Criteria for Adverse Events versioning 
 
Administration, typographical, and formatting changes were made throughout the 
protocol 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20180060 
Date:  09 March 2020 
Page 1 of 16 
CONFIDENTIAL 
 
 
Amendment 2 
Protocol Title:  Effect of Erenumab-aooe on Disability and Work Productivity in 
Employed Subjects With Episodic Migraine Who Have Previously Failed 1 or More 
Migraine Preventive Treatments 
 
Amgen Protocol Number (Erenumab-aooe [AMG 334]) 20180060 
 
Amendment Date: 
09 March 2020 
 
Rationale: 
This protocol is being amended to address the following: 
1) Study periods and procedures 
 
Introduction of up to 1 rescreening attempt in instances where the 
condition leading to screen failure is considered to be transient and likely 
to improve/resolve 
2) Eligibility requirements 
 
Reduction from 80% to 75% as the minimal eDiary compliance threshold 
for this study is proposed 
 
Non-essential exclusion requirements are proposed to be removed or 
edited.  These include: 
o Removal of BMI restrictions 
o Removal of restrictions for lifetime use of any type of anti-CGRP 
product use 
o Reduction of the exclusionary period for opioid/barbiturate use in 
excess of 4 days per month to the last month prior to screening 
3) Concomitant medication/device/procedure 
 
Allowance of a second concomitant oral migraine preventive medication 
in instances where a second medication is required to treat a comorbid 
medical condition (eg, depression, hypertension) 
 
Removal of prohibition on certain procedures that may affect subjects 
lifestyle choices (eg, biofeedback, relaxation techniques) 
4) Sample size 
 
Editorial adjustments made to allow for the study to be finalized at the 
time of last subject enrolled for the primary analysis irrespective of the 
number of Science37 subjects enrolled 
 
Approved 
 
 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20180060 
Date:  14 June 2019  
Page 1 of 47 
CONFIDENTIAL 
 
 
Amendment 1 
Protocol Title:  Effect of Erenumab-aooe on Disability and Work Productivity in 
Employed Subjects With Episodic Migraine Who Have Previously Failed 1 or More 
Migraine Preventive Treatments 
 
Amgen Protocol Number 20180060 
 
Amendment Date: 
14 June 2019 
 
Rationale: 
This protocol is being amended to: 
• 
Clarify information surrounding: 
− 
Data collection in regards to the primary, secondary, and exploratory endpoints. 
− 
Eligibility criteria between Part 1 and Part 2  
− 
Medication that is prohibited versus medication that is allowed with 
circumstances  
− 
Definition of prior treatment and concomitant medication 
− 
Medical history will include a targeted neurological medical history 
• 
Align with changes being made across the AMG 334 program, which include: 
− 
Add biomarker collection (optional central laboratory) 
− 
Removed the need for local laboratory collection in a phase 4 trial 
• 
Make editorial and administrative changes for grammatical reasons as well as for 
internal consistency within the protocol 
 
Approved 
 
 

SAP_001.pdf: 
Product:  Erenumab (AMG 334) 
Protocol Number:  20180060 
Date:  20 October 2020 
Page 1 of 40 
CONFIDENTIAL 
 
 
Statistical Analysis Plan 
Protocol Title: 
Effect of Erenumab-aooe on Disability and Work 
Productivity in Employed Subjects With Episodic 
Migraine Who Have Previously Failed 1 or More 
Migraine Preventive Treatments 
Short Protocol Title: 
Effect of Erenumab-aooe on Disability and Work 
Productivity in Employed Subjects With Episodic 
Migraine 
Protocol Number: 
20180060 
NCT Number: 
NCT03912337 
Authors: 
 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive  
Thousand Oaks, CA 91320 
SAP Date: 
Document Version 
Date 
Original (v1.0) 
20 October 2020 


Product:  Erenumab (AMG 334) 
Protocol Number:  20180060 
Date:  20 October 2020 
Page 2 of 40 
CONFIDENTIAL 
 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
20OCT2020 
NA 


Product:  Erenumab (AMG 334) 
Protocol Number:  20180060 
Date:  20 October 2020 
Page 3 of 40 
CONFIDENTIAL 
 
 
Table of Contents 
Table of Contents ............................................................................................................ 3 
1. 
Introduction ............................................................................................................. 7 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 7 
2.1 
Objectives and Endpoints ............................................................................ 7 
2.2 
Hypotheses and/or Estimations ................................................................. 11 
3. 
Study Overview .................................................................................................... 12 
3.1 
Study Design ............................................................................................. 12 
3.2 
Sample Size .............................................................................................. 12 
4. 
Covariates and Subgroups ................................................................................... 13 
4.1 
Planned Covariates ................................................................................... 13 
4.2 
Subgroups ................................................................................................. 13 
5. 
Definitions ............................................................................................................. 14 
5.1 
Definition of Terms Included in Study Endpoints ....................................... 14 
5.1.1 
Efficacy Endpoints Based on Daily Data Collection ................... 14 
5.1.2 
Efficacy Endpoints Based on Weekly Collection ........................ 16 
5.1.3 
Efficacy Endpoints Based on Monthly Collection ....................... 16 
5.1.4 
Efficacy Endpoints Collected at Specific Visits ........................... 17 
5.1.5 
Efficacy Endpoints Based on Wearable Device 
Collection .................................................................................. 19 
5.1.6 
Safety Endpoints ....................................................................... 21 
5.2 
Study Dates .............................................................................................. 21 
5.3 
Study Points of Reference ......................................................................... 22 
5.4 
Study Time Intervals ................................................................................. 22 
5.4.1 
Monthly Intervals for Efficacy Endpoints Derived From 
Daily, Weekly, or Wearable Data Collection .............................. 22 
5.4.2 
Analysis Visits for Endpoints Based on Monthly 
Collection .................................................................................. 24 
5.5 
Subject Disposition .................................................................................... 25 
5.6 
Arithmetic Calculations .............................................................................. 25 
5.7 
Disease Characteristics ............................................................................. 26 
6. 
Analysis Sets ........................................................................................................ 26 
6.1 
Full Analysis Set........................................................................................ 26 
6.2 
Efficacy Analysis Set ................................................................................. 27 
6.3 
Safety Analysis Set ................................................................................... 27 
7. 
Planned Analyses ................................................................................................. 27 
8. 
Data Screening and Acceptance ........................................................................... 27 
8.1 
General Principles ..................................................................................... 27 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 27 


Product:  Erenumab (AMG 334) 
Protocol Number:  20180060 
Date:  20 October 2020 
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8.3 
Handling of Missing and Incomplete Data ................................................. 28 
8.4 
Detection of Bias ....................................................................................... 29 
8.5 
Outliers ..................................................................................................... 29 
8.6 
Distributional Characteristics ..................................................................... 30 
8.7 
Validation of Statistical Analyses ............................................................... 30 
9. 
Statistical Methods of Analysis.............................................................................. 30 
9.1 
General Considerations ............................................................................. 30 
9.2 
Subject Accountability ............................................................................... 31 
9.3 
Important Protocol Deviations ................................................................... 31 
9.4 
Demographic and Baseline Characteristics ............................................... 31 
9.5 
Efficacy Analyses ...................................................................................... 32 
9.5.1 
Analyses of Primary and Secondary Efficacy 
Endpoints .................................................................................. 35 
9.5.2 
Analyses of Exploratory Efficacy Endpoints ............................... 36 
9.6 
Safety Analyses ........................................................................................ 36 
9.6.1 
Analyses of Safety Endpoint(s) .................................................. 36 
9.6.2 
Adverse Events ......................................................................... 36 
9.6.3 
Exposure to Investigational Product .......................................... 37 
9.6.4 
Exposure to Concomitant Medication ........................................ 37 
10. 
Changes From Protocol-specified Analyses.......................................................... 37 
11. 
Literature Citations / References ........................................................................... 38 
12. 
Data Not Covered by This Plan............................................................................. 39 
13. 
Appendices ........................................................................................................... 40 
List of Tables 
Table 3-1.  Sample Size Assumptions and Statistical Power for Traditional 
Sites ....................................................................................................... 13 
Table 5-1.  Monthly Intervals for Efficacy Endpoints Derived From Daily, 
Weekly, or Physical Activity Wearable Data Collection ........................... 23 
Table 5-2.  Monthly Intervals for Sleep Associated Endpoints ....................................... 23 
Table 5-3.  Modified MIDAS and MFIQ Analysis Visit Windows ..................................... 24 
Table 5-4.  PHQ-9, GAD-7, PSQI, ESS, Patient Satisfaction at Work and PVT 
Analysis Visit Windows ........................................................................... 24 
Table 5-5.  HRU Analysis Visit Windows ....................................................................... 25 
Table 9-1.  Primary Efficacy Endpoint Summary Table .................................................. 33 
Table 9-2.  Secondary Efficacy Endpoint Summary Table ............................................. 34 
Table 9-3.  Exploratory Efficacy Endpoint Summary Table ............................................ 34 


Product:  Erenumab (AMG 334) 
Protocol Number:  20180060 
Date:  20 October 2020 
Page 5 of 40 
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List of Abbreviations and Definition of Terms 
Abbreviation or Term 
Definition/Explanation 
AMPP 
American Migraine Prevalence and Prevention 
ANCOVA 
analysis of covariance 
ASP 
average sleep propensity 
BMI 
body mass index 
CaMEO 
Chronic Migraine Epidemiology and Outcomes 
CGRP 
calcitonin gene-related peptide 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBTP 
double-blind treatment period 
DCTS 
decentralized clinical trial site 
DSM-IV 
Diagnostic and Statistical Manual (of Mental Disorders) fourth 
edition 
DSM-V 
Diagnostic and Statistical Manual (of Mental Disorders) fifth 
edition 
EAS 
efficacy analysis set 
eDiary 
electronic diary 
EM 
episodic migraine 
ESS 
Epworth Sleepiness Scale 
FAS 
full analysis set 
GAD 
generalized anxiety disorder 
GAD-7 
Generalized Anxiety Disorder 7-item Scale 
HRU 
Health Resource Utilization 
ICH 
International Council for Harmonisation 
IP 
investigational product 
IRT 
interactive response technology  
LIBERTY 
A Study Evaluating the Effectiveness of AMG 334 Injection in 
Preventing Migraines in Adults Having Failed Other Therapies 
MAR 
missing at random 
MFIQ 
Migraine Functional Impact Questionnaire 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
Modified MIDAS 
modified Migraine Disability Assessment 
MIDAS 
Migraine Disability Assessment 
MMD 
Monthly migraine days 
MNAR 
missing not at random 


Product:  Erenumab (AMG 334) 
Protocol Number:  20180060 
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Abbreviation or Term 
Definition/Explanation 
NCT 
National Clinical Trials 
PHQ-9 
Patient Health Questionnaire 
PSQI 
Pittsburgh Sleep Quality Index 
PVT 
Psychomotor Vigilance Task 
SAS 
safety analysis set 
SAP 
statistical analysis plan 
US 
United States 
WPAI 
Work Productivity and Activity Impairment Questionnaire 
 


Product:  Erenumab (AMG 334) 
Protocol Number:  20180060 
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Page 7 of 40 
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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 amendment 3 for study 20180060, 
Erenumab-aooe (AMG 334) dated 31 August 2020.  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 effect of erenumab 
compared to placebo on disability in 
employed subjects with episodic migraine 
(EM) who have previously failed 1 or 
more migraine preventive treatments 
 
Sum of monthly changes from baseline in 
modified Migraine Disability Assessment 
(MIDAS) total score over the 6-month 
double-blind treatment period (DBTP) 
Primary Estimand 
The primary estimand for the primary objective on migraine-related disability consists of: 
 
The target population, which includes employed subjects with EM who have previously 
failed 1 or more migraine preventive treatments  
 
The endpoint, which is the sum of monthly changes from baseline in modified MIDAS total 
score over the 6-month DBTP 
 
The intercurrent event is adherence to treatment.  The treatment effect of interest will be 
assessed for all randomized subjects enrolled from traditional sites who receive at least 
1 dose of investigational product (IP) and have a baseline value and at least 1 
post-baseline value of modified MIDAS total score, regardless of adherence to treatment 
 
The summary measure, which is the difference in means of the endpoint between the 
erenumab group and the placebo group 
The primary estimand is the difference in means between erenumab and placebo of the sum of 
monthly changes from baseline in modified MIDAS total score over the 6-month DBTP in 
employed subjects with EM who have previously failed 1 or more migraine preventive 
treatments and who are randomized, receive at least 1 dose of IP, and have a baseline value 
and at least 1 post-baseline value of modified MIDAS total score, regardless of adherence to 
treatment. 
Secondary 
 
To evaluate the effect of erenumab 
compared to placebo on monthly migraine 
days (MMD) in employed subjects with 
EM who have previously failed 1 or more 
migraine preventive treatments 
 
Change from baseline in mean MMD over 
months 4, 5, and 6 of the 6-month DBTP 


Product:  Erenumab (AMG 334) 
Protocol Number:  20180060 
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Objectives 
Endpoints 
Secondary (Continued) 
The estimand for the secondary objective on MMD consists of: 
 
The target population, which includes employed subjects with EM who have previously 
failed 1 or more migraine preventive treatments  
 
The endpoint, which is the change from baseline in mean MMD over months 4, 5, and 6 of 
the 6-month DBTP 
 
The intercurrent event is adherence to treatment.  The treatment effect of interest will be 
assessed for all randomized subjects enrolled from traditional sites who receive at least 
1 dose of IP and have a baseline value and at least 1 post-baseline value of MMD, 
regardless of adherence to treatment 
 
The summary measure, which is the difference between the mean of the endpoint for the 
erenumab group and the placebo group 
The estimand is the difference in means between erenumab and placebo of the change from 
baseline in mean MMD over months 4, 5, and 6 of the 6-month DBTP in employed subjects 
with EM who have previously failed 1 or more migraine preventive treatments and who are 
randomized, receive at least 1 dose of IP, and have a baseline value and at least 1 
post-baseline value of MMD, regardless of adherence to treatment.  
 
To evaluate the effect of erenumab 
compared to placebo on work impairment 
in employed subjects with EM who have 
previously failed 1 or more migraine 
preventive treatments 
 
Change from baseline in mean monthly 
percent work impairment over months 4, 
5, and 6 of the 6-month DBTP, as 
measured by the Work Productivity and 
Activity Impairment Questionnaire 
(WPAI):  Migraine V2.0 
(WPAI questions 2, 4, and 5) 
Note:  the monthly percent work 
impairment equals to the arithmetic mean 
of the observed weekly percent work 
impairment over the monthly interval. 
The estimand for the secondary objective on work impairment consists of: 
 
The target population, which includes employed subjects with EM who have previously 
failed 1 or more migraine preventive treatments  
 
The endpoint, which is the change from baseline in mean monthly percent work impairment 
over months 4, 5, and 6 of the 6-month DBTP 
 
The intercurrent event is adherence to treatment.  The treatment effect of interest will be 
assessed for all randomized subjects enrolled from traditional sites who receive at least 
1 dose of IP and have a baseline value and at least 1 post-baseline value of monthly 
percent work impairment, regardless of adherence to treatment 
 
The summary measure, which is the difference in means of the endpoint between the 
erenumab group and the placebo group 


Product:  Erenumab (AMG 334) 
Protocol Number:  20180060 
Date:  20 October 2020 
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Objectives 
Endpoints 
Secondary (Continued) 
The estimand is the difference in means between erenumab and placebo of the change from 
baseline in mean monthly percent work impairment over months 4, 5, and 6 of the 6-month 
DBTP in employed subjects with EM who have previously failed 1 or more migraine preventive 
treatments and who are randomized, receive at least 1 dose of IP, and have a baseline value 
and at least 1 post-baseline value of monthly percent work impairment, regardless of 
adherence to treatment. 
 
To evaluate the effect of erenumab 
compared to placebo on physical function, 
usual activities, and social function in 
employed subjects with EM who have 
previously failed 1 or more migraine 
preventive treatments 
 
Change from baseline in mean physical 
function domain score over months 4, 5, 
and 6 of the 6-month DBTP, as measured 
by Migraine Functional Impact 
Questionnaire (MFIQ) 
 
Change from baseline in mean usual 
activities domain score over months 4, 5, 
and 6 of the 6-month DBTP, as measured 
by MFIQ 
 
Change from baseline in mean social 
function domain score over months 4, 5, 
and 6 of the 6-month DBTP, as measured 
by MFIQ 
The estimand for the secondary objective on function (physical, usual activities, and social) 
consists of: 
 
The target population, which includes employed subjects with EM who have previously 
failed 1 or more migraine preventive treatments  
 
The endpoints include: 
1) the change from baseline in mean physical function domain score over months 4, 5, 
and 6 of the 6-month DBTP, as measured by MFIQ 
2) the change from baseline in mean usual activities domain score over months 4, 5, and 
6 of the 6-month DBTP, as measured by MFIQ 
3) the change from baseline in mean social function domain score over months 4, 5, and 
6 of the 6-month DBTP, as measured by MFIQ 
 
The intercurrent event is adherence to treatment.  The treatment effect of interest will be 
assessed for all randomized subjects enrolled from traditional sites who receive at least 
1 dose of IP and have a baseline value and at least 1 post-baseline value of the respective 
MFIQ domain score, regardless of adherence to treatment 
 
The summary measure, which is the difference in means of the respective endpoint 
between the erenumab group and the placebo group 


Product:  Erenumab (AMG 334) 
Protocol Number:  20180060 
Date:  20 October 2020 
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Objectives 
Endpoints 
Exploratory 
 
To evaluate the effect of erenumab 
compared to placebo on work impairment 
in employed subjects with EM who have 
previously failed 1 or more migraine 
preventive treatments 
 
Change from baseline in monthly average 
percent overall work impairment at each 
monthly assessment time point during the 
6-month DBTP, as measured by the 
WPAI (questions 2, 4, and 5) 
 
To evaluate the effect of erenumab 
compared to placebo on MMD in 
employed subjects with EM who have 
previously failed 1 or more migraine 
preventive treatments 
 
Change from baseline in MMD at each 
monthly assessment time points during 
the 6-month DBTP 
 
To evaluate the effect of erenumab 
compared to placebo on function and 
quality of life in employed subjects with 
EM or who have previously failed 1 or 
more migraine preventive treatments 
 
Change from baseline in mean emotional 
function domain score over months 4, 5, 
and 6 of the 6-month DBTP, as measured 
by MFIQ 
 
Change from baseline in mean overall 
impact on usual activities global item 
score over months 4, 5, and 6 of the 
6-month DBTP, as measured by MFIQ 
 
Change from baseline in MFIQ domain 
scores of function (physical, usual 
activities, social, and emotional) and 
overall impact on usual activities global 
item score at each monthly assessment 
time point during the 6-month DBTP 
 
Change from baseline in depression at 
months 1, 3, and 6 of the 6-month DBTP, 
as measured by the Patient Health 
Questionnaire (PHQ-9) total score 
 
Change from baseline in anxiety at 
months 1, 3, and 6 of the 6-month DBTP, 
as measured by Generalized Anxiety 
Disorder 7-item Scale (GAD-7) total score 
 
Change from baseline in insomnia at 
months 1, 3, and 6 of the 6-month DBTP, 
as measured by the Pittsburgh Sleep 
Quality Index (PSQI) total score 


Product:  Erenumab (AMG 334) 
Protocol Number:  20180060 
Date:  20 October 2020 
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Objectives 
Endpoints 
Exploratory (Continued) 
 
 
Change from baseline in excessive 
daytime sleepiness at months 1, 3, and 6 
of the 6-month DBTP, as measured by 
the Epworth Sleepiness Scale (ESS) total 
score 
 
Change from baseline in monthly average 
activity level during and between migraine 
days at each monthly assessment time 
point during the 6-month DBTP, as 
measured by a wearable 
 
Change from baseline in patient 
satisfaction at work at months 1, 3, and 6 
of the 6-month DBTP, as measured by 
the questions in Section 5.1.3 
 
To describe the effect of erenumab on 
migraine-related health resource 
utilization (HRU) in employed subjects 
with EM who have previously failed 1 or 
more migraine preventive treatments 
 
Occurrence of at least 1 migraine-related 
hospitalization or outpatient HRU during 
the 6-month DBTP 
 
Occurrence of at least 1 migraine-related 
hospitalization during the 6-month DBTP 
 
Occurrence of at least 1 migraine-related 
outpatient HRU during the 6-month DBTP 
 
Occurrence of at least 1 migraine-related 
outpatient emergency room visit during 
the 6-month DBTP 
 
Occurrence of at least 1 migraine-related 
outpatient urgent care visit during the 
6-month DBTP 
 
Occurrence of at least 1 migraine-related 
outpatient clinic visit during the 6-month 
DBTP 
 
To evaluate the effect of erenumab 
compared to placebo on attention in 
employed subjects with EM who have 
previously failed 1 or more migraine 
preventive treatments 
 
Change from baseline in mean reaction 
time at months 1, 3, and 6 of the 6-month 
DBTP, as measured by the Psychomotor 
Vigilance Test (PVT)  
 
Change from baseline in number of 
lapses and errors at months 1, 3, and 6 of 
the 6-month DBTP, as measured by PVT 
 
2.2 
Hypotheses and/or Estimations 
The primary clinical hypothesis is that preventive treatment with monthly injections of 
erenumab is superior to placebo in reducing disability in employed subjects with EM who 
have previously failed 1 or more migraine preventive treatments. 


Product:  Erenumab (AMG 334) 
Protocol Number:  20180060 
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3. 
Study Overview 
3.1 
Study Design 
Study 20180060 is a phase 4, 24-week, prospective, double-blind, randomized, 
placebo-controlled, multicenter study in the United States (US), evaluating the effect of 
erenumab on disability and work productivity in employed patients with EM who have 
previously failed 1 or more migraine preventive treatments.  Subjects will enter initial 
screening (up to 21 days) to determine if they meet Eligibility Criteria Part 1.  If Part 1 
eligibility criteria are met, subjects will enter baseline (28 days).  After subjects complete 
baseline and are found eligible based on Eligibility Criteria Part 2, they will be enrolled 
and randomized in a 1:1 ratio to either erenumab 140 mg or placebo.  Randomization 
will be performed separately within traditional sites and decentralized clinical trial site 
(DCTS).  Subjects will then enter a 24-week DBTP which will conclude with an 
end-of-study visit at week 24. 
3.2 
Sample Size 
The total sample size of 240 subjects (120 subjects per treatment group) enrolled from 
traditional sites will provide at least a 94% power for the primary efficacy hypothesis.  
The statistical power for secondary efficacy hypotheses ranges from 88% to 99%.  This 
sample size is not inflated for dropouts since subjects who drop out early during the 
6-month DBTP are likely to have at least 1 post-baseline measurement and therefore will 
still be included in the analysis based on the primary estimand utilizing a repeated 
measures linear mixed model approach.  Table 3-1 provides sample size assumptions 
and resulting statistical power for each hypothesis. 


Product:  Erenumab (AMG 334) 
Protocol Number:  20180060 
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Table 3-1.  Sample Size Assumptions and Statistical Power for Traditional Sites 
Hypothesis 
Assumed Treatment Effect 
(Erenumab – Placebo) 
Assumed Common 
Standard Deviation 
Power for 
Sample Size of 
240 Subjects 
Primary:  modified MIDAS 
total score 
-20 
43 
94% 
Secondary:  
 
 
 
 
MMD 
-2.0 
3.4 
> 99% 
 
Work impairment 
(WPAI) 
-10.0 
23.1 
91% 
 
MFIQ physical 
function 
-7.6 
16.2 
95% 
 
MFIQ usual activities 
-6.1 
14.9 
88% 
 
MFIQ social function 
-6.8 
15.6 
91% 
MFIQ = Migraine Functional Impact Questionnaire; MIDAS = Migraine Disability Assessment; 
MMD = monthly migraine days; WPAI = Work Productivity and Activity Impairment. 
Note:  All power calculations are based on a 2-sided significance level of 0.05 and not adjusted to reflect the 
sequential testing procedure.  The assumed treatment effects and common standard deviations for 
modified MIDAS, MMD, and MFIQ hypotheses are derived from a subset of subjects in erenumab 
Study 20120296 satisfying the key entry criteria of the current study.  The assumed treatment effect and 
common standard deviation for the work impairment hypothesis is derived from the LIBERTY study.   
In addition, a total sample size of 100 subjects (50 per treatment group) will be enrolled 
as part of the DCTS for pilot purposes. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
All model-adjusted analyses of efficacy endpoints will include the corresponding baseline 
value for the endpoint being analyzed. 
4.2 
Subgroups 
The primary and secondary endpoints will be summarized in the subgroups defined by 
number of prior treatment failures (1, 2, and 3 or more treatment failures) for the 
traditional sites only. 
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. 


Product:  Erenumab (AMG 334) 
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5. 
Definitions 
5.1 
Definition of Terms Included in Study Endpoints 
5.1.1 
Efficacy Endpoints Based on Daily Data Collection 
The eDiary collects headache events (including start and stop time, pain features, 
symptoms, and severity), aura events (including start and stop time), and acute 
headache medications (including taken time) in 3 independent modules.  The eDiary 
design includes optional any-time diaries and a mandatory evening diary from 
5:00:00 pm to 11:59:59 pm (local time) each day for data collection.   
Acute Headache Medication (AHM) 
Acute headache medications include following categories collected in the eDiary: 
 
Triptan-based migraine medications 
 
Ergotamine-based migraine medications 
 
Non-opioid acute headache medications 
 
Non-opioid butalbital containing medications 
 
Opioid-containing acute headache medications 
 
Opioid-containing butalbital containing medications 
Acute Migraine-specific Medication (AMSM) 
A subset of acute headache medication consisting of triptan-based migraine medications 
and ergotamine-based migraine medications 
Qualified Headache  
A qualified headache is defined as 
 
A headache of duration ≥ 30 minutes 
 
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 
 
Acute migraine-specific medications taken during an aura (start and end time 
inclusive) 
Headache Day 
A calendar day (00:00 to 23:59) in which the subject experiences ≥ 1 qualified headache  


Product:  Erenumab (AMG 334) 
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Headache Pain Intensity 
Worst or peak pain intensity collected on a headache ranges from 0 (no pain) to 10 with 
a higher score indicating more severe pain.  Pain intensity are categorized into mild 
(1 to 3), moderate (4 to 6), and severe (7 to 10). 
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 (ie, headache pain intensity ≥ 4) 
 
Exacerbated with exercise/physical activity 
b) ≥ 1 of the following associated symptoms:  
 
Nausea 
 
Vomiting  
 
Photophobia and phonophobia 
 
A headache with acute migraine-specific medications taken during the headache 
(start time and end time inclusively) regardless of the headache duration, pain 
features, and associated symptoms 
 
Acute migraine-specific medications taken during aura 
Migraine Day 
A calendar day (00:00 to 23:59) in which the subject experiences ≥ 1 qualified migraine 
headache.  
Diary Day  
A calendar day (00:00 to 23:59) with complete headache, aura, and acute headache 
medication data recorded in the eDiary device. 
Information Day  
A calendar day (00:00 to 23:59) which is either a diary day or a headache day that can 
be derived based on available information. 
Monthly Migraine Days (MMD)  
Number of migraine days during one monthly interval as defined below.  


Product:  Erenumab (AMG 334) 
Protocol Number:  20180060 
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Number of Diary 
Days in a Monthly 
Interval 
Monthly Migraine Days 
 
≥ 14 days 
Prorate to 28-day equivalent without rounding as follows: 
 
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑜𝑏𝑠𝑒𝑟𝑣𝑒𝑑 𝑚𝑖𝑔𝑟𝑎𝑖𝑛𝑒 𝑑𝑎𝑦𝑠 𝑤𝑖𝑡ℎ𝑖𝑛 𝑒𝑎𝑐ℎ 𝑚𝑜𝑛𝑡ℎ𝑙𝑦 𝑖𝑛𝑡𝑒𝑟𝑣𝑎𝑙
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑖𝑟𝑎𝑦 𝑑𝑎𝑦𝑠 𝑤𝑖𝑡ℎ𝑖𝑛 𝑒𝑎𝑐ℎ 𝑚𝑜𝑛𝑡ℎ𝑙𝑦 𝑖𝑛𝑡𝑒𝑟𝑣𝑎𝑙
 𝑥 28 
 
< 14 days 
Set to missing 
Monthly Headache Days (MHD)  
Number of headache days during one monthly interval as defined below.  
Number of Diary 
Days in a Monthly 
Interval 
Monthly Headache Days 
 
≥ 14 days 
Prorate to 28-day equivalent without rounding as follows: 
 
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑜𝑏𝑠𝑒𝑟𝑣𝑒𝑑 ℎ𝑒𝑎𝑑𝑎𝑐ℎ𝑒 𝑑𝑎𝑦𝑠 𝑤𝑖𝑡ℎ𝑖𝑛 𝑒𝑎𝑐ℎ 𝑚𝑜𝑛𝑡ℎ𝑙𝑦 𝑖𝑛𝑡𝑒𝑟𝑣𝑎𝑙
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑖𝑛𝑓𝑜𝑟𝑚𝑎𝑡𝑖𝑜𝑛 𝑑𝑎𝑦𝑠 𝑤𝑖𝑡ℎ𝑖𝑛 𝑒𝑎𝑐ℎ 𝑚𝑜𝑛𝑡ℎ𝑙𝑦 𝑖𝑛𝑡𝑒𝑟𝑣𝑎𝑙
 𝑥 28 
 
< 14 days 
Set to missing 
5.1.2 
Efficacy Endpoints Based on Weekly Collection 
Work Productivity and Activity Impairment (WPAI) Questionnaire 
In the WPAI-Migraine questionnaire, subjects are asked 6 questions about work and 
activity impairment due to their migraine, including hours worked and hours missed in 
the last 7 days.  The questionnaire will be collected weekly during baseline and 
post-baseline.  
The weekly percent work impairment score is calculated based on questions 2, 4 and 5. 
Higher score indicates worse outcome. 
The monthly percent work impairment equals to the arithmetic mean of the observed 
weekly percent work impairment scores over the monthly interval, if the number of 
weekly scores during baseline period or each of the monthly interval during 
post-baseline is ≥ 2. Otherwise, monthly measurement will be set to missing. 
5.1.3 
Efficacy Endpoints Based on Monthly Collection 
Modified Migraine Disability Assessment (Modified MIDAS) 
The modified MIDAS Questionnaire is a 5-item self-administered questionnaire that 
assesses in the past month the number of productive days lost in 2 settings (workplace 
and home) and disability in family, social, and leisure activities.   Absenteeism score is 


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the response from question 1, and presenteeism score is the response from question 2. 
The total score ranging from 0 to 93 is the sum of the responses to all 5 items. Higher 
scores indicate worse outcome. The modified MIDAS will be collected monthly during 
baseline and post-baseline.   
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 during baseline and 
post-baseline. 
5.1.4 
Efficacy Endpoints Collected at Specific Visits 
Patient Health Questionnaire (PHQ-9) 
The Patient Health Questionnaire (PHQ) is a 9-question, self-administered instrument for 
screening, diagnosing, monitoring, and measuring the severity of depression. Each item 
has response as “0” (not at all) to “3” (nearly every day).  The score is calculated as the 
sum of the 9 item responses, ranging from 0 to 27 with higher score representing 
severer depression. PHQ-9 will be collected at baseline and at months 1, 3 and 6 
post-baseline.  
Generalized Anxiety Disorder 7-item Scale Questionnaire (GAD-7) 
The GAD-7 is a self-administered 7-item instrument to identify probable cases of GAD 
along with measuring anxiety symptom severity.  Responders are asked to rate the 
frequency of anxiety symptoms in the last 2 weeks on a Likert scale ranging from 0 (not 
at all) to 3 (nearly every day).  Items are summed to provide a total score, ranging from 
0 to 21 with higher score indicating severer symptoms. GAD-7 will be collected at 
baseline and at months 1, 3 and 6 post-baseline.  


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Pittsburgh Sleep Quality Index (PSQI) 
The PSQI is a self-reported questionnaire that assesses sleep quality over a 1-month 
time interval.  The measure consists of 19 individual items, creating 7 components that 
produce 1 global score.  Each component scored 0 (better) to 3 (worse). The global 
score is the sum of each component score, ranging from 0 to 21 with higher score 
indicating worse sleep quality. PSQI will be collected at baseline and at months 1, 3 and 
6 post-baseline. 
Epworth Sleepiness Scale (ESS) 
The ESS is a self-administered questionnaire with 8 questions designed to assess 
daytime sleepiness.  Respondents are asked to rate, on a 4-point scale (0 to 3), their 
usual chances of dozing off or falling asleep while engaged in 8 different activities.  The 
ESS score (the sum of 8 item scores, 0 to 3) can range from 0 to 24 with higher ESS 
scores indicating higher average sleep propensity (ASP) in daily life, or “daytime 
sleepiness”.  ESS will be collected at baseline and at months 1, 3 and 6 post-baseline. 
Patient Satisfaction at Work 
To better understand impact of depression, anxiety, sleepiness, and inability to 
concentrate on work productivity, subjects will be asked to complete the following 
questions on a 10-point scale with higher score representing severer impacts:  
 
How much does your depressed mood, as a result of your migraines, impact your 
ability to function at work?   Scale, 0 = no impact to 10 = severely impacts 
 
How much does your anxiety, as a result of your migraines, impact your ability to 
function at work?   Scale, 0 = no impact to 10 = severely impacts 
 
How much does your sleepiness, as a result of your migraines, impact your 
ability to function at work? Scale, 0 = no impact to 10 = severely impacts 
 
How much does your inability to concentrate, as a result of your migraines, 
impact your ability to function at work? Scale, 0 = no impact to 10 = severely 
impacts 
 
How would you rate your overall satisfaction with your productivity at work? 
Scale, 0 = as dissatisfied as you can imagine to 10 = as satisfied as you can 
imagine 
These questions are not part of a validated questionnaire and will be scored individually.  
The recall period is the past month. Patient satisfaction at work will be collected at 
baseline and at months 1, 3 and 6 post-baseline. 


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Psychomotor Vigilance Task (PVT) 
Psychomotor Vigilance Task is a sustained-attention, reaction-timed task that measures 
the speed with which a subject responds to a visual stimulus.  Mean reaction time in 
millisecond, number of lapses and errors will be calculated from the individual elapsed 
time recordings during the 10-minute session.  PVT will be collected at baseline and at 
months 1, 3 and 6 post-baseline. 
Subjects enrolled as part of the DCTS will not complete this assessment. 
Health Resource Utilization (HRU) Questionnaire 
The questionnaire is designed to collect data on HRU.  Specifically, the aim is to capture 
frequency of migraine-related hospitalizations and outpatient visits including emergency 
department visits, urgent care visits, and other clinical visits.  The recall period for the 
HRU questionnaire is 24 weeks, and the HRU questionnaire will be administered on 
day 1, and week 24 of the DBTP.  The questionnaire assessed at the early termination 
visit before week 24 should only include HRU recalled since the previous assessment at 
day 1 to avoid collecting duplicate information.  HRU will be collected at baseline and at 
month 6 post-baseline. 
5.1.5 
Efficacy Endpoints Based on Wearable Device Collection 
Physical activity will be measured continuously by a wearable device (accelerometer) 
from baseline through the end of study except when recharging. Analysis of physical 
activity endpoints will only include activity data collected while subjects are wearing the 
device and are awake (not sleeping), ie, during wear and awake time.   
Valid Day 
A valid day is defined when there are at least 10 hours (600 minutes) of wear and awake 
time per calendar day (00:00 to 23:59).  Analysis of physical activity endpoints will only 
include activity data collected during wear and awake time on valid days.  
Physical Activity Category 
Physical activity level can be defined in the following 6 categories:  
 
Sedentary 
 
Light 
 
Lifestyle 


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 
Moderate 
 
Vigorous 
 
Very vigorous  
Note:  The raw data will include total minutes of wear and awake time corresponding to 
each physical activity category per calendar day.   
Total Minutes of Wear and Awake Time in a Valid Day 
Sum of total minutes of wear and awake time for each of the 6 physical activity 
categories in a valid day 
Daily Proportion of Time Spent in Each Physical Activity Category per Valid Day 
𝑇𝑜𝑡𝑎𝑙 𝑚𝑖𝑛𝑢𝑡𝑒𝑠 𝑜𝑓 𝑤𝑒𝑎𝑟 𝑎𝑛𝑑 𝑎𝑤𝑎𝑘𝑒 𝑡𝑖𝑚𝑒 𝑠𝑝𝑒𝑛𝑡 𝑖𝑛 𝑒𝑎𝑐ℎ 𝑝ℎ𝑦𝑠𝑖𝑐𝑎𝑙 𝑎𝑐𝑡𝑖𝑣𝑖𝑡𝑦 𝑐𝑎𝑡𝑒𝑔𝑜𝑟𝑦 𝑖𝑛 𝑎 𝑣𝑎𝑙𝑖𝑑 𝑑𝑎𝑦 
𝑇𝑜𝑡𝑎𝑙 𝑚𝑖𝑛𝑢𝑡𝑒𝑠 𝑜𝑓 𝑤𝑒𝑎𝑟 𝑎𝑛𝑑 𝑎𝑤𝑎𝑘𝑒 𝑡𝑖𝑚𝑒 𝑖𝑛 𝑎 𝑣𝑎𝑙𝑖𝑑 𝑑𝑎𝑦
  
Note:  Since total minutes of wear and awake time vary daily, daily proportion is meant 
to normalize the daily physical activity level before calculating the monthly average.   
Monthly Average of Daily Proportion of Time Spent in Each Physical Activity 
Category on Valid Days 
Number of 
Valid Days in a 
Monthly 
Interval 
Monthly average of daily proportion of time spent in each physical activity 
category 
 
≥ 14 days 
𝑆𝑢𝑚 𝑜𝑓 (𝑑𝑎𝑖𝑙𝑦 𝑝𝑟𝑜𝑝𝑜𝑟𝑡𝑖𝑜𝑛 𝑜𝑓 𝑡𝑖𝑚𝑒 𝑠𝑝𝑒𝑛𝑡 𝑖𝑛 𝑒𝑎𝑐ℎ 𝑝ℎ𝑦𝑠𝑖𝑐𝑎𝑙 𝑎𝑐𝑡𝑖𝑣𝑖𝑡𝑦 𝑐𝑎𝑡𝑒𝑔𝑜𝑟𝑦) 
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑣𝑎𝑙𝑖𝑑 𝑑𝑎𝑦𝑠 𝑖𝑛 𝑎 𝑚𝑜𝑛𝑡ℎ
 
 
< 14 days 
Set to missing 
Sleep Period 
A sleep period is defined to be at least 160 minutes long that starts when 5 consecutive 
minutes marked as “sleep” and ends once there are 10 consecutive minutes marked as 
“awake”.  
Sleep Efficiency 
Sleep efficiency is the total number of minutes marked as sleep during the total length of 
the sleep period in minutes.  
𝑠𝑙𝑒𝑒𝑝 𝑡𝑖𝑚𝑒 𝑖𝑛 𝑚𝑖𝑛𝑢𝑡𝑒𝑠 
𝑇𝑜𝑡𝑎𝑙 𝑚𝑖𝑛𝑢𝑡𝑒𝑠 𝑜𝑓 𝑠𝑙𝑒𝑒𝑝 𝑝𝑒𝑟𝑖𝑜𝑑 (𝑠𝑙𝑒𝑒𝑝 𝑚𝑖𝑛𝑢𝑡𝑒𝑠+ 𝑎𝑤𝑎𝑘𝑒 𝑚𝑖𝑛𝑢𝑡𝑒𝑠)  


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5.1.6 
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  
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 Treatment-emergent Adverse Event  
A treatment-emergent adverse event with the indicator flag “Serious” equal to “Yes” on 
the Events eCRF 
Treatment-emergent Adverse Device Effect 
A treatment-emergent adverse event 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 Device Ready for Entry 
The date on which an eDiary device is ready for entry after completion of initial 
screening. 
Randomization (Enrollment) Date  
Randomization (Enrollment) Date is the date on which a subject is assigned to one of 
the treatments through Interactive Response Technology (IRT). 
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.  


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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. 
5.3 
Study Points of Reference 
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 
and weekly eDiary collection) 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, 
Weekly, or Wearable Data Collection 
The (4-week) monthly intervals for efficacy endpoints derived from daily eDiary 
collection, weekly collection for WPAI, or wearable device (physical activity data only) 
will be determined based on each subject’s monthly IP dosing dates.  When an IP is 


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missed, discontinued, or no longer required, a 28-day monthly interval will be used.  Any 
eDiary or wearable 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) 
 
Monthly headache days (MHD) 
 
Monthly percent work impairment as measured by WPAI 
 
Monthly average daily proportion of time spent in each physical activity category: 
sedentary, light, lifestyle, moderate, vigorous, and very vigorous    
Table 5-1.  Monthly Intervals for Efficacy Endpoints Derived From Daily, Weekly, or 
Physical Activity Wearable 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 c 
Day prior to study day 1 
Double-blind 
Treatment Period 
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 
Week 16 (Month 4) 
Week 12 dose date  
Week 16 dose date – 1 
Week 20 (Month 5) 
Week 16 dose date  
Week 20 dose date – 1 
Week 24 (Month 6) 
Week 20 dose date  
Week 20 dose date + 27 
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 
c For physical activity wearable data, Baseline Start Date (day) is defined as Max (Earliest valid activity 
date, week -4 visit date) 
Sleep associated endpoints from each sleep period will utilize the monthly invervals 
defined in Table 5-2 based on the sleep start date/time.   
Table 5-2.  Monthly Intervals for Sleep Associated Endpoints 
Study 
Period 
Assessment 
Timepoint 
Monthly Interval 
Start Date/Time a 
End Date/Time b 
Baseline 
Period 
Baseline 
Max (Earliest recorded 
sleep start date, week -4 
visit date) 
Day 1 dose date/time 
Double-blind 
Treatment 
Period 
 
Week 4 (Month 1) 
Day 1 dose date/time  
Week 4 dose date/time 
Week 8 (Month 2) 
Week 4 dose date/time  
Week 8 dose date/time 
Week 12 (Month 3) 
Week 8 dose date/time 
Week 12 dose date/time 
Week 16 (Month 4) 
Week 12 dose date/time  
Week 16 dose date/time 
Week 20 (Month 5) 
Week 16 dose date/time  
Week 20 dose date/time 
Week 24 (Month 6) 
Week 20 dose date/time  
≤ Week 24 visit date 
a Start Date/Time = End date/time of previous monthly interval if IP dose date is not available 
b End Date/Time = Start date/time of current monthly interval + 27 if IP dose date is not available 


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5.4.2 
Analysis Visits for Endpoints Based on Monthly 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:  
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.  Modified MIDAS and MFIQ Analysis Visit Windows 
Study Period 
Analysis Visit 
Target Day 
Visit Window (Study Day) 
Double-blind  
Treatment  
Period 
Day 1 (Baseline) 
1 
Last measurement ≤ Day 1 
Week 4 (Month 1) 
29 
16 to 43 
Week 8 (Month 2) 
57 
44 to 71 
Week 12 (Month 3) 
85 
72 to 99 
Week 16 (Month 4) 
113 
100 to 127 
Week 20 (Month 5) 
141 
128 to 155 
Week 24 (Month 6) 
169 
156 to 183 
Table 5-4.  PHQ-9, GAD-7, PSQI, ESS, Patient Satisfaction at Work and PVT 
Analysis Visit Windows 
Study Period 
Analysis Visit 
Target Day 
Visit Window (Study Day) 
Double-blind  
Treatment  
Period 
Day 1 (Baseline) 
1 
Last measurement ≤ Day 1 
Week 4 (Month 1) 
29 
16 to 43 
Week 12 (Month 3) 
85 
72 to 99 
Week 24 (Month 6) 
169 
156 to 183 


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Table 5-5.  HRU Analysis Visit Windows 
Study Period 
Analysis Visit 
Target Day 
Visit Window (Study Day) 
Double-blind  
Treatment  
Period 
Day 1 (Baseline) 
1 
Last measurement ≤ Day 1 
Week 24 (Month 6) 
169 
156 to 183 
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”. 
Completing Study 
Subjects are defined as completing study if they complete the entire 24 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 considered on-study if they have been randomized and have not yet had 
their EOS visit. 
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. 


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Duration of IP Exposure 
Minimum (Last Dose Date + 27, EOS Date) – First Dose Date + 1 
Change From Baseline 
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.   
Mean Monthly Change From Baseline Over Multiple Months 
Mean monthly change from baseline 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.  
Sum of Monthly Changes From Baseline Over the 6-month DBTP 
Sum of monthly changes from baseline over the 6-month DBTP is calculated as the 
arithmetic mean of the monthly change from baseline over the same 6-month period 
times 6.   
Note:  This prorated value will be used to provide summary statsitics of the primary 
efficacy endpoint.   
Subject Incidence 
The subject incidence for a given event in a given period is defined as the number of 
subjects with at least one reported occurrence of the event divided by the number of 
subjects who enter that period (ie, number of at-risk subjects).  For subjects with multiple 
occurrences of the same event in a given period, the event will only be counted once per 
subject in that period. 
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 reaction” or “Intolerance” on the Prior 
Migraine Prophylactic Medication eCRF. 
6. 
Analysis Sets 
6.1 
Full Analysis Set 
The respective full analysis set (FAS) consists of all subjects who were randomized in 
the study through traditional study sites or DCTS. Analysis of disposition, demographic 


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and baseline characteristics, and important protocol deviations will utilize the respective 
FAS.   
6.2 
Efficacy Analysis Set 
The respective efficacy analysis set (EAS) consists of a subset of subjects from 
traditional study sites or DCTS who receive at least 1 dose of IP 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 EAS. 
6.3 
Safety Analysis Set 
The respective safety analysis set (SAS) will consist of all randomized subjects from 
traditional study sites or DCTS who received at least 1 dose of IP.  Subjects will be 
analyzed according to the randomized treatment unless a subject has received the 
incorrect randomized treatment during the entire DBTP. Analysis for safety endpoints 
and summary of IP administration will utilize the respective SAS. 
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 24 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. The 
primary analysis at the end of the study will be based on cleaned, locked data. 
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. The database will be subjected to edit check outlined in the Data 
Management Plan (DMP). eDiary data, physical activity and sleep data collected through 
wearable, pharmacogenetic, and biomarkers data is outside of RAVE database. All the 
datasets to be used for planned analyses will be received from GSO-DM department. 
Additional details will be provided in the DMP and Data Transfer Plan (DTP). 


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8.3 
Handling of Missing and Incomplete Data 
Subjects may miss specific data points for a variety of causes. In general, data could be 
missing due to a subject’s early withdrawal from study, a missed visit, or inability to 
evaluate an endpoint at a point in time. For this study, most of the efficacy endpoint will 
be collected via eDiary and subjects could miss entering several days of data in each 
monthly interval. The general procedures outlined below describe what will be done 
when a data point is missing.  
Missing daily data in the calculation of monthly measurements about subjects’ migraine 
and non-migraine headaches will be handled using the following proration method, also 
described in Section 5.1.1. 
 
For each monthly interval with  14 days of eDiary use:  
 
Monthly frequency measurements will be prorated to 28-day equivalents.  
Prorated result does not need to be rounded. 
 
Monthly average scores will be calculated as the average of observed scores. 
 
For monthly intervals with  14 days of eDiary use, all monthly measurements will be 
set as missing.  
Missing monthly efficacy measurements will not be imputed in the primary analysis 
method utilizing a generalized linear mixed model to handle missing data under MAR 
assumption. In the sensitivity analysis on primary and secondary efficacy endpoints, 
missing data in monthly values will be handled using multiple imputation (MI) with 
assumption of missing not at random (MNAR) (with control-based pattern imputation). 
For the descriptive summary the mean monthly value over months 4, 5, and 6 is 
calculated using the arithmetic mean of observed monthly values from each of months 4, 
5, and 6 of the DBTP.  Therefore, a subject with at least one monthly value at months 4, 
5, and 6 will contribute to the summary statistics.   
For the descriptive summary the primary endpoint, sum of monthly changes from 
baseline in MIDAS total score over the 6-month DBTP, will be prorated as follows for 
subjects with missing data in monthly changes from baseline: 
𝑆𝑢𝑚 𝑜𝑓 𝑜𝑏𝑠𝑒𝑟𝑣𝑒𝑑 𝑚𝑜𝑛𝑡ℎ𝑙𝑦 𝑐ℎ𝑎𝑛𝑔𝑒𝑠 𝑓𝑟𝑜𝑚 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑖𝑛 𝑀𝐼𝐷𝐴𝑆 𝑠𝑐𝑜𝑟𝑒  𝑤𝑖𝑡ℎ𝑖𝑛 6 𝑚𝑜𝑛𝑡ℎ 𝐷𝐵𝑇𝑃
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑚𝑜𝑛𝑡ℎ𝑠 𝑤𝑖𝑡ℎ 𝑜𝑏𝑠𝑒𝑟𝑣𝑒𝑑 𝑚𝑜𝑛𝑡ℎ𝑙𝑦 𝑣𝑎𝑙𝑢𝑒𝑠 𝑤𝑖𝑡ℎ𝑖𝑛 6 𝑚𝑜𝑛𝑡ℎ 𝐷𝐵𝑇𝑃
 𝑥 6 
Missing safety endpoints will not be imputed.  Missing or incomplete dates will be listed 
as reported, except for incomplete start date of an adverse event or concomitant 
medication, which will be imputed as follows: 


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Missing 
Imputation 
Exception on adverse event start date 
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 
None 
- 
 
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/or tabulated. If necessary, the incidence of other factors will be tabulated.   
Any breaking of the blind for individual subjects prior to formal unblinding of the study will 
be documented in the CSR.   
The reasons for early withdrawal from treatment and from study will be tabulated and/or 
listed. 
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 corrected 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 
All analyses will be conducted separately for subjects enrolled from traditional sites and 
subjects from DCTS. Formal statistical hypothesis testing for the primary and secondary 
endpoints will be performed for subjects enrolled from traditional sites only. Subject 
characteristics for both traditional sites and DCTS will be summarized descriptively. 
Summary statistics by each treatment group will be tabulated at each assessment time 
point if applicable. For continuous endpoints, the descriptive statistics include:  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 order of modified 
MIDAS total score, MMD, WPAI, MFIQ physical function, MFIQ usual activity, and MFIQ 
social function endpoints. An endpoint will only be tested if the endpoint tested in the 
previous step is statistically significant at 2-sided significance level of 0.05. 


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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 IP, who complete IP, 
discontinue IP and reasons for discontinuing, who complete the study, and who withdraw 
prematurely from the study and their reasons for withdrawal. 
A footnote on the subject disposition tables will include the number of subjects screened. 
A summary of the study reporting period including a description of key dates will also be 
provided, including dates of the first and last subject enrolled and the last subject’s end 
of study date. 
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 study. Eligibility deviations are defined in the 
protocol.  In addition, protocol deviations related to COVID-19 control measures will be 
summarized and listed.   
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. 
At baseline, the following demographic and baseline characteristics will be summarized:  
 
Age 
 
Sex 
 
Ethnicity 
 
Race 
 
Height (cm) 
 
Weight (kg) 
 
Body Mass Index (BMI, kg/m2) 
 
Targeted neurological disease diagnosis at baseline 


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 
Disease duration of migraine with or without aura (years) 
 
Age at onset of migraine 
 
Number of prior migraine preventive treatment failure categories 
 
Summary of prior migraine preventive medication and reasons for discontinuation 
 
Summary of current migraine preventive treatment at baseline 
 
Acute headache medication used during baseline period:  
a) Migraine-specific 
b) Non-migraine-specific 
 
Monthly migraine days during baseline period 
 
Monthly headache days during baseline period  
 
Monthly acute migraine-specific medication days during baseline period 
 
Monthly acute migraine-specific medication days during baseline period among 
baseline users 
 
Monthly acute headache medication days during baseline period 
 
Monthly acute headache medication days during baseline period among baseline 
users 
 
Modified MIDAS total score, absenteeism score, and presenteeism score 
 
Monthly percent work impairment as measured by WPAI during baseline period 
 
MFIQ domain scores of function (physical, usual activities, social, and emotional) 
and overall impact on usual activities global item score 
9.5 
Efficacy Analyses 
The primary analysis of efficacy endpoints will utilize the EAS.  Subjects will be analyzed 
according to their randomized treatment group regardless of the actual treatment 
received during the study.   


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For primary analysis, the continuous change from baseline efficacy endpoints calculated 
by the method as specified in Section 5.6 will be analyzed using generalized linear 
mixed effect models including treatment group, scheduled visit, the interaction between 
treatment group and scheduled visit and the baseline value on observed data.  
Detailed primary analysis methods, sensitivity analyses, and covariates included in the 
models are summarized in the table below. 
Table 9-1.  Primary Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis 
Method  
Sensitivity Analysis 
Sum of monthly 
changes from baseline 
in modified MIDAS total 
score over the 6-month 
double-blind treatment 
period (DBTP) 
 
(Note: Results from 
individual time point 
during the DBTP will 
also be generated in 
the same generalized 
linear mixed effect 
model.) 
1. Summary statistics by visit 
using observed data at each 
visit and the calculated sum of 
each monthly change from 
baseline value over 6 months 
2. Least squares means from a 
generalized linear mixed effect 
model including treatment 
group, scheduled visit, 
interaction of treatment and 
scheduled visit and baseline 
value using observed data 
3. Test treatment difference 
(AMG 334 – Placebo) using a 
contrast from the model in #2. 
MI with assumption of MNAR 
(control-based pattern 
imputation) 


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Table 9-2.  Secondary Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis 
Method  
Sensitivity Analysis 
Change from baseline in mean 
MMD over months 4, 5, and 6; 
Change from baseline in mean 
monthly percent work 
impairment as measured by 
WPAI over months 4, 5, and 6; 
 
Change from baseline in MFIQ 
domain scores of function 
(physical function, usual 
activities, and social function) 
over months 4, 5, and 6 
 
(Note: Results from individual 
time point during the DBTP as 
exploratory endpoints will also 
be generated in the same 
generalized linear mixed effect 
model.) 
1. Summary statistics by visit 
using observed data at each 
visit, and the calculated mean 
monthly migraine days or mean 
domain scores over months 4, 
5, and 6 
2. Least squares means from a 
generalized linear mixed effect 
model including treatment 
group, scheduled visit, 
interaction of treatment and 
scheduled visit and baseline 
value using observed data 
3. Test treatment difference 
(AMG 334 – Placebo) using a 
contrast from the model in #2. 
MI with assumption of 
MNAR (control-based 
pattern imputation) 
Table 9-3.  Exploratory Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis Method  
Sensitivity 
Analysis 
Change from baseline 
in mean emotional 
function domain score 
over months 4, 5, and 6 
of the 6-month DBTP, 
as measured by MFIQ a 
 
(Note: Results from 
individual time point 
during the DBTP will 
also be generated in 
the same generalized 
linear mixed effect 
model.) 
1. Summary statistics by visit using observed data at 
each visit, and the calculated mean domain score 
over months 4, 5, and 6 
2. Least squares means from a generalized linear 
mixed effect model including treatment group, 
scheduled visit, interaction of treatment group and 
scheduled visit and baseline value using observed 
data 
3. Test treatment difference (AMG 334 – Placebo) 
using a contrast from the model in #2. 
 
Endpoints defined as 
change from baseline 
at months 1, 3, and 6 b 
1. Summary statistics by visit using observed data  
2. Least squares means from a generalized linear 
mixed effect model including treatment group, 
scheduled visit, interaction of treatment group and 
scheduled visit and baseline value using observed 
data 
3. Test treatment difference (AMG 334 – Placebo) 
from the model in #2. 
 
Page 1 of 2 
Footnotes defined on last page of the table 


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Table 9-3.  Exploratory Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis Method  
Sensitivity 
Analysis 
Endpoints defined as 
change from baseline 
at each monthly 
assessment time point c 
1. Summary statistics by visit using observed data  
2. Least squares means from a generalized linear 
mixed effect model including treatment group, 
scheduled visit, interaction of treatment group and 
scheduled visit and baseline value using observed 
data 
3. Test treatment difference (AMG 334 – Placebo) 
from the model in #2. 
 
Occurrence of at least 
1 migraine-related 
hospitalization or 
outpatient HRU during 
the 6-month DBTP d 
1. Summary statistics using observed data at month 6 
 
Page 2 of 2 
a The same analysis methods will be applied to the endpoints: 
               Change from baseline in mean overall impact on usual activities global item score over months 4, 
               5, and 6 of the 6-month DBTP, as measured by MFIQ. 
b The same analysis methods will be applied to the following endpoints at months 1, 3, and 6: 
                PHQ-9 total score,  
                GAD-7 total score,  
                PSQI total score, 
                ESS total score, 
                Patient satisfaction at work,  
                Mean reaction time, number of lapses, and number of errors as measured by PVT. 
c The same analysis methods will be applied to the following endpoints at all 6 months: 
                Change from baseline in monthly average daily proportion of time spent in each physical activity 
                category: sedentary, light, lifestyle, moderate, vigorous, and very vigorous,  
                Change from baseline in monthly average sleep efficiency. 
d The same analysis method will be applied to all HRU endpoints.               
 
9.5.1 
Analyses of Primary and Secondary Efficacy Endpoints 
The primary analysis of the primary and secondary endpoints will be performed using a 
generalized linear mixed model based on observed monthly data with appropriate 
contrasts for treatment comparison relative to placebo for the corresponding efficacy 
endpoints: sum of monthly changes from baseline value over the 6-month DBTP, and 
change from baseline in mean monthly values or mean domain scores over months 4, 5 
and 6.  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% confidence intervals, difference of LSMs compared to placebo 
group, associated 95% confidence intervals and nominal two-sided p-values will be 
tabulated by visit, as well as for the mean monthly values over months 4, 5, and 6 of the 
DBTP. 


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Sensitivity analysis described below will be performed for the primary and secondary 
endpoints: 
1. MI with assumption of MNAR (control-based pattern imputation). 
2. Primary summary and analysis by the subgroup of treatment failure of prior 
migraine prophylactic medications (Section 4.2) 
The purpose of the subgroup analyses is to explore if the treatment effect varies across 
subgroups of interest.  Analysis within each interested subgroup will be performed using 
the same primary analysis method for the same endpoint.  The treatment difference with 
associated 95% confidence interval and p-value will be reported within each subgroup. 
The heterogeneity of the treatment effect across the subgroups will be evaluated by 
examining the treatment-by-subgroup interaction p-value obtained from the primary 
analysis model with the addition of treatment-by-subgroup interaction.   
9.5.2 
Analyses of Exploratory Efficacy Endpoints 
The primary analysis of the exploratory efficacy endpoints will be conducted in the same 
way as that for the primary and secondary endpoints as outlined in Table 9-3.  No 
sensitivity analyses will be performed for the exploratory efficacy endpoints.   
9.6 
Safety Analyses 
9.6.1 
Analyses of Safety Endpoint(s) 
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 22.0 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.   


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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 (Broad) 
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. 
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. 
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 IP 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.  Missed 
doses due to COVID-19 control measures will also be summarized.   
9.6.4 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving headache-related medications will be 
summarized by acute medication category for each treatment group.  
10. 
Changes From Protocol-specified Analyses 
In addition to modified MIDAS total score, absenteeism score and presenteeism score 
will also be analyzed as exploratory endpoints.  


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11. 
Literature Citations / References 
Quade, D. (1966), Rank analysis of covariance, University of North Carolina, Institute of 
Statistics Mimeo Series. No. 483  
 


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12. 
Data Not Covered by This Plan 
There are no plans to specifically analyze or summarize the following data points.  
 
Data from pharmacogenetic substudy 
 
Data for biomarker development 


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13. 
Appendices 
NA