Clinical trial NCT04825678
Conditions: Migraine
Keywords: Migraine Chronic Migraine Episodic Migraine Erenumab
Sponsor: Amgen
Start date: 2021-06-11; Completion date: 2023-09-28
Enrollment: 240 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main purpose of this study is to evaluate the effect of erenumab on medication-specific treatment satisfaction.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Erenumab
Intervention descriptions: intervention 1: Administered as a subcutaneous injection via the SureClick® Autoinjector Pen (AI/Pen).

Protocol documents:
Prot_000.pdf: 
Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389  
Date:  18 March 2022 
Page 1 of 91 
CONFIDENTIAL  
 
 
Title Page 
Protocol Title: 
Phase 4, Open-label Study to Evaluate 
Treatment Satisfaction With Erenumab in 
Patients With Migraine 
Short Protocol Title: 
Erenumab Treatment Satisfaction Study 
Protocol Number: 
20190389 
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: 
, MD 
Function: 
Vice President, Global Development 
 
Key 
Sponsor 
Contact 
Name: 
 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Telephone Number: 
 
Email Address: 
 
 
EudraCT Number: 
Not applicable 
NCT Number: 
NCT04825678 
Protocol Version Date: 
Document 
Version 
Date 
Original 
Superseded 
Original 
Amendment 1 
Amendment 2 
30 October 2020 
20 November 2020 
 
18 December 2020 
18 March 2022 
Data Elements Standards 
Version: 
7.0 
 
This protocol was developed, reviewed, and approved in accordance with Amgen’s 
standard operating procedures.  This format and content of this protocol is aligned with 
Good Clinical Practice:  Consolidated Guidance (ICH E6). 
 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389  
Date:  18 March 2022 
Page 2 of 91 
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; Amgen’s general 
number in the US, 1-805-447-1000. 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389  
Date:  18 March 2022 
Page 3 of 91 
CONFIDENTIAL  
 
 
Investigator’s Agreement: 
I have read the attached protocol entitled Phase 4, Open-label Study to Evaluate 
Treatment Satisfaction With Erenumab in Patients With Migraine, dated 18 March 2022, 
and agree to abide by all provisions set forth therein.   
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP), Declaration of Helsinki, and applicable 
national or regional regulations/guidelines.   
I agree to ensure that Financial Disclosure Statements will be completed by: me 
(including, if applicable, my spouse or legal partner and dependent children) and my 
subinvestigators (including, if applicable, their spouses or legal partners and dependent 
children) at the start of the study and for up to 1 year after the study is completed, if 
there are changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc. 
 
_______________________________ 
Signature 
 
_______________________________ 
____________________________ 
Name of Investigator  
 
 
Date (DD Month YYYY) 
 
 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389  
Date:  18 March 2022 
Page 4 of 91 
CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents ................................................................................................... 4 
1. 
Protocol Summary .................................................................................................. 8 
1.1 
Synopsis ..................................................................................................... 8 
1.2 
Study Schema ........................................................................................... 14 
1.3 
Schedule of Activities (SoA) ...................................................................... 15 
2. 
Introduction ........................................................................................................... 20 
2.1 
Study Rationale ......................................................................................... 20 
2.2 
Background ............................................................................................... 21 
2.2.1 
Disease ..................................................................................... 21 
2.2.2 
Amgen Investigational Product Background:  
Erenumab ................................................................................. 21 
2.3 
Benefit/Risk Assessment ........................................................................... 22 
3. 
Objectives and Endpoints/Estimands .................................................................... 23 
4. 
Study Design ........................................................................................................ 27 
4.1 
Overall Design .......................................................................................... 27 
4.2 
Patient Input into the Study Design ........................................................... 29 
4.3 
Justification for Investigational Product Dose ............................................ 29 
4.4 
End of Study ............................................................................................. 29 
5. 
Study Population .................................................................................................. 29 
5.1 
Inclusion Criteria ....................................................................................... 30 
5.2 
Exclusion Criteria ...................................................................................... 31 
5.3 
Subject Enrollment .................................................................................... 33 
5.4 
Screen Failures ......................................................................................... 34 
6. 
Study Intervention ................................................................................................. 34 
6.1 
Study Interventions Administered .............................................................. 35 
6.1.1 
Investigational Products ............................................................ 35 
6.1.2 
Non-investigational Products ..................................................... 35 
6.1.3 
Medical Devices ........................................................................ 35 
6.1.4 
Other Protocol-required Therapies ............................................ 36 
6.1.5 
Other Intervention Procedures ................................................... 36 
6.1.6 
Product Complaints ................................................................... 36 
6.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 36 
6.2 
Dose Modification ...................................................................................... 38 
6.2.1 
Dose-[group/cohort] Study Escalation/De-escalation 
and Stopping Rules ................................................................... 38 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation of Amgen 
Investigational Product: Erenumab ............................................ 38 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389  
Date:  18 March 2022 
Page 5 of 91 
CONFIDENTIAL  
 
 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 39 
6.3 
Preparation/Handling/Storage/Accountability ............................................ 39 
6.4 
Measures to Minimize Bias:  Randomization and Blinding ......................... 39 
6.4.1 
Method of Treatment Assignment .............................................. 39 
6.4.2 
Blinding ..................................................................................... 39 
6.5 
Treatment Compliance .............................................................................. 39 
6.6 
Treatment of Overdose ............................................................................. 40 
6.7 
Prior and Concomitant Treatment ............................................................. 40 
6.7.1 
Migraine Preventive Medications ............................................... 40 
6.7.2 
Prior Treatment ......................................................................... 40 
6.7.3 
Concomitant Treatment ............................................................. 40 
7. 
Discontinuation of Study Treatment and Subject 
Discontinuation/Withdrawal ................................................................................... 40 
7.1 
Discontinuation of Study Treatment........................................................... 41 
7.2 
Subject Discontinuation/Withdrawal From the Study ................................. 41 
7.2.1 
Reasons for Removal From Washout Period, Run-in 
Period, or Invasive Procedures ................................................. 42 
7.2.2 
Reasons for Removal From Study ............................................. 42 
7.3 
Lost to Follow-up ....................................................................................... 42 
8. 
Study Assessments and Procedures .................................................................... 42 
8.1 
General Study Periods .............................................................................. 43 
8.1.1 
Screening, Enrollment and/or Randomization ............................ 43 
8.1.2 
Treatment Period ....................................................................... 43 
8.1.3 
End of Study .............................................................................. 44 
8.2 
General Assessments ............................................................................... 44 
8.2.1 
Informed Consent ...................................................................... 44 
8.2.2 
Demographics ........................................................................... 44 
8.2.3 
Medical History .......................................................................... 44 
8.2.4 
Physical Measurements ............................................................ 44 
8.3 
Efficacy Assessments ............................................................................... 45 
8.3.1 
Treatment Satisfaction Questionnaire for Medication ................. 45 
8.3.2 
Migraine Global Impression Item ............................................... 45 
8.3.3 
Migraine Functional Impact Questionnaire ................................. 45 
8.3.4 
Expectation of Treatment Scale ................................................. 45 
8.3.5 
Migraine Symptom Severity Scale ............................................. 45 
8.3.6 
Migraine Interictal Burden Scale ................................................ 46 
8.3.7 
Generalized Anxiety Disorder Scale .......................................... 46 
8.3.8 
Patient Health Questionnaire ..................................................... 46 
8.3.9 
Electronic Diary ......................................................................... 47 
8.4 
Safety Assessments .................................................................................. 47 
8.4.1 
Clinical Laboratory Assessments ............................................... 47 
8.4.2 
Adverse Events and Serious Adverse Events ............................ 47 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389  
Date:  18 March 2022 
Page 6 of 91 
CONFIDENTIAL  
 
 
8.4.2.1 
Time Period and Frequency for Collecting 
and Reporting Safety Event Information .................. 48 
8.4.2.2 
Method of Detecting Adverse Events and 
Serious Adverse Events .......................................... 49 
8.4.2.3 
Follow-up of Adverse Events and Serious 
Adverse Events ....................................................... 49 
8.4.2.4 
Regulatory Reporting Requirements for 
Serious Adverse Events .......................................... 50 
8.4.2.5 
Safety Monitoring Plan ............................................ 50 
8.4.2.6 
Pregnancy and Lactation ......................................... 50 
8.4.2.7 
Adverse Device Effects ........................................... 51 
8.5 
Optional Substudy: Qualitative Interviews ................................................. 51 
8.5.1 
Substudy Background and Rationale ......................................... 51 
8.5.2 
Research Question and Objectives of the Qualitative 
Interview Substudy .................................................................... 52 
8.5.3 
Substudy Design ....................................................................... 52 
8.5.4 
Summary of Substudy Participation Criteria............................... 53 
8.5.5 
Substudy Duration and Substudy Procedures ........................... 54 
8.5.6 
Variables ................................................................................... 55 
8.5.6.1 
Substudy Outcome Variable(s) ................................ 55 
8.5.6.2 
Exposure Variable(s) ............................................... 56 
8.5.7 
Substudy Data Analysis ............................................................. 56 
8.5.8 
Collection of Safety Information and Product 
Complaints ................................................................................ 57 
8.5.8.1 
Definition of Safety Events ...................................... 57 
8.5.8.2 
Safety Reporting Requirements .............................. 57 
9. 
Statistical Considerations ...................................................................................... 58 
9.1 
Statistical Hypotheses ............................................................................... 58 
9.2 
Sample Size Determination ....................................................................... 58 
9.3 
Populations for Analysis ............................................................................ 59 
9.3.1 
Covariates ................................................................................. 59 
9.3.2 
Subgroups ................................................................................. 59 
9.4 
Statistical Analyses ................................................................................... 60 
9.4.1 
Planned Analyses ...................................................................... 60 
9.4.1.1 
Interim Analysis and Early Stopping 
Guidelines ............................................................... 60 
9.4.1.2 
Primary Analysis ..................................................... 60 
9.4.1.3 
Final Analysis .......................................................... 60 
9.4.2 
Methods of Analyses ................................................................. 60 
9.4.2.1 
General Considerations ........................................... 60 
9.4.2.2 
Efficacy Analyses .................................................... 61 
9.4.2.3 
Safety Analyses ...................................................... 62 
10. 
References ........................................................................................................... 63 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389  
Date:  18 March 2022 
Page 7 of 91 
CONFIDENTIAL  
 
 
11. 
Appendices ........................................................................................................... 65 
11.1 
Appendix 1.  List of Abbreviations ............................................................. 66 
11.2 
Appendix 2.  Clinical Laboratory Tests ...................................................... 68 
11.3 
Appendix 3.  Study Governance Considerations ....................................... 69 
11.4 
Appendix 4.  Safety Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ....................................... 77 
Definition of Adverse Event ....................................................................... 77 
11.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ........................................................ 86 
 
List of Tables 
Table 1-1.  Subject Study Visits Through Open-label Treatment Phase......................... 15 
Table 1-2.  Schedule of Activities for Key Family Members ........................................... 18 
Table 1-3.  Optional Substudy: Schedule of Activities for Participating 
Subjects, Clinicians, and Key Family Members ....................................... 19 
Table 6-1.  Investigational Products ............................................................................... 35 
Table 6-2.  Excluded Treatments, Medical Devices, and Procedures ............................ 37 
Table 9-1.  Half-width of 95% CI for Various Estimated Percentages With 
Effective Sample Size of 289 Subjects ................................................... 58 
 
List of Figures 
Figure 1-1.  Study Schema ............................................................................................ 14 
Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Report 
Form (paper-based form) ........................................................................ 83 
Figure 11-2.  Pregnancy and Lactation Notification Forms ............................................. 90 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389  
Date:  18 March 2022 
Page 8 of 91 
CONFIDENTIAL  
 
 
1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title: Phase 4, Open-label Study to Evaluate Treatment Satisfaction With 
Erenumab in Patients With Migraine 
Short Protocol Title:  Erenumab Treatment Satisfaction Study 
Study Phase:  4 
Indication:  Preventive treatment of migraine in adults 
Rationale 
Migraine is a prevalent and disabling neurological disorder, with a significant impact on 
the individual, family, workplace, and society.  Objectives commonly assessed in 
registrational clinical trials for migraine prevention include changes in monthly 
migraine days and use of acute migraine-specific medications.  These parameters, 
however, do not fully capture the whole breadth of the impact of migraine preventive 
treatments on the daily lives of patients and their families, including their satisfaction with 
treatment.  
There is interest in the migraine provider community not only for clinical outcomes data, 
but also associated patient-centric data (eg, treatment satisfaction and global impression 
of change in migraine from different perspectives such as those of patients, providers 
and key family members).  Health systems are also tracking patient satisfaction as a 
metric for quality of care delivery.  These factors begin to define a new treatment 
paradigm for migraine management that includes both clinical and treatment-related 
satisfaction outcomes. 
The Erenumab Treatment Satisfaction Study is a phase 4 United States (US), 
open-label, interventional, prospective 24-week study evaluating treatment satisfaction 
with erenumab as a preventive treatment in adult subjects with episodic migraine (EM) 
or chronic migraine (CM) currently on 1 standard of care migraine prevention therapy.  
The study will measure change in subject satisfaction with erenumab and subject, 
clinician, and key family member global impression of change in subject’s migraine 
condition over the life of the study.  
This study seeks to mirror real-world US clinical practice by providing subjects and 
investigators the flexibility to optimize erenumab dosing while maintaining or 
discontinuing the existing migraine prevention therapy (ie, standard of care). 
 
Objective(s) and Endpoint(s)/Estimands 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the effect of erenumab 
on medication-specific treatment 
satisfaction 
 
Change from baseline in the 
Treatment Satisfaction Questionnaire 
for Medication (TSQM) overall 
satisfaction scale score at week 24, 
as measured by items 12 to 14 of the 
TSQM version 1.4  


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389  
Date:  18 March 2022 
Page 9 of 91 
CONFIDENTIAL  
 
 
Primary Estimand 
The estimand for the primary efficacy objective consists of: 
 The target population, which includes subjects with EM or CM currently on 1 standard 
of care migraine prevention therapy 
 The endpoint, which is the change from baseline in TSQM overall satisfaction scale 
score at week 24, as measured by items 12 to 14 of the TSQM 
 There are 2 intercurrent events, discontinuation of investigational product (IP) due to 
lack of efficacy or adverse event, and discontinuation of IP due to other reasons.  The 
treatment effect of interest will be assessed for all subjects who receive least 1 dose of 
IP and have a baseline score and at least 1 post-baseline score on the TSQM overall 
satisfaction scale.  A composite strategy will be used for subjects who discontinued IP 
due to lack of efficacy or adverse event with data after IP discontinuation, defined by 
the worst postbaseline value observed up to IP discontinuation (inclusive).  A 
hypothetical strategy will be used for those subjects who discontinued IP due to other 
reasons with data collected after IP discontinuation censored. 
 The treatment, which is erenumab 70 or 140 mg every 4 weeks 
 The summary measure, which is the mean change from baseline in TSQM overall 
satisfaction scale score at week 24, as measured by items 12 to 14 of the TSQM 
The primary estimand for the primary efficacy objective is the mean change from baseline in 
TSQM overall satisfaction scale score at week 24 in subjects with EM or CM who are currently 
on 1 standard of care migraine prevention therapy and who receive at least 1 dose of IP and 
have a baseline and at least 1 post-baseline TSQM overall satisfaction scale score, and a 
composite strategy will be used for subjects who discontinued IP due to lack of efficacy or 
adverse event with data after IP discontinuation defined by the worst postbaseline value 
observed up to IP discontinuation (inclusive), while a hypothetical strategy will be used for 
those subjects who discontinued IP due to other reasons with data collected after IP 
discontinuation censored. 
Secondary 
 
To assess the effect of erenumab on 
medication-specific treatment 
satisfaction 
 
Achievement of overall satisfaction at 
week 24 as defined by subject 
reporting of satisfied, very satisfied, or 
extremely satisfied on Item 14 of the 
TSQM version 1.4 
The estimand for the secondary efficacy objective on treatment satisfaction consists of: 
 
The target population, which includes subjects with EM or CM currently on 1 standard 
of care migraine prevention therapy 
 
The endpoint, which is achievement of overall satisfaction at week 24 as defined by 
subject reporting of satisfied, very satisfied, or extremely satisfied on Item 14 of the 
TSQM 
 
There are 2 intercurrent events, discontinuation of IP due to lack of efficacy or adverse 
event, and discontinuation of IP due to other reasons.  The treatment effect of interest 
will be assessed for all subjects who receive at least 1 dose of IP and have a baseline 
value and at least 1 post-baseline value for Item 14 of the TSQM.  A composite 
strategy will be used for subjects who discontinued IP due to lack of efficacy or 
adverse event where they will be defined as not satisfied after IP discontinuation.  A 
hypothetical strategy will be used for those subjects who discontinued IP due to other 
reasons with data collected after IP discontinuation censored. 
 
The treatment, which is erenumab 70 or 140 mg every 4 weeks 
 
The summary measure, which is the proportion of subjects who achieves overall 
satisfaction at week 24 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389  
Date:  18 March 2022 
Page 10 of 91 
CONFIDENTIAL  
 
 
The estimand for the secondary efficacy objective on treatment-related satisfaction is the 
proportion of subjects who achieves overall satisfaction at week 24 as defined by subject 
reporting of satisfied, very satisfied, or extremely satisfied on Item 14 of the TSQM version 1.4, 
in subjects with EM or CM who are currently on 1 standard of care migraine prevention therapy 
and who receive at least 1 dose of IP and have a baseline value and at least 1 post-baseline 
value for Item 14 of the TSQM.  A composite strategy will be used for subjects who 
discontinued IP due to lack of efficacy or adverse event where they will be defined as not 
satisfied after IP discontinuation, while a hypothetical strategy will be used for those subjects 
who discontinued IP due to other reasons with data collected after IP discontinuation censored. 
 
To assess the effect of erenumab on 
global impression of change in 
migraine (by subject, treating 
clinician, and key family member) 
 
Improvement in subject global 
impression at week 24, as defined by 
subject reporting of much improved or 
a little improved on the migraine 
Global Impression Item (mGI-I)  
 
Improvement in treating clinician’s 
global impression at Week 24, as 
defined by treating clinician’s 
reporting of much improved or a little 
improved on the mGI-I for each 
individual subject  
 
Improvement in key family member’s 
impression at week 24, as defined by 
key family member’s reporting of 
much improved or a little improved on 
the mGI-I for each individual subject 
The estimand for the secondary efficacy objectives on impression of change in migraine 
consists of: 
 The target population, which includes subjects with EM or CM currently on 1 standard 
of care migraine prevention therapy 
 The endpoints, which include: 
 Improvement in subject global impression at week 24, as defined by subject 
reporting of much improved or a little improved on the mGI-I 
 Improvement in treating clinician’s global impression at week 24, as defined by the 
clinician’s reporting of much improved or a little improved on the mGI-I for each 
individual subject  
 Improvement in key family member’s global impression at week 24, as defined by 
family member’s reporting of much improved or a little improved on the mGI-I for 
each individual subject 
 There are 2 intercurrent events, discontinuation of IP due to lack of efficacy or adverse 
event, and discontinuation of IP due to other reasons.  The treatment effect of interest 
will be assessed for all subjects who receive at least 1 dose of IP and have at least 
1 post-baseline value of each respective mGI-I item.  A composite strategy will be used 
for subjects who discontinued IP due to lack of efficacy or adverse event where they 
will be defined as not improved after IP discontinuation.  A hypothetical strategy will be 
used for those subjects who discontinued IP due to other reasons with data collected 
after IP discontinuation censored. 
 The treatment, which is erenumab 70 or 140 mg every 4 weeks 
 The summary measure, which is the proportion of subjects who achieves impression of 
improvement at week 24.   
The estimand for the secondary efficacy objective on impression of change in migraine is the 
proportion of subjects who achieves global impression of migraine improvement at week 24 as 
defined by subject, treating clinician, or family member reporting of much improved or a little 
improved on the mGI-I, in subjects with EM or CM who are currently on 1 standard of care 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389  
Date:  18 March 2022 
Page 11 of 91 
CONFIDENTIAL  
 
 
migraine prevention therapy and who receive at least 1 dose of IP and have at least 
1 post-baseline value of the respective mGI-I, and a composite strategy will be used for 
subjects who discontinued IP due to lack of efficacy or adverse event where they will be 
defined as not improved after IP discontinuation, while a hypothetical strategy will be used for 
those subjects who discontinued IP due to other reasons with data collected after IP 
discontinuation censored. 
 
To assess the effect of erenumab on 
subject functional impairment 
 
Change from baseline in physical 
function domain score at week 24, as 
measured by the Migraine Functional 
Impact Questionnaire (MFIQ) 
 
Change from baseline in usual 
activities domain score at week 24 as 
measured by MFIQ 
 
Change from baseline in emotional 
function domain score at week 24 as 
measured by MFIQ 
 
Change from baseline in social 
function domain score at week 24 as 
measured by MFIQ 
The estimand for the secondary efficacy objective on subject functional impairment consists of: 
 
The target population, which includes subjects with EM or CM currently on 1 standard 
of care migraine prevention therapy 
 
The endpoints, which include: 
 
Change from baseline in MFIQ physical function domain score at week 24  
 
Change from baseline in MFIQ usual activities domain score at week 24 
 
Change from baseline in MFIQ emotional function domain score at week 24 
 
Change from baseline in MFIQ social function domain score at week 24 
 
There are 2 intercurrent events, discontinuation of IP due to lack of efficacy or 
adverse event, and discontinuation of IP due to other reasons.  The treatment effect 
of interest will be assessed for all subjects 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 
scores.  A composite strategy will be used for subjects who discontinued IP due to 
lack of efficacy or adverse event with data after IP discontinuation defined by the 
worst postbaseline value observed up to IP discontinuation (inclusive).  A hypothetical 
strategy will be used for those subjects who discontinued IP due to other reasons with 
data collected after IP discontinuation censored. 
 
The treatment, which is erenumab 70 or 140 mg every 4 weeks 
 
The summary measure, which is change from baseline in each MFIQ domain score at 
week 24  
The estimand for the secondary efficacy objective on subject functional impairment is the 
change from baseline at week 24 in each MFIQ domain score, in subjects with EM or CM who 
are currently on 1 standard of care migraine prevention therapy and who receive at least 
1 dose of IP and have a baseline value and at least 1 post-baseline value in each MFIQ 
domain score, and a composite strategy will be used for subjects who discontinued IP due to 
lack of efficacy or adverse event with data after IP discontinuation defined by the worst 
postbaseline value observed up to IP discontinuation (inclusive), while a hypothetical strategy 
will be used for those subjects who discontinued IP due to other reasons with data collected 
after IP discontinuation censored. 
 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389  
Date:  18 March 2022 
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Overall Design 
The study will comprise the following periods:  
 
A combined screening/baseline period consisting of the following:  
 
A screening visit (which may coincide with the first day of the baseline period) for 
the assessment of eligibility criteria  
 
A baseline period of approximately 4 weeks (no less than 28 days; up to 35 days) 
to collect data on migraine headaches and acute headache medication use using 
electronic diary (eDiary) and to assess compliance in eDiary usage  
 
A 24-week open-label treatment period 
Subjects will sign the informed consent and be screened at the screening visit; eligible 
subjects may enter the baseline period at the same visit or may delay baseline 
procedures up to 3 weeks after the screening visit.  At completion of the baseline period, 
those who meet eligibility criteria and choose to proceed will be enrolled and will enter 
the open-label treatment period. 
The treating clinician and a key family member (if available) for each participating 
subject will be invited to complete an mGI-I at weeks 12, 16, 20, and 24/End of Study 
(EOS).  The key family member must sign an informed consent before completing any 
study-specific procedures.  The same clinician and key family member of each subject 
should complete the mGI-I across all visits.  If the clinician or key family member is 
unable to complete a visit, the assessment for that visit should be noted as missed. 
Qualitative interviews will be conducted with a selected subset of subjects, their treating 
clinicians, and key family members as part of an optional substudy.  These interviews 
will be used to provide qualitative information on satisfaction/improvement and details 
into the drivers of satisfaction and improvement that might not be captured by 
self-assessment alone. 
Number of Subjects 
Approximately 322 subjects will be enrolled into the main study.  The ratio of EM:CM will 
be approximately 1:1 to allow for qualitative assessments of satisfaction and impression 
of change in migraine for the two migraine types.  A subset of approximately 20 enrolled 
subjects at select sites, their clinicians, and key family members will be invited to 
participate in an optional qualitative interview-based substudy with interviews to be 
conducted at the start and end of the study. 
Summary of Eligibility Criteria 
Subjects eligible for the study include those who are ≥ 18 years of age, have a history of 
migraine with or without aura for ≥ 12 months before screening, have ≥ 4 migraine days 
per month on average over the 3 months prior to screening, can be classified as EM or 
CM, report to their provider intolerance or insufficient response with their current 
preventive treatment, and demonstrate at least 75% compliance with the eDiary during 
the baseline period. 
Key family members eligible for the study should be a family member/caregiver of an 
enrolled patient and a person in the subject’s life with whom s/he interacts significantly 
on a day-to-day basis. 
Clinicians eligible for the study must be licensed and practicing healthcare practitioners 
(HCPs) in the US and be currently treating the subject on Study 20190389. 
For a full list of eligibility criteria, please refer to Section 5.1 to Section 5.2. 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389  
Date:  18 March 2022 
Page 13 of 91 
CONFIDENTIAL  
 
 
Treatments 
Subjects will receive erenumab 70 or 140 mg once every 4 weeks (Q4W) by 
subcutaneous (SC) injections during the 24-week open-label treatment period.  
Erenumab will be packaged in a SureClick Autoinjector (AI)/Pen(s) containing 1 mL of 
70 mg/mL or 140 mg/mL of erenumab for SC injection. 
All subjects will be started on a 70 mg dose of erenumab at day 1 with provider 
discretion for dose optimization, which is recommended to be completed by week 12.  
Dose optimization will allow subjects to remain on 70 mg, increase the dose from 70 to 
140 mg, and if needed decrease the dose back down from 140 to 70 mg.  After week 12, 
it is highly recommended that all subjects remain on the week 12 erenumab dose for the 
rest of the study.  Additional dose adjustments after week 12 are not recommended and 
must only be made if deemed medically necessary by the investigator. 
All subjects will be required to enter the study on 1 standard of care preventive 
medication for their migraine.  Post-baseline, at their and the investigator’s discretion, 
subjects will be allowed to remain on their standard of care preventive treatment, or they 
may fully discontinue standard of care therapy.  Any changes to standard of care 
preventive treatment, including dose adjustments or tapering off medication, should be 
completed by the week 12 visit.  Standard of care dose adjustments are not permitted 
after week 12. 
Statistical Considerations 
Sample Size Considerations:   
The total sample size of approximately 322 subjects (effective sample size of 
289 assuming 10% dropout at Week 24) is driven by the precision of the proportion 
estimates for the binary secondary endpoints, which target a half-width of around 5% for 
estimated 95% confidence intervals (CIs) (see Table 9-1). 
Planned Analyses:   
The final analysis will be conducted when all enrolled subjects have completed the week 
24/EOS visit and the data have been entered, cleaned, and locked. 
The primary endpoint will be analyzed using a repeated measures mixed effects model, 
including baseline TSQM overall satisfaction scale score, visit, the prevailing erenumab 
dose from week 12 onward, and baseline monthly migraine days (MMD) based on 
observed data.  The least-squares mean (LSM) change from baseline in the TSQM 
overall satisfaction scale score at week 24 will be estimated, and the corresponding 
95% CI will be provided. 
Analysis of all secondary proportion endpoints will be descriptive only, where point 
estimates of the proportion and the corresponding 95% CI will be provided for each 
endpoint.  All other secondary endpoints will be analyzed in a similar manner to the 
primary endpoint. 
For a full description of statistical analysis methods, please refer to Section 9. 
Statistical Hypotheses 
The study is descriptive in nature without a comparator arm, and as such no formal 
statistical hypothesis is defined.  
Sponsor Name:  Amgen Inc. 
 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389 
Date:  18 March 2022 
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CONFIDENTIAL  
 
 
1.2 
Study Schema 
Figure 1-1.  Study Schema 
  
* All subjects will be started on a 70 mg dose of erenumab at day 1 with provider discretion for dose optimization.  Dose optimization will allow patients to remain 
on 70 mg, increase the dose from 70 mg to 140 mg, and if needed decrease the dose back down from 140 mg to 70 mg.  It is highly recommended that all 
erenumab dose adjustments be completed by week 12, after which all subjects should remain on the week 12 erenumab dose for the rest of the study.  Additional 
dose adjustments after week 12 are not recommended and must only be made if deemed medically necessary by the investigator. 
** Baseline may begin on the same day as screening. 


Product:  Erenumab-aooe (AMG 334) 
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1.3 
Schedule of Activities (SoA) 
Table 1-1.  Subject Study Visits Through Open-label Treatment Phase 
PROCEDURE 
Screening 
(up to 3 
weeks 
before 
baseline)c 
Baseline 
(4-5 
weeks 
before day 
1)c  
Open-label Treatment Period (24 weeks) 
Notes 
Day 1e Week  
4 
Week  
8 
Week 
12 
Week 
16 
Week 
20 
Week  
24/ 
EOS 
GENERAL ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
Neurological medical history 
X 
 
 
 
 
 
 
 
 
 
Gastrointestinal medical history 
X 
 
 
 
 
 
 
 
 
 
Headache and migraine 
frequency medical history 
X 
 
 
 
 
 
 
 
 
 
Migraine preventive medications 
review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
At screening, a review of the subject’s 
history of migraine preventive use (past 
and current) will be conducted. At 
subsequent visits, information will be 
collected regarding concomitant 
standard of care preventive status 
(ie, whether still taking and at what 
dose). 
Prior therapies review 
X 
 
 
 
 
 
 
 
 
Includes all prior medications (other 
than prior migraine preventive 
medications) that were being 
taken/used within 120 days prior to 
screening through the signing of the 
informed consent. 
Concomitant therapies review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Eligibility criteria after baseline 
period 
 
 
X 
 
 
 
 
 
 
Compliance with eDiary usage will be 
assessed on day 1 to determine 
eligibility before any other day 1 
assessments. 
Physical measurements 
 
 
X 
 
 
 
 
 
 
Height/weight for BMI 
Page 1 of 3 
Footnotes are defined on the last page of this table. 
 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389 
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Table 1-1.  Subject Study Visits Through Open-Label Treatment Phase 
PROCEDURE 
Screening 
(up to 3 
weeks 
before 
baseline)c 
Baseline 
(4-5 
weeks 
before 
day 1)c 
Open-label Treatment Period (24 weeks) 
Notes 
Day 1e Week  
4 
Week  
8 
Week 
12 
Week 
16 
Week 
20 
Week  
24/ 
EOS  
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 
 
 
Product complaints 
 
 
X 
X 
X 
X 
X 
X 
 
 
LABORATORY ASSESSMENTS 
Urine pregnancy test (females of 
childbearing potential only) 
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. 
CLINICAL OUTCOME ASSESSMENTS 
eDiary 
 
Daily 
 
 
 
Daily 
 
ETS 
 
 
X 
 
 
 
 
 
 
 
GAD-7 
 
 
X 
 
 
X 
 
 
X 
 
MFIQ 
 
 
X 
 
 
X 
X 
X 
X 
 
mGI-I 
 
 
 
 
 
X 
X 
X 
X 
To be completed by subject and 
clinician 
MIBS-4 
 
 
X 
 
 
X 
X 
X 
X 
 
MSSS 
 
 
X 
 
 
X 
X 
X 
X 
 
PHQ-9 
Xd 
 
X 
 
 
X 
 
 
X 
 
TSQM version 1.4  
 
 
X 
 
 
X 
X 
X 
X 
TSQM will assess satisfaction with 
standard of care migraine preventive 
medication at day 1 and only 
investigational product at subsequent 
time points. 
STUDY TREATMENT 
Amgen investigational product 
administratione 
 
  
X 
X 
X 
X 
X 
X  
 
 
Page 2 of 3 
Footnotes are defined on the last page of this table. 
 
 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389 
Date:  18 March 2022 
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Table 1-1.  Subject Study Visits Through Open-Label Treatment Phase 
PROCEDURE 
Screening 
(up to 3 
weeks 
before 
baseline)c 
Baseline 
(4-5 
weeks 
before 
day 1)c 
Open-label Treatment Period (24 weeks) 
Notes 
Day 1e Week  
4 
Week  
8 
Week 
12 
Week 
16 
Week 
20 
Week  
24/ 
EOS  
STUDY VISITS 
Onsite visita 
X 
X 
X 
 
 
X 
 
 
X 
 
Remote visit – site staff phone 
call with subjectb 
 
 
 
X 
X 
 
X 
X 
 
 
 
Page 3 of 3 
BMI = body mass index; eDiary = electronic diary; EOS = End of Study; ETS = Expectation of Treatment Scale; GAD-7 = General Anxiety Disorder Scale; 
MFIQ = Migraine Functional Impact Questionnaire; mGI-I = Migraine Global Impression Item; MIBS-4 = Migraine Interictal Burden Scale; MSSS = Migraine Symptom 
Severity Scale; PHQ-9 = Patient Health Questionnaire; TSQM = Treatment Satisfaction Questionnaire for Medication 
a Screening, Baseline, day 1, week 12, and week 24/EOS visits are required to take place onsite.  Subjects will be provided the doses necessary to continue 
erenumab monthly treatment at a non-investigative site (eg, subject’s home).  Additional onsite visits are optional at the investigator’s discretion. 
b For remote visits (ie, visits not conducted onsite), visit data will be collected by site staff via telephone or via electronic device as applicable (eg, clinical outcomes 
assessments). 
c Baseline may start on the same day as the screening visit. 
d Screening PHQ-9 is to assess eligibility and will be collected on a paper form.  On-study PHQ-9 assessments will be collected on the subject’s eDiary device. 
e All day 1 procedures must be completed before investigational product is administered. 
 
 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389 
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Table 1-2.  Schedule of Activities for Key Family Members 
PROCEDURE 
Screening 
(up to 3 
weeks 
before 
baseline)a 
Baseline  
(4-5 weeks 
before 
day 1)a 
Open-Label Treatment Period (24 weeks) 
Notes 
Day  
1 
Week 
4 
Week 
8 
Week  
12 
Week  
16 
Week 
20 
Week 
24/ 
EOS 
GENERAL ASSESSMENTS 
Informed consent for key family 
members 
X 
 
 
 
Signing of informed consent can occur 
any time at or before the week 12 visit. 
Informed consent must be signed 
before the week 12 mGI-I is 
administered. 
CLINICAL OUTCOMES ASSESSMENTS 
mGI-I 
 
 
 
 
 
X 
X 
X 
X 
 
EOS = End of Study; mGI-I = Migraine Global Impression Item 
a Baseline may begin on the same day as the screening visit. 
 
 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389 
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Table 1-3.  Optional Substudy: Schedule of Activities for Participating Subjects, Clinicians, and Key Family Members 
PROCEDURE 
Screening 
(up to 3 
weeks 
before 
baseline)a 
Baseline  
(4-5 weeks 
before 
day 1)a 
Open-Label Treatment Period (24 weeks) 
Notes 
Day  
1 
Week 
4 
Week 
8 
Week  
12 
Week 
16 
Week 
20 
Week 
24/ 
EOS 
HEALTH ECONOMIC ASSESSMENTS 
Qualitative substudy informed 
consent 
X 
 
 
 
 
 
 
 
Written consent will be collected from 
subject and key family member.  
 
Signing of informed consent and 
participant screening can occur any 
time at or before the day 1 visit. 
Qualitative substudy interviews 
(conducted by third-party 
interviewer)b 
 
 
X 
 
 
 
 
 
X 
Participating subjects’ clinicians will 
also be interviewed.   
 
Interviewers will attempt to conduct the 
interview as soon as possible and 
within 7 days after day 1 and week 
24/EOS visits. 
EOS = End of Study 
a Baseline may begin on the same day as the screening visit. 
b Each participant (subject, clinician, and key family member) will be interviewed separately by the third-party interviewer. 
 
 
 
 
 
 


Product:  Erenumab-aooe (AMG 334) 
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2. 
Introduction 
2.1 
Study Rationale 
Migraine is a prevalent and disabling neurological disorder, with a significant impact on 
the individual, family, workplace, and society.  Objectives commonly assessed in 
registrational clinical trials for migraine prevention include changes in monthly 
migraine days (MMD) and use of acute migraine-specific medications.  These 
parameters, however, do not fully capture the whole breadth of the impact of migraine 
preventive treatments on the daily lives of patients and their families, including their 
satisfaction with treatment.   
There is interest in the migraine provider community not only for clinical outcomes data, 
but also associated patient-centric data (eg, treatment satisfaction and global impression 
of change in migraine from different perspectives such as those of patients, providers, 
and key family members).  Health systems are also tracking patient satisfaction as a 
metric for quality of care delivery.  These factors begin to define a new treatment 
paradigm for migraine management that includes both clinical and treatment-related 
satisfaction outcomes. 
The Erenumab Treatment Satisfaction Study is a phase 4 United States (US), 
open-label, interventional, prospective 24-week study evaluating treatment satisfaction 
with erenumab as a preventive treatment in adult subjects with episodic migraine (EM) 
or chronic migraine (CM) currently on 1 standard of care migraine prevention therapy.  
The study will measure change in subject satisfaction with erenumab and subject, 
clinician, and key family member global impression of change in subject’s migraine 
condition over the life of the study.  
This study seeks to mirror real-world US clinical practice by providing subjects and 
investigators the flexibility to optimize erenumab dosing and maintain or discontinue the 
existing migraine prevention therapy (ie, standard of care). 
The study will be the first to evaluate patient satisfaction in a real-world migraine setting 
using the Treatment Satisfaction Questionnaire for Medication (TSQM), a questionnaire 
validated in the migraine population.  It will also be the first to validate the migraine 
Global Impression Item (mGI-I) in migraine patients, their treating clinician, and key 
family member.  With this validation work, it will be the first study to allow the capture of 
information on impression of improvement in the patient’s overall condition from multiple 
perspectives: patient, clinician, and key family member. 


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2.2 
Background 
2.2.1 
Disease 
Migraine is a disabling disorder characterized by primary recurrent headaches (referred 
to as attacks) with or without aura (ie, visual, sensory, and/or speech symptoms that 
occur just before or at the onset of migraine headache), lasting 4 to 72 hours (if not 
treated) with at least 2 of the following pain characteristics: unilateral, pulsating, 
moderate or severe intensity, or aggravated by routine physical activity.  Migraine 
attacks are often accompanied by nausea, vomiting, and sensitivity to light 
(photophobia) and sound (phonophobia).  Migraine affects more than 10% of the world’s 
population (Robbins and Lipton, 2010), and the prevalence of migraine is approximately 
11.7% in the United States, 14.6% in Canada, and 14.7% in Europe (Stovner and 
Andree, 2010; Lipton et al, 2007). 
The patient burden and disability, as well as the societal impact, increase with higher 
attack frequency.  For this reason, migraine is categorized in 2 major classifications, 
according to frequency of migraine days per month: EM is typically defined as 0 to 
14 headache days per month (Katsarava et al, 2012).  According to the International 
Classification of Headache Disorders (ICHD)-4 interim recommendations in 2020, 
EM is better defined as “Headache occurring on  15 days a month over the last 
3 months, which on some days is migraine” (Goadsby & Evers, 2020).  Chronic 
migraine is defined as 15 or more headache days per months, at least 8 of which have 
to be typical migraine days, with migraine prevention typically considered in individuals 
with ≥ 4 MMD (Headache Classification Committee of the International Headache 
Society, 2018).  All patients suffering from migraine can be treated with acute 
medications, and those suffering from frequent/long-lasting attacks and/or significant 
disability induced by the attacks should be considered for preventive treatment (The 
American Headache Society Position Statement On Integrating New Migraine 
Treatments Into Clinical Practice, 2018; Antonaci et al, 2010; Evers et al, 2006).  
Reports suggest that out of the approximately 25% of patients with migraine in need of 
migraine prevention, only half of them receive migraine preventive treatments (Lipton et 
al, 2007). 
2.2.2 
Amgen Investigational Product Background:  Erenumab 
Erenumab is a human immunoglobulin G2 monoclonal antibody that is directed against 
the canonical calcitonin gene-related peptide (CGRP) receptor complex and inhibits the 
action of CGRP.  


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389 
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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).  
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) has been approved in more than 
60 countries, including the US, Australia, Switzerland, and the European Union. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of erenumab 
is provided in the Investigator’s Brochure. 
2.3 
Benefit/Risk Assessment 
Benefits  
Globally, the totality of data from phase 2 and phase 3 studies in subjects with CM and 
EM provides substantial evidence for the efficacy and safety of erenumab in adults with 
migraine.  The key benefits of erenumab include reduction in MMD, reduction in acute 
migraine-specific medication use, as well as improvements in a range of other patient-
reported outcomes (PROs), favorable tolerability, low treatment discontinuation rates, 
convenience (Q4W injections with the option of self-administration), and rapid onset of 
effect.  
Risks  
The safety profile of erenumab has been favorable in clinical trials and in the 
post-marketing setting.  A limited number of adverse drug reactions (injection site 
reactions, constipation, muscle spasm, and pruritus) have been identified at low 
frequencies ( 5) in clinical trials.  In the long-term use of erenumab, the safety profile 
remained consistent through 5 years of open-label treatment.  In post-marketing 
settings, hypertension, hypersensitivity reactions (including rash, angioedema and 
anaphylactoid reactions), and constipation with serious complications have been 
reported.  In addition, oral sores (eg, stomatitis, mouth ulceration, oral mucosal 
blistering), alopecia and rash (eg, rash papular, exfoliative rash, rash erythematous, 
urticaria, blister) have been observed in post-marketing surveillance.   
The above benefit risk assessment supports the conduct of this clinical trial.  Reference 
should be made to the currently approved Investigator’s Brochure and Prescribing 
Information, where Aimovig is approved, for further data on erenumab. 
 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389 
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3. 
Objectives and Endpoints/Estimands 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the effect of erenumab 
on medication-specific treatment 
satisfaction 
 
Change from baseline in the 
Treatment Satisfaction Questionnaire 
for Medication (TSQM) overall 
satisfaction scale score at week 24, 
as measured by items 12 to 14 of the 
TSQM version 1.4  
Primary Estimand 
The estimand for the primary efficacy objective consists of: 
 The target population, which includes subjects with EM or CM currently on 1 standard 
of care migraine prevention therapy 
 The endpoint, which is the change from baseline in TSQM overall satisfaction scale 
score at week 24, as measured by items 12 to 14 of the TSQM 
 There are 2 intercurrent events, discontinuation of investigational product (IP) due to 
lack of efficacy or adverse event, and discontinuation of IP due to other reasons.  The 
treatment effect of interest will be assessed for all subjects who receive least 1 dose of 
IP and have a baseline score and at least 1 post-baseline score on the TSQM overall 
satisfaction scale.  A composite strategy will be used for subjects who discontinued IP 
due to lack of efficacy or adverse event with data after IP discontinuation, defined by 
the worst postbaseline value observed up to IP discontinuation (inclusive).  A 
hypothetical strategy will be used for those subjects who discontinued IP due to other 
reasons with data collected after IP discontinuation censored. 
 The treatment, which is erenumab 70 or 140 mg every 4 weeks 
 The summary measure, which is the mean change from baseline in TSQM overall 
satisfaction scale score at week 24, as measured by items 12 to 14 of the TSQM 
The primary estimand for the primary efficacy objective is the mean change from baseline in 
TSQM overall satisfaction scale score at week 24 in subjects with EM or CM who are currently 
on 1 standard of care migraine prevention therapy and who receive at least 1 dose of IP and 
have a baseline and at least 1 post-baseline TSQM overall satisfaction scale score, and a 
composite strategy will be used for subjects who discontinued IP due to lack of efficacy or 
adverse event with data after IP discontinuation defined by the worst postbaseline value 
observed up to IP discontinuation (inclusive), while a hypothetical strategy will be used for 
those subjects who discontinued IP due to other reasons with data collected after IP 
discontinuation censored. 
Secondary 
 
To assess the effect of erenumab on 
medication-specific treatment 
satisfaction 
 
Achievement of overall satisfaction at 
week 24 as defined by subject 
reporting of satisfied, very satisfied, or 
extremely satisfied on Item 14 of the 
TSQM version 1.4 
The estimand for the secondary efficacy objective on treatment satisfaction consists of: 
 
The target population, which includes subjects with EM or CM currently on 1 standard 
of care migraine prevention therapy 
 
The endpoint, which is achievement of overall satisfaction at week 24 as defined by 
subject reporting of satisfied, very satisfied, or extremely satisfied on Item 14 of the 
TSQM 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389 
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 
There are 2 intercurrent events, discontinuation of IP due to lack of efficacy or adverse 
event, and discontinuation of IP due to other reasons.  The treatment effect of interest 
will be assessed for all subjects who receive at least 1 dose of IP and have a baseline 
value and at least 1 post-baseline value for Item 14 of the TSQM.  A composite 
strategy will be used for subjects who discontinued IP due to lack of efficacy or 
adverse event where they will be defined as not satisfied after IP discontinuation.  A 
hypothetical strategy will be used for those subjects who discontinued IP due to other 
reasons with data collected after IP discontinuation censored. 
 
The treatment, which is erenumab 70 or 140 mg every 4 weeks 
 
The summary measure, which is the proportion of subjects who achieves overall 
satisfaction at week 24 
The estimand for the secondary efficacy objective on treatment-related satisfaction is the 
proportion of subjects who achieves overall satisfaction at week 24 as defined by subject 
reporting of satisfied, very satisfied, or extremely satisfied on Item 14 of the TSQM version 1.4, 
in subjects with EM or CM who are currently on 1 standard of care migraine prevention therapy 
and who receive at least 1 dose of IP and have a baseline value and at least 1 post-baseline 
value for Item 14 of the TSQM.  A composite strategy will be used for subjects who 
discontinued IP due to lack of efficacy or adverse event where they will be defined as not 
satisfied after IP discontinuation, while a hypothetical strategy will be used for those subjects 
who discontinued IP due to other reasons with data collected after IP discontinuation censored. 
 
To assess the effect of erenumab on 
global impression of change in 
migraine (by subject, treating 
clinician, and key family member) 
 
Improvement in subject global 
impression at week 24, as defined by 
subject reporting of much improved or 
a little improved on the migraine 
Global Impression Item (mGI-I)  
 
Improvement in treating clinician’s 
global impression at Week 24, as 
defined by treating clinician’s 
reporting of much improved or a little 
improved on the mGI-I for each 
individual subject  
 
Improvement in key family member’s 
impression at week 24, as defined by 
key family member’s reporting of 
much improved or a little improved on 
the mGI-I for each individual subject 
The estimand for the secondary efficacy objectives on impression of change in migraine 
consists of: 
 The target population, which includes subjects with EM or CM currently on 1 standard 
of care migraine prevention therapy 
 The endpoints, which include: 
 Improvement in subject global impression at week 24, as defined by subject 
reporting of much improved or a little improved on the mGI-I 
 Improvement in treating clinician’s global impression at week 24, as defined by the 
clinician’s reporting of much improved or a little improved on the mGI-I for each 
individual subject  
 Improvement in key family member’s global impression at week 24, as defined by 
family member’s reporting of much improved or a little improved on the mGI-I for 
each individual subject 
 There are 2 intercurrent events, discontinuation of IP due to lack of efficacy or adverse 
event, and discontinuation of IP due to other reasons.  The treatment effect of interest 
will be assessed for all subjects who receive at least 1 dose of IP and have at least 
1 post-baseline value of each respective mGI-I item.  A composite strategy will be used 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389 
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for subjects who discontinued IP due to lack of efficacy or adverse event where they 
will be defined as not improved after IP discontinuation.  A hypothetical strategy will be 
used for those subjects who discontinued IP due to other reasons with data collected 
after IP discontinuation censored. 
 The treatment, which is erenumab 70 or 140 mg every 4 weeks 
 The summary measure, which is the proportion of subjects who achieves impression of 
improvement at week 24.   
The estimand for the secondary efficacy objective on impression of change in migraine is the 
proportion of subjects who achieves global impression of migraine improvement at week 24 as 
defined by subject, treating clinician, or family member reporting of much improved or a little 
improved on the mGI-I, in subjects with EM or CM who are currently on 1 standard of care 
migraine prevention therapy and who receive at least 1 dose of IP and have at least 
1 post-baseline value of the respective mGI-I, and a composite strategy will be used for 
subjects who discontinued IP due to lack of efficacy or adverse event where they will be 
defined as not improved after IP discontinuation, while a hypothetical strategy will be used for 
those subjects who discontinued IP due to other reasons with data collected after IP 
discontinuation censored. 
 
To assess the effect of erenumab on 
subject functional impairment 
 
Change from baseline in physical 
function domain score at week 24, as 
measured by the Migraine Functional 
Impact Questionnaire (MFIQ) 
 
Change from baseline in usual 
activities domain score at week 24 as 
measured by MFIQ 
 
Change from baseline in emotional 
function domain score at week 24 as 
measured by MFIQ 
 
Change from baseline in social 
function domain score at week 24 as 
measured by MFIQ 
The estimand for the secondary efficacy objective on subject functional impairment consists of: 
 
The target population, which includes subjects with EM or CM currently on 1 standard 
of care migraine prevention therapy 
 
The endpoints, which include: 
 
Change from baseline in MFIQ physical function domain score at week 24  
 
Change from baseline in MFIQ usual activities domain score at week 24 
 
Change from baseline in MFIQ emotional function domain score at week 24 
 
Change from baseline in MFIQ social function domain score at week 24 
 
There are 2 intercurrent events, discontinuation of IP due to lack of efficacy or 
adverse event, and discontinuation of IP due to other reasons.  The treatment effect 
of interest will be assessed for all subjects 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 
scores.  A composite strategy will be used for subjects who discontinued IP due to 
lack of efficacy or adverse event with data after IP discontinuation defined by the 
worst postbaseline value observed up to IP discontinuation (inclusive).  A hypothetical 
strategy will be used for those subjects who discontinued IP due to other reasons with 
data collected after IP discontinuation censored. 
 
The treatment, which is erenumab 70 or 140 mg every 4 weeks 
 
The summary measure, which is change from baseline in each MFIQ domain score at 
week 24  


Product:  Erenumab-aooe (AMG 334) 
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The estimand for the secondary efficacy objective on subject functional impairment is the 
change from baseline at week 24 in each MFIQ domain score, in subjects with EM or CM who 
are currently on 1 standard of care migraine prevention therapy and who receive at least 
1 dose of IP and have a baseline value and at least 1 post-baseline value in each MFIQ 
domain score, and a composite strategy will be used for subjects who discontinued IP due to 
lack of efficacy or adverse event with data after IP discontinuation defined by the worst 
postbaseline value observed up to IP discontinuation (inclusive), while a hypothetical strategy 
will be used for those subjects who discontinued IP due to other reasons with data collected 
after IP discontinuation censored. 
 
non-GR AAS Styl e found: : N o Spaci ng 
 
Exploratory 
 
To explore the effect of erenumab on 
the change from baseline in monthly 
medication-specific treatment 
satisfaction 
 
Change from baseline in TSQM 
overall satisfaction scale score at 
weeks 12, 16, and 20 and mean over 
weeks 16, 20, and 24 
 
Change from baseline in TSQM 
sub-scale domain scores at weeks 12, 
16, 20 and 24 and mean over weeks 
16, 20, and 24: 
‒ 
effectiveness 
‒ 
side effects  
‒ 
convenience 
 
To explore the effect of erenumab on 
monthly global impression of 
improvement in migraine 
 
Improvement in subject global 
impression at weeks 12, 16, and 20, 
as defined by subject reporting of 
much improved or a little improved on 
the mGI-I 
 
Improvement in treating clinician’s 
global impression at weeks 12, 16, 
and 20, as defined by treating 
clinician’s reporting of much improved 
or a little improved on the mGI-I 
 
Improvement in key family member’s 
global impression at weeks 12, 16, 
and 20, as defined by key family 
member’s reporting of much improved 
or a little improved on the mGI-I 
 
To explore the effect of erenumab on 
the change from baseline in monthly 
functional impairment 
 
Change from baseline in MFIQ 
functional impairment domain scores, 
at weeks 12, 16, and 20, and mean 
over weeks 16, 20, and 24: 
‒ Impact on physical function 
‒ Impact on usual activities 
‒ Impact on emotional function 
‒ Impact on social function 
 
To explore the effect of erenumab on 
the change from baseline in the 
burden of migraine 
 
Change from baseline in the Migraine 
Symptom Severity Scale (MSSS) total 
score at weeks 12, 16, 20, and 24 
and mean over weeks 16, 20, and 24 
 
Change from baseline in the Migraine 
Interictal Burden Scale (MIBS-4) total 


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score at weeks 12, 16, 20, and 24 
and mean over weeks 16, 20, and 24 
 
To explore the effect of erenumab on 
the change from baseline in number 
of monthly migraine days (MMD) 
 
Change from baseline in mean MMD 
over weeks 16, 20, and 24  
 
Change from baseline in MMD at 
weeks 16, 20, and 24 
 
Achievement of at least a 50% 
reduction from baseline in mean 
MMD over weeks 16, 20, and 24 
 
Achievement of at least a 50% 
reduction from baseline in MMD at 
weeks 16, 20, and 24 
 
To explore the effect of erenumab on 
the change from baseline in acute 
migraine-specific medication use 
 
Change from baseline in mean 
monthly acute migraine-specific 
medication days over weeks 16, 20, 
and 24 
 
Change from baseline in monthly 
acute migraine-specific medication 
days at weeks 16, 20, and 24 
 
To explore the effect of erenumab on 
the change from baseline in anxiety 
and depression 
 
Change from baseline in General 
Anxiety Disorder scale (GAD-7) total 
score at weeks 12 and 24 
 
Change from baseline in Patient 
Health Questionnaire (PHQ-9) total 
score at weeks 12 and 24 
 
4. 
Study Design 
4.1 
Overall Design 
This is a phase 4 open-label study that will enroll subjects with EM or CM in an 
approximately 1:1 ratio.  The study will comprise the following periods:  
 
 A combined screening/baseline period consisting of the following:  
 
A screening visit (which may coincide with the first day of the baseline period) for 
the assessment of eligibility criteria  
 
A baseline period of approximately 4 weeks (no less than 28 days; up to 35 days) 
to collect data on migraine headaches and acute headache medication use using 
electronic diary (eDiary) and to assess compliance in eDiary usage 
 
A 24-week open-label treatment period  
Subjects will sign the informed consent and be screened at the screening visit; eligible 
subjects may enter the baseline period at the same visit or may delay baseline 
procedures up to 3 weeks after the screening visit.  At completion of the baseline period, 


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those who meet all eligibility criteria and choose to proceed will be enrolled and will enter 
the open-label treatment period. 
For visits that take place onsite, study assessments will be performed by staff onsite with 
the exception of investigational product administration, which can be completed by site 
staff or by subject self-administration.  Subjects will be provided the doses necessary to 
continue erenumab monthly treatment at a non-investigative site (eg, subject’s home) 
between onsite visits, as detailed in the Schedule of Activities (Table 1-1).  Site staff will 
contact subjects by telephone between scheduled onsite visits to perform a remote visit 
as described below and determine potential need for an onsite visit.  Changes in 
erenumab dosing may require an onsite visit.  Subjects may also contact the site at any 
time in between scheduled onsite visits and the investigator will determine if an 
additional unscheduled onsite visit is necessary. 
For visits not performed onsite, safety assessments, concomitant therapies review, and 
standard of care migraine preventive medication status will be performed by site staff on 
a telephone call with the subject and recorded in the subject’s medical record and 
electronic case report form (eCRF).  After speaking with site staff, subject or designee 
will administer investigational product to subject at a non-investigative site (eg, subject’s 
home).  The subject will record dose and lot number in their eDiary.  The dose data will 
be transcribed into the subject’s medical record and eCRF at the next onsite visit.   
All clinical outcomes assessments (COAs) detailed in the Schedule of Activities 
(Table 1-1) will be performed on the subject’s eDiary device regardless of visit location. 
The treating clinician and a key family member (if available) for each participating 
subject will be invited to complete an mGI-I at weeks 12, 16, 20, and 24/EOS.  The key 
family member should be a person in the subject’s life with whom s/he interacts 
significantly on a day-to-day basis.  This person should have a deep understanding of 
the impact migraine has on the subject.  They should also be able to provide their 
perspective of change in the subject’s migraines over time.  The person the subject 
chooses to nominate can be anyone such as a spouse, daughter or son, parent, sibling, 
or other relative or the person with whom the subject is in a de facto relationship.  The 
key family member must sign an informed consent before completing any study-specific 
procedures.  The same clinician and key family member of each subject should 
complete the mGI-I across all visits.  If the clinician or key family member is unable to 
complete a visit, the assessment for that visit should be noted as missed. 


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4.2 
Patient Input into the Study Design 
The overall study design is described by a study schema in Section 1.2.  The endpoints 
are defined in Section 3. 
Approximately 322 subjects will be enrolled in the study.  The ratio of EM:CM will be 
approximately 1:1 to allow for qualitative assessments of satisfaction and impression of 
change in migraine for the 2 migraine types.  A subset of approximately 20 enrolled 
subjects at selected sites, their clinicians and key family members will be invited to 
participate in an optional qualitative interview-based substudy with interviews to be 
conducted at the start and end of the study. 
Subjects in this clinical investigation shall be referred to as “subjects.”  Clinicians and 
key family members will be referred to as “participants.”  For the sample size 
justification, see Section 9.2. 
4.3 
Justification for Investigational Product Dose 
Erenumab 70 and 140 mg SC Q4W are approved in Europe and the US for the 
prevention of migraine in adults.  Regulatory approval was granted on the basis of 
established superiority against placebo for each dose in 4 independent randomized 
clinical studies (1 CM and 3 EM) (Sun et al, 2016; Goadsby et al, 2017; Tepper et al, 
2017; Dodick et al, 2018). 
4.4 
End of Study 
An individual subject is considered to have completed the study if he/she has completed 
the last visit shown in the Schedule of Activities.  The total study duration for an 
individual subject, including the screening/baseline period and 24-week open-label 
treatment period, is approximately 28 to 32 weeks. 
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. 
5. 
Study Population 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).  This log may be completed and updated via an Interactive Response 
Technology (IRT) system. 
Eligibility criteria will be evaluated during screening and baseline period. 


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Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Section 11.3). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, will not be provided. 
5.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
101 
Age ≥ 18 years upon entry into screening 
102 
Subject has provided informed consent prior to initiation of any study specific 
activities/procedures. 
103 
History of migraine (with or without aura) for ≥ 12 months before screening 
according to the International Headache Society (IHS) Classification ICHD-III 
(Headache Classification Committee of the International Headache Society, 
2018) based on medical records and/or patient self-report 
104 
Migraine frequency: ≥ 4 migraine days per month on average across the 
3 months prior to screening 
105 
History of CM or EM migraine across the 3 months prior to screening: 
 
CM is defined as: ≥ 15 headache days a month of which ≥ 8 headache days 
meet criteria as migraine days per subject self-report and investigator 
assessment 
 
EM is defined as: < 15 headache days a month over the last 3 months, 
which on some days is migraine, but does not fulfil ICHD-3 criteria for CM 
per subject self-report and investigator assessment 
106 
Subject reports to their provider intolerance or insufficient response with their 
current preventive treatment.  Insufficient response is defined as insufficient 
reduction in headache frequency, duration, or severity at the generally accepted 
therapeutic dose for at least 6 weeks and is based on the investigator's 
assessment. 
107 
Concomitant treatment with 1 migraine preventive medication is required under 
the following conditions: 
 
Drug regimen (ie, formulation, frequency of use and dose) is stable for 
≥ 2 months prior to baseline period start or injection paradigm is stable for 
2 injection cycles (acceptable range of injection frequency is every 10 to 
16 weeks) AND 
 
Drug regimen or injection paradigm is at generally accepted doses and 
frequency for its use in migraine AND 
 
Drug regimen or injection paradigm is not anticipated to change during the 
baseline period AND 
 
Drug regimen or injection paradigm is either: 
 
not anticipated to change post-baseline OR 
 
anticipated to be fully discontinued irrespective of tapering off schedules 
by no later than end of week 12 


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 
Medication is 1 of the following: 
 
Divalproex sodium, sodium valproate, topiramate 
 
Beta blockers (eg, atenolol, bisoprolol, metoprolol, nadolol, nebivolol, 
pindolol, propranolol, timolol)  
 
Tricyclic antidepressants (eg, amitriptyline, nortriptyline, protriptyline)  
 
Duloxetine, milnacipran  
 
Verapamil  
 
Lisinopril, candesartan  
 
Clonidine, guanfacine  
 
Cyproheptadine 
 
OnabotulinumtoxinA (subjects using concomitant 
onabotulinumtoxinA for migraine prevention are allowed [but not 
required] to also take one oral preventive migraine medication) 
During the baseline period: 
108 
Must have ≥ 4 MMD based on the eDiary data during the last 28 days of the 
baseline (if longer than 28 days) 
110 
Must have demonstrated ≥ 75% compliance with the eDiary, based on the last 
28 days of the baseline period (if longer than 28 days) 
5.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
Disease Related 
201 
 50 years of age at migraine onset  
202 
History of cluster headache or hemiplegic migraine headache 
203 
Unable to differentiate migraine from other headaches 
Other Medical Conditions 
204 
Malignancy (except non-melanoma skin cancers, cervical or breast ductal 
carcinoma in situ) within the last 5 years 
205 
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 locally at investigator’s 
discretion during screening (with the exception of prescribed medications such as 
opioids or barbiturates that may result in a positive urine drug test) 
206 
Active chronic pain syndromes (eg, fibromyalgia and chronic pelvic pain) 
207 
History of major psychiatric disorder (eg, schizophrenia or other psychotic 
disorders, bipolar disorder, obsessive-compulsive disorder, post-traumatic stress 
disorder), or current evidence of moderately severe or severe depression based 
on a Patient Health Questionnaire-9 (PHQ-9) total score ≥ 15 at screening 
 
Subjects with history of anxiety disorder and/or major depressive disorder are 
permitted in the study if they are considered by the investigator to be stable 


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(with PHQ-9 < 15) and are taking no more than 1 medication for each 
disorder.   
 
For subjects taking antianxiety and/or antidepressant medication, dose must 
be stable for at least 3 months prior to the start of the baseline phase. 
208 
The subject is at risk of self-harm or harm to others as evidenced by past suicidal 
behavior. 
Prior/Concomitant Therapy 
209 
No therapeutic response with > 3 of the following 9 medication categories for 
preventive treatment of migraine after an adequate therapeutic trial.  These 
medication categories are: 
 Category 1:  Topiramate 
 Category 2:  Other antiepileptics (eg, divalproex sodium, sodium valproate, 
gabapentin) 
 Category 3:  Beta blockers 
 Category 4:  Tricyclic antidepressants 
 Category 5:  Other antidepressants (eg, serotonin-norepinephrine reuptake 
inhibitors, selective serotonin-reuptake inhibitors) 
 Category 6:  Calcium channel blockers (eg, verapamil, amlodipine, cinnarizine, 
lomerizine) or calcium antagonists (eg, flunarizine) 
 Category 7:  Angiotensin receptor blockers (eg, candesartan) or 
angiotensin-converting enzyme (ACE) inhibitors (eg, lisinopril) 
 Category 8:  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) 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 
210 
Used a prohibited medication, device, or procedure listed in Section 6.1.7 and 
Table 6-2.  
211 
Anticipated to require any excluded medication, device, or procedure during the 
study.  
220 
Any prior exposure to erenumab.  
221 
Use of gepants for migraine prevention.  
222 
Previously treated with a ligand-based anti-CGRP monoclonal antibody 
(ie, fremanezumab, galcanezumab, and/or eptinezumab) in a manner 
consistent with migraine prevention that either:  
(a) in the opinion of the investigator, did not offer any evidence of a 
therapeutic response, OR 
(b) was discontinued for  12 weeks from the date of initial screening, OR 


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(c) was previously discontinued due to a known adverse drug reaction.  
Prior/Concurrent Clinical Study Experience 
212 
Currently receiving treatment in another investigational device or drug study, or 
less than 90 days or 5 half-lives (for investigational drugs), whichever is longer, 
since ending treatment on another investigational device or drug study(ies).  
Other Exclusions 
213 
Female subjects of childbearing potential unwilling to use 1 acceptable method of 
contraception (see Section 11.5) during treatment and for an additional 16 weeks 
after the last dose of investigational product 
214 
Female subjects who are breastfeeding or who plan to breastfeed while on study 
through 16 weeks after the last dose of investigational product 
215 
Female subjects planning to become pregnant while on study through 16 weeks 
after the last dose of investigational product 
216 
Female subjects of childbearing potential with a positive pregnancy test 
assessed at screening and/or day 1 by a urine pregnancy test 
217 
Subject has known sensitivity to any of the products [or components] to be 
administered during dosing. 
218 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures (eg, COAs) to 
the best of the subject and investigator’s knowledge. 
219 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures or completion. 
5.3 
Subject Enrollment 
Before subjects or key family members begin participation in any study-specific 
activities/procedures, Amgen requires a copy of the site’s written institutional review 
board/independent ethics committee (IRB/IEC) approval of the protocol, informed 
consent form, and all other subject information and/or recruitment material, if applicable 
(see Section 11.3). 
The subject and key family member 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.  This should occur on study day 1, after completion of the screening/ 
baseline period.  The investigator is to document this decision and date in the subject’s 
medical record and in/on the Subject Enrollment eCRF. 
Each subject who enters into the screening period for the study (defined as when the 
subject signs the informed consent form) receives a unique subject identification number 
before any study-related activities/procedures are performed.  The subject identification 


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number will be assigned by the IRT system.  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. 
Sites that do not enroll subjects within 3 months of site initiation may be closed. 
5.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
criteria, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened once if, in the opinion of the investigator, the reason for the initial screen 
failure has been resolved or is no longer applicable.  Refer to Section 8.1.1. 
6. 
Study Intervention 
Study intervention is defined as any investigational product(s), non-investigational 
product(s), placebo, combination product(s), or medical device(s) intended to be 
administered to a study subject according to the study protocol. 
Note that in several countries, investigational product and non-investigational product 
are referred to as investigational medicinal product and non-investigational medicinal 
product, respectively. 
A summary of the dosing and administration of each treatment is shown in Table 6-1 
below. 
 
 


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6.1 
Study Interventions Administered 
6.1.1 
Investigational Products 
Table 6-1.  Investigational Products 
Study Treatment 
Name 
Amgen Investigational Product:a 
Erenumab 
Dosage 
Formulation 
Erenumab will be packaged in a SureClick AI/Pen containing 1 mL of 
70 or 140 mg/mL of erenumab formulated with sodium acetate, sucrose, 
and polysorbate 80. 
Unit Dose 
Strength(s)/ 
Dosage Level(s) 
and Dosage 
Frequency 
Erenumab 70 or 140 mg will be administered subcutaneously every 
4 weeks.  
Route of 
Administration 
Subcutaneous injection 
Accountability 
The quantity, start date, and lot number(s) of investigational product are 
to be recorded on each subject’s eCRF. 
Dosing 
Instructions 
On day 1, erenumab may be administered by site staff or 
self-administered by the subject, under site staff’s supervision, at the 
investigator’s discretion.  At remaining onsite visits, erenumab will be 
administered to subjects by site staff or by subject self-administration.  
Between onsite visits, subjects will continue dosing by self-administration 
or administration by a designated person every 4 weeks in a 
non-investigator site setting (eg, at subject’s home). 
Device 
AI/Pen 
AI = autoinjector; eCRF = electronic case report form 
a Erenumab will be manufactured and packaged by Amgen and distributed using Amgen clinical study drug 
distribution procedures. 
 
6.1.2 
Non-investigational Products 
Non-investigational products will not be used in this study. 
6.1.3 
Medical Devices 
The investigational medical device provided by Amgen for use in this study is the 
erenumab SureClick Autoinjector Pen (AI/Pen) (Table 6-1). 
The erenumab SureClick AI/Pen is a single use disposable, handheld mechanical 
“spring-based” device for fixed dose SC injection of erenumab 1 mL deliverable volume. 
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard care. 
Non-Amgen non-investigational medical devices (eg, syringes, sterile needles), that are 
commercially available are not usually provided or reimbursed by Amgen (except, for 


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example, if required by local regulation).  The investigator will be responsible for 
obtaining supplies of these devices. 
6.1.4 
Other Protocol-required Therapies 
Other protocol-required therapies will not be used in this study. 
6.1.5 
Other Intervention Procedures 
Other intervention procedures will not be used in this study. 
6.1.6 
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, combination product or device after it is released for 
distribution to market or clinic by either (1) Amgen or (2) distributors or partners for 
whom Amgen manufactures the material.  This includes all components distributed 
with the drug, such as packaging drug containers, delivery systems, labeling, and 
inserts.  
This includes any investigational/noninvestigational product(s), device(s) or 
combination product(s) provisioned and/or repackaged/modified by Amgen SureClick 
AI pen. 
Any product complaint(s) associated with an investigational product(s), 
noninvestigational product(s), devices(s), or combination product(s) supplied by 
Amgen are to be reported. 
6.1.7 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
Subjects are required to be on 1 migraine preventive medication to be eligible for the 
study.  In addition to the 1 migraine preventive medication required for eligibility, subjects 
may be taking up to 1 additional medication from the list provided below, provided that 
this medication (1) is being taken for an indication other than migraine prevention, 
(2) has been stable for at least 3 months prior to the start of the baseline period, and 
(3) is expected to remain stable during the study.  If a subject is receiving 
onabotulinumtoxinA for migraine prevention, one oral migraine preventive 
medication in addition to onabotulinumtoxinA is permitted.   
Initiation of any new oral migraine preventive medication is prohibited from 2 months 
before the start of the baseline period and throughout the study.  Such medications 
include:  


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 
Antiepileptics (eg, divalproex sodium, sodium valproate, topiramate, 
carbamazepine, levetiracetam)  
 
Angiotensin receptor blockers (eg, candesartan) or ACE inhibitors (eg, lisinopril)  
 
Beta blockers  
 
Calcium channel blockers (eg, verapamil, amlodipine, cinnarizine) or calcium 
antagonists (eg, flunarizine)  
 
Tricyclic antidepressants  
 
Other antidepressants (eg, serotonin-norepinephrine reuptake inhibitors, 
selective serotonin-reuptake inhibitors)  
 
Other drugs or supplements used for migraine prevention (eg, clonidine, 
guanfacine, methysergide, cyproheptadine, pizotifen) 
Initiation of botulinum toxin for any indication involving the head, face, or neck 
region is prohibited if less than 2 injection cycles of dose stability and injection 
paradigm.  Only onabotulinumtoxinA formulation will be allowed in the head, face, 
or neck region.  All other botulinum toxin formulations are only allowed in 
anatomic regions outside of the head, face, and neck.  
Additional excluded treatments, medical devices, and procedures are provided in 
Table 6-2. 
Table 6-2.  Excluded Treatments, Medical Devices, and Procedures 
Prohibited Medications, Devices, and Procedures 
Time Period for Exclusion 
Ergotamine-derivatives, steroids, and triptans used for 
migraine prevention 
2 months before the start of the 
baseline period and throughout the 
study 
Use of the following medications for the acute treatment 
of migraine for ≥ 4 days/month:  
 
Barbiturates and/or butalbital-containing 
analgesics  
 
Opioid and/or opioid-containing analgesics 
2 months before the start of the 
baseline period and throughout the 
study 
Gepants for migraine prevention (eg, atogepant) 
Use of the following medications for acute treatment 
of migraine for  6 days/month: 
 
Gepants (eg, rimegepant and ubrogepant) 
 
Lasmiditan 
Throughout screening and 
baseline, and while on study 
Page 1 of 2 


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Prohibited Medications, Devices, and Procedures 
Time Period for Exclusion 
Anti-CGRP monoclonal antibodies (ie, eptinezumab, 
galcanezumab, gremanezumab) 
12 weeks before the start of the 
screening period, and 
throughout the study 
Previously treated and currently being treated with 
erenumab 
At any time in the past, 
throughout screening/baseline, 
and while on study 
Investigational medications 
90 days or 5 half-lives (whichever is 
longer) before the start of the 
screening period and throughout 
the study 
For any indication: Devices (eg, neuromodulation 
devices) or procedures (eg, nerve blocks, trigger-point 
injections, and acupuncture) depending on anatomic 
region and impact.  
2 months before the start of the 
baseline period and throughout the 
study 
Cognitive behavioral therapy (CBT), biofeedback, and 
psychotherapy for migraine prevention.  
Note: Subjects on a stable, maintenance phase of these 
therapies for migraine will be allowed to participate. 
Note: Stable, maintenance phase of CBT is defined as 
≥ 6 weekly or biweekly sessions administered by 
adequately trained psychologists and only “booster” 
sessions at a monthly, bimonthly, or quarterly frequency 
at least 3 months before the start of the screening 
period. 
3 months before the start of the 
baseline period and throughout the 
study 
Note: Subjects who have 
discontinued CBT within 3 months 
prior to the start of the baseline 
phase are eligible for the study 
provided that there is evidence of 
CBT failure/lack of efficacy prior to 
initial screening (per medical 
records or investigator’s 
assessment). 
Page 2 of 2 
ACE = angiotensin-converting enzyme; CBT = cognitive behavioral therapy; CGRP = calcitonin gene 
related peptide.  
 
6.2 
Dose Modification 
6.2.1 
Dose-[group/cohort] Study Escalation/De-escalation and Stopping 
Rules 
Dose-cohort study escalation/de-escalation and stopping rules do not apply to this study. 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation of Amgen Investigational Product: 
Erenumab 
All subjects will be started on a 70 mg dose of erenumab at day 1 with provider 
discretion for dose optimization, which is recommended to be completed by week 12.  
Dose optimization will allow patients to remain on 70 mg, increase the dose from 70 to 
140 mg, and if needed decrease the dose back down from 140 to 70 mg.  It is highly 
recommended that all erenumab dose adjustments be completed by week 12, after 
which all subjects should remain on the week 12 erenumab dose for the rest of the 
study.  Additional dose adjustments after week 12 are not recommended and must only 


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be made if deemed medically necessary by the investigator.  All erenumab dose 
changes, regardless of timing, will require an onsite visit. 
The reason for each dose change of erenumab is to be recorded on each subject’s 
eCRF(s). 
At any time during the study, the investigator may discontinue investigational product 
administration for any subject who experiences a severe or life-threatening adverse 
event reported by the investigator to be related to investigational product.  Refer to 
Section 8.4.2 for details regarding adverse event reporting. 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules 
No samples assessing hepatotoxicity will be collected in this study.  
6.3 
Preparation/Handling/Storage/Accountability 
Guidance and information on drug accountability for the investigational product and 
device will be provided to the site. 
6.4 
Measures to Minimize Bias:  Randomization and Blinding 
6.4.1 
Method of Treatment Assignment 
Subjects who meet eligibility criteria and enroll in the study will be assigned to treatment 
with erenumab 70 mg initially, as defined in Section 6.2.2. 
The enrollment date is to be documented in the subject’s medical record and on the 
Subject Enrollment eCRF. 
6.4.2 
Blinding 
This is an open-label study; blinding procedures are not applicable. 
6.5 
Treatment Compliance 
Site staff will train subjects on self-administration of erenumab at the day 1 visit.  At 
subsequent onsite visits, subjects will receive erenumab administration directly from the 
investigator or designee or will self-administer the dose in the clinic under medical 
supervision.  The date and lot number of each dose administered in the clinic will be 
recorded in the source documents and recorded in the eCRF. 
When subjects self-administer erenumab at home, they should enter the dose and lot 
number in the eDiary for each dose.  The data will be transcribed into the subject’s 
medical record and eCRF at the next onsite visit. 
Noncompliance is to be documented in the medical file and will be reflected in the eCRF.  
Noncompliant subjects are to be re-educated on the importance of adhering to the 


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investigational product administration schedule and reminded that repeated cycles of 
noncompliance could be a reason for discontinuation of study treatment. 
6.6 
Treatment of Overdose 
Overdose with this product has not been reported.  No specific antidote exists.  In the 
case of an overdose, the subject should be treated symptomatically, and supportive 
measures implemented as necessary. 
6.7 
Prior and Concomitant Treatment 
6.7.1 
Migraine Preventive Medications 
All prior and current migraine preventive therapies will be collected.  
All subjects will be required to enter the study on 1 standard of care preventive 
medication for their migraine.  Subjects will be allowed to remain on their standard of 
care therapy during the study or fully discontinue the standard of care therapy by the 
week 12 visit.  Standard of care therapy status (ie, continued or discontinued) is to be 
recorded. 
6.7.2 
Prior Treatment 
All prior therapies other than prior migraine preventive medications that were being 
taken/used from 120 days before screening through the signing of the informed consent 
will be collected in the concomitant medication eCRF. 
6.7.3 
Concomitant Treatment 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.1.7. 
Concomitant therapies are to be collected from the signing of informed consent through 
the end of study in the concomitant medication eCRF. 
7. 
Discontinuation of Study Treatment and Subject 
Discontinuation/Withdrawal 
Subjects have the right to withdraw from investigational product, protocol procedures, or 
the study as a whole at any time and for any reason without prejudice to their future 
medical care by the physician or at the institution. 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, device, protocol procedures, or the study as a whole at any time prior to study 
completion for the reasons listed in Section 7. 


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7.1 
Discontinuation of Study Treatment 
Subjects can decline to continue receiving investigational product and/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 investigational product or procedures and must discuss with the subject the 
possibilities for continuation of the Schedule of Activities (see Table 1-1) including 
different options of follow-up (eg, in person, by phone/mail, through family/friends, in 
correspondence/communication with other treating physicians, from the review of 
medical records) and collection of data, including endpoints, adverse events, and 
device-related events and must document this decision in the subject’s medical records.  
Subjects who have discontinued investigational product and/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. 
Reasons for early removal from protocol-required investigational product(s) or 
procedural assessments may include any of the following: 
 
Decision by Sponsor 
 
Lost to follow-up 
 
Death 
 
Adverse event 
 
Lack of efficacy 
 
Subject request 
 
Ineligibility determined 
 
Protocol deviation 
 
Non-compliance 
 
Pregnancy 
7.2 
Subject Discontinuation/Withdrawal 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.  Subjects who are 
withdrawn or removed from treatment or the study will not be replaced. 


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Refer to the Schedule of Activities (Table 1-1) for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be 
completed. 
7.2.1 
Reasons for Removal From Washout Period, Run-in Period, or 
Invasive Procedures 
Washout, run-in, or invasive procedures do not apply to this study. 
7.2.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
Decision by sponsor 
 
Withdrawal of consent from study 
 
Death 
 
Lost to follow-up 
7.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
 
The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or is able to 
continue in the study. 
 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where possible, 
3 telephone calls and, if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods).  These contact attempts are to be 
documented in the subject’s medical record. 
 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
 
For subjects who are lost to follow-up, the investigator should 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. 
8. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Table 1-1).  


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If an enrolled subject is subsequently determined to be ineligible for the study, this must 
be discussed with the sponsor immediately upon occurrence or awareness to determine 
if the subject is to continue or discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
8.1 
General Study Periods 
8.1.1 
Screening, Enrollment and/or Randomization 
Informed consent must be obtained before completing any screening procedure.  After 
the subject has signed the informed consent form, the site will register the subject in the 
IRT and screen the subject in order to assess eligibility for participation.  The screening 
window is up to 21 days. 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, (see Section 5.4) as applicable. 
The baseline period can begin on the same day as the screening visit or up to 3 weeks 
after the screening visit.  The baseline period begins when the subject has met all the 
screening eligibility criteria and begins baseline study procedures and ends the day 
before the day 1 visit.  The total duration of the baseline period must be at least 28 days 
and no more than 35 days. 
If a subject has not met all eligibility criteria at the end of the baseline period, the subject 
will be registered as a screen failure.  Subjects who have screen-failed may be 
re-screened only once if, in the opinion of the investigator, the reason for the initial 
screen failure has been resolved or is no longer applicable.  Rescreen subjects must first 
be registered as screen failures in IRT and subsequently registered as rescreens.  Once 
the subject is registered as rescreened, a new screening window will begin.  Subjects 
will retain the same subject identification number assigned at the original screening.  If 
the rescreening period begins more than 45 days after the original signing of the 
informed consent form, all screening procedures, including informed consent, must be 
repeated. 
8.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (Table 1-1).  On-study visits may be 
completed within  7 days.  The date of the first dose of erenumab is defined as day 1.  


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All subsequent doses and study visits will be scheduled based on the day 1 date.  
Erenumab is to be administered by site staff or by subject self-administration as the last 
procedure of the onsite visits.  All other doses of erenumab are to be administered by 
subject or designee at a non-investigative site setting (eg, at home), unless a site visit is 
deemed warranted by the investigator (eg, for changes in erenumab dose). 
8.1.3 
End of Study 
The end of study visit occurs at week 24 ( 7 days) or when a subject discontinues from 
the study before the week 24 visit.  All assessments will be performed at the end of 
study visit as per the Schedule of Activities (Table 1-1). 
8.2 
General Assessments  
8.2.1 
Informed Consent 
All subjects must sign and personally date the IRB/IEC approved informed consent 
before any study-specific procedures are performed.  Key family members must also 
sign an informed consent prior to completing any mGI-I assessments. 
8.2.2 
Demographics 
Subject 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 and satisfaction. 
8.2.3 
Medical History 
The Investigator or designee will collect a complete subject medical history that started 
within 120 days prior to screening through baseline.  Medical history will include 
information on the subject's concurrent medical conditions.  Record all findings on the 
medical history eCRF.  In addition to the medical history, migraine history must date 
back to the original diagnosis. The current severity will be collected for each condition 
that has not resolved.  
Targeted medical history is to be recorded on the appropriate eCRF for neurologic 
medical history, gastrointestinal medical history, and headache and migraine frequency 
medical history. 
8.2.4 
Physical Measurements 
The subject’s height (in centimeters) should be measured without shoes.  Weight (in 
kilograms) should be measured without shoes. 


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8.3 
Efficacy Assessments 
8.3.1 
Treatment Satisfaction Questionnaire for Medication 
The TSQM version 1.4 is a 14-item instrument designed to measure important 
dimensions of patients' experiences with their medication.  It has 4 domains: 
effectiveness, side effects, convenience, and global satisfaction.  Scores range from 0 to 
100 with higher scores indicating greater satisfaction.  The recall period is the last 2 to 
3 weeks, or since the medication was last used. 
8.3.2 
Migraine Global Impression Item 
The mGI-I is a single item instrument designed to measure improvement/worsening in 
migraine.  The 3 versions of the instrument include the perspective of study subjects, 
key family members, and treating clinicians measured on the following scale: much 
improved; a little improved; no change; a little worse; or much worse.  The recall period 
is the past 7 days. 
8.3.3 
Migraine Functional Impact Questionnaire 
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.  The 
scores will be calculated as the sum of the item responses and the sum will be rescaled 
to a 0 - 100 scale, with higher scores representing greater burden.  The recall period is 
the past 7 days. 
8.3.4 
Expectation of Treatment Scale 
The Expectation of Treatment Scale (ETS) is a 5-item questionnaire.  Responses 
are scored on a 5-point Likert scale, and subjects’ item scores are summed to provide a 
total score ranging between 5 and 20.  Higher scores indicate higher perceived 
expectations. 
8.3.5 
Migraine Symptom Severity Scale 
The MSSS is a 7-item questionnaire that assesses frequency of pain and other 
symptoms associated with migraines.  Responses are as follows: “never,” “rarely,” 
“less than half the time,” “half the time or more,” and “all or nearly all of the time.”  The 
responses are given a value from 1 to 3 as follows: Never = 0, Rarely = 1, Less Than 


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Half the Time = 2, Half the Time or More = 3, and All or Nearly All of the time = 3.  The 
MSSS score is the sum of the 7 items and has a range from 0 to 21. 
8.3.6 
Migraine Interictal Burden Scale  
The MIBS-4 measures interictal migraine-related burden with 4 questions that assess 
impairment in work or school, impairment in family and social life, difficulty making plans 
or commitments, and emotional/affective and cognitive distress.  Each of the 4 questions 
is responded to using 1 of 6 response categories: “Don’t know/NA” (Score=0), “Never” 
(Score=0), “Rarely” (Score=1), “Some of the time” (Score=2), “Much of the time” 
(Score=3) or “Most or all of the time” (Score=3).  Each question is multiplied with its 
score and summed up to produce total score ranges from 0 to 12.  The MIBS-4 total 
scores are categorized into 4 level of interictal burden: None (0), Mild (1 to 2), Moderate 
(3 to 4) and Severe (5 or higher). 
8.3.7 
Generalized Anxiety Disorder Scale 
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.  
8.3.8 
Patient Health Questionnaire 
The PHQ-9 is a self-administered questionnaire, widely used for diagnosis and severity 
assessment of depression in primary care settings. The PHQ-9 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.  The 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 1 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. 


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8.3.9 
Electronic Diary 
The eDiary will collect migraine-related parameters at home, including the following:  
 
presence or absence of headache and whether the headache is a migraine  
 
presence or absence of aura  
 
use of acute headache medications and whether the acute headache medication is a 
triptan  
 
worst headache severity  
At the start of the baseline period, which may coincide with the screening visit, the site 
staff will instruct the subject on eDiary use (eg, accessing the application, navigating 
screens, transmitting data, contacting the help desk for technical assistance).  The 
subject will be instructed to interact with the eDiary as per the Schedule of Activities 
(Table 1-1).  At the day 1 visit, the investigator will use the subject’s eDiary to review all 
data entered during the baseline period and confirm the relevant inclusion and exclusion 
criteria. 
8.4 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
(Table 1-1). 
8.4.1 
Clinical Laboratory Assessments 
Refer to Section 11.2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Table 1-1) for the timing and frequency.  
All protocol-required laboratory assessments, as defined in Section 11.2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities 
(Table 1-1).  Note: the only protocol-required laboratory assessment is the urine 
pregnancy test for women of childbearing potential. 
8.4.2 
Adverse Events and Serious Adverse Events  
The method of recording, evaluating, and assessing causality of adverse events, 
adverse device events, and serious adverse events and the procedures for 
completing and transmitting serious adverse event reports are provided in 
Section 11.4.   


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8.4.2.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
8.4.2.1.1 
Adverse Events 
The adverse event grading scale to be used for this study will be the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 and is described in 
Section 11.4. 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of investigational 
product through the end of study are reported using the Events eCRF. 
8.4.2.1.2 
Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through end of study are reported using the Events eCRF. 
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee within 24 hours of the investigator’s awareness of the event, as indicated in 
Section 11.4.  The investigator will submit any updated serious adverse event data to the 
sponsor within 24 hours of it being available. 
Since the criteria for the CTCAE grading scale differs from the regulatory criteria for 
serious adverse events, if adverse events correspond to grade 4 CTCAE toxicity 
grading scale criteria (eg, laboratory abnormality reported as grade 4 without 
manifestation of life-threatening status), it will be left to the investigator’s judgment 
to also report these abnormalities as serious adverse events.  Laboratory abnormality 
with clinical significance will be reported as an adverse event.  If an adverse event 
associated with a laboratory abnormality meets the criteria of a serious event, it 
will be reported as a serious adverse event based upon the investigator’s 
judgment.  For any adverse event that applies to this situation, comprehensive 
documentation of the event’s severity must be recorded in the subject medical 
records. 
8.4.2.1.3 
Serious Adverse Events After the Protocol-required Reporting 
Period 
After End of study, there is no requirement to actively monitor study subjects after the 
study has ended with regards to study subjects treated by the investigator.  
However, if the investigator becomes aware of serious adverse events suspected to 
be related to investigational product, then these serious adverse events will be 


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reported to Amgen within 24 hours following the investigator’s awareness of the 
event.  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 awareness of the event.  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 awareness 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 investigational product.  If further safety related data is needed to 
fulfill any regulatory reporting requirements for a reportable event, then additional 
information may need to be collected from the subject’s records after the subject 
ends the study. 
The method of recording, evaluating, and assessing causality of adverse events, 
adverse device effects, and serious adverse events and the procedures for completing 
and transmitting serious adverse event reports are provided in Section 11.4. 
8.4.2.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the subject is the 
preferred method to inquire about adverse event occurrence. 
8.4.2.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is required to 
proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 7.3).  
Further information on follow-up procedures is given in Section 11.4. 
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following awareness 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.  


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Information provided about the serious adverse event must be consistent with that 
recorded on the Events CRF. 
8.4.2.4 
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 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. 
8.4.2.5 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and 
signal management processes. 
8.4.2.6 
Pregnancy and Lactation 
A urine pregnancy test should be completed at screening and within 7 days of initiation 
of investigational product for females of childbearing potential. 
Note:  Females who have undergone a bilateral tubal ligation/occlusion should have 
pregnancy testing per protocol requirements.  (If a female subject, or the partner of a 
male subject, becomes pregnant it must be reported on the Pregnancy Notification 
Form (Figure 11-2).  Refer to Section 11.5 for contraceptive requirements.  
Additional pregnancy testing should be performed at intervals of every 12 weeks 
(+/- 7 days) during treatment with protocol-required therapies and at the end of study. 


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Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion, if there is suspicion that a female subject is pregnant, or as required per local 
laws and regulations. 
Details of all pregnancies and/or lactation in female subjects will be collected after the 
start of study treatment and until 16 weeks after the last dose of investigational product. 
If a pregnancy is reported, the investigator is to inform Amgen within 24 hours of learning 
of the pregnancy and/or lactation and is to follow the procedures outlined in 
Section 11.5.  Amgen Global Patient Safety will follow-up with the investigator regarding 
additional information that may be requested. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events. 
Further details regarding pregnancy and lactation are provided in Section 11.5. 
8.4.2.7 
Adverse Device Effects 
In order to fulfill regulatory reporting obligations worldwide, the investigator is 
responsible for the detection and documentation of any adverse device effects that occur 
during the study with such devices.  
An adverse device effect is any adverse event related to the use of a combination 
product or medical device.  Adverse device effects include adverse events resulting from 
insufficient or inadequate instructions for use, adverse events resulting from any 
malfunction of the device, or adverse events resulting from use error or from intentional 
misuse of the device. 
All adverse device effects are to be reported as adverse events following the same 
reporting periods and procedures. 
Product complaints are described in Section 6.1.6. 
Further details regarding adverse device effects can be found in Section 11.4. 
8.5 
Optional Substudy: Qualitative Interviews 
8.5.1 
Substudy Background and Rationale  
Qualitative interviews enable access to qualitative aspects of experiences of clinical trial 
participants to supplement the quantitative data collected as part of the study.  For 
example, treatment satisfaction can be assessed to understand which aspects of the 
treatment are valued by subjects such as symptom benefit, delivery method, and safety 
and tolerability.  Interviewing clinical trial participants at the start and end of the 


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treatment period can also help identify benefits most relevant and meaningful to patients.  
This can also complement and help interpret the quantitative data collected using COA 
instruments in the clinical trial.   
Regulatory agencies are showing increasing interest in understanding patients’ 
experiences of the risk-benefit related to new interventions being tested in clinical trials 
(FDA, 2017).  Qualitative interviews at the start and end of clinical trials help to 
understand the patient experience of the treatment in the trial setting: their experience of 
the convenience of treatment, changes they perceive as result of treatments, and 
informal assessments of trade-offs on benefit and risks they perceive about the 
treatment. 
8.5.2 
Research Question and Objectives of the Qualitative Interview 
Substudy  
The aim of this substudy is to collect qualitative data to assess the experience of 
treatment from a subset of adults who have participated in Study 20190389, their 
clinicians, and key family members to provide a more in-depth understanding of patients’ 
experience with migraine and the impact of migraine, including perception of symptoms 
and burden of disease.  The objectives are to elicit the subject’s, clinician’s, and family 
member’s perceptions of migraine, associated symptoms, and symptom impact/burden 
and interference on the subject’s life, subject perceptions of meaningful changes in 
experience of migraine, and to explore subject experience with treatment administration.  
8.5.3 
Substudy Design 
Qualitative interviews will be conducted with approximately 20 subjects, their clinicians, 
and key family members (collectively referred to as “participants”) who opt in to this 
optional substudy.  The substudy sample size is based on a convenience sample to 
allow for sufficient numbers of EM and CM subjects enrolled.  Best efforts will be made 
to ensure that the sample includes subjects with diverse demographic characteristics 
from the pool of trial subjects.  
Interviews will be conducted at study entry, within 7 days of the first investigational 
product dose (Day 1), and at study exit, within 7 days of the week 24 visit or within 
approximately 14 days of the early termination visit.  If possible, within 7 days from early 
termination notification will be targeted.  No protocol deviation will occur if these 
interviews are conducted outside of these timeframes.   
Note: Subjects must have received a first dose of investigational product before the entry 
interview is conducted. 


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8.5.4 
Summary of Substudy Participation Criteria  
Study subjects must meet the following criteria to be considered for enrollment into the 
substudy:  
1) Be enrolled in Study 20190389; 
2) Have provided supplementary informed consent to participate in the substudy;  
3) Be willing and able to participate in 2 telephone interviews lasting approximately 
1 hour each;  
4) Be able to read, understand, and speak English sufficiently to participate in the 
interviews;  
5) Be willing to be audio-recorded during the interview sessions. 
The key family member should be a family member/caregiver of an enrolled patient and 
should be the person in the subject’s life that s/he interacts with the most on a day-to-
day basis.  Key family members must meet the following criteria to be considered for 
enrollment into the substudy: 
1) Should have a deep understanding of the impact migraine has on the subject.  They 
should also be able to provide their perspective of change in the subject’s migraines 
over time.  The person the subject chooses to nominate can be anyone such as a 
spouse, daughter or son, parent, sibling, or other relative or the person the subject is in a 
de facto relationship with. 
2) Have provided informed consent to participate in the substudy;  
3) Be willing and able to participate in 2 telephone interviews lasting approximately 
1 hour each;  
4) Be able to read, understand, and speak English sufficiently to participate in the 
interviews;  
5) Be willing to be audio-recorded during the interview sessions. 
Clinicians must meet the following criteria to be considered for enrollment into the 
substudy: 
1) Be a US-licensed and practicing healthcare practitioner (HCP) at the clinical site 
(eg, neurologist, headache specialist, primary care physician, nurse practitioner, 
physician assistant) currently treating the subject on Study 20190389; 


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2) Be willing and able to participate in 2 telephone interviews lasting approximately 
1 hour each;  
3) Be able to read, understand, and speak English sufficiently to participate in the 
interviews;  
4) Be willing to be audio-recorded during the interview sessions. 
Meeting any of the following criteria will exclude a subject, key family member, or 
clinician from enrollment into the substudy:  
1) Expected to be unable to complete entry interview within 7 days from first 
investigational product dose;  
2) Expected to be unable to complete exit interview within 7 days prior to week 24 visit or 
within approximately 14 days post early termination visit; 
3) Has any clinically relevant medical or psychiatric condition that, in the opinion of the 
investigator and/or study coordinator, would interfere with the completion of the substudy 
activities.  This includes but is not limited to language, speech, hearing or cognitive 
disorders that could impact a participant’s ability to participate in an interview-based 
discussion. 
8.5.5 
Substudy Duration and Substudy Procedures  
Subjects, clinicians, and key family members will participate in 2 telephone interviews, 
lasting approximately 1 hour each.  Entry interviews will be conducted within 7 days from 
first investigational product dose (day 1); exit interviews will be conducted within 7 days 
prior to week 24 visit or within approximately 14 days post early termination visit.  If 
possible, within 7 days from early termination notification will be targeted.  No protocol 
deviation will occur if these interviews are conducted outside of these timeframes.  
Subjects enrolled in Study 20190389 will be approached by clinic staff for recruitment 
and possible enrollment into this substudy.  
At participating sites, subjects will be provided an option to opt-in to the qualitative 
interview substudy and be provided with additional information about the substudy either 
at time of screening for the main study or after enrollment and successful dosing with 
investigational product, depending on site preference.  Clinical site staff will explain the 
substudy objectives and procedures to the subject and their selected key family member 
and obtain a supplementary written informed consent from each participant.  Each 
subject and key family member will sign 2 copies of the consent form.  Sites will send a 


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wet-ink version of the informed consent to Evidera, the third-party supplier who is 
performing the substudy, and will retain a copy of the signed informed consent for their 
study records.  Clinic site staff will provide Evidera contact information for each 
participant enrolled in the substudy and Evidera will subsequently contact each 
participant to schedule interviews. 
Once consent has been obtained, the subject ID and site details can be communicated 
by the site to the interview scheduler from Evidera along with potential dates for the day 
1 and week 24 visits.  The interview scheduler will obtain contact information and 
schedule tentative dates and times for the interviews with the subject, clinician, and key 
family member.  Evidera will confirm with the site that the subject has completed study 
procedures for the day 1 and week 24 visits before confirming the interview dates and 
times of the interviews to ensure compliance to the substudy protocol.  
Evidera staff, who are trained and experienced in qualitative data collection, will conduct 
telephone interviews using a semi-structured interview guide.  Participants will be 
interviewed about the subject’s pre-treatment status, any perceived changes during the 
study, and the meaningfulness of the changes experienced.  During the interviews, 
interviewers will ask participants for specific examples to qualitatively illustrate the 
subjects’ experience.  
Participants will be specifically asked about the subject’s functional abilities during and 
between migraine attacks after the start of the study; ie, perceptions of migraine, 
associated symptoms, and symptom impact/burden and interference on the subject’s 
life; perceptions of meaningful changes in experience of migraine; and experience with 
treatment administration. 
After open-ended questions, if participants do not mention concepts associated with the 
domains of the COA instrument in the clinical trial, the interviewer will specifically probe 
about those concepts.  The interviewers will also explore what aspects of improvement 
or worsening of the subject’s migraine (eg, frequency, severity, and duration) drove the 
changes, as well as the meaningfulness of change/no change reported by the subject. 
8.5.6 
Variables  
8.5.6.1 
Substudy Outcome Variable(s)  
Qualitative data on changes resulting from treatment received in the open-label 
treatment period will be collected via telephone interview.  Concepts that emerge from 
the qualitative interviews in relation to migraine impact, treatment efficacy, and migraine 


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experience will be the outcome.  Data will be analyzed to achieve the study objectives, 
using qualitative data analysis software (ie, ATLAS.ti). 
8.5.6.2 
Exposure Variable(s)  
Subjects will be started on the 70 mg dose of erenumab with provider discretion for dose 
optimization.  Dose optimization will allow patients to remain on 70 mg, increase the 
dose from 70 to 140 mg and if needed decrease the dose back down from 140 to 70 mg.  
After week 12, all subjects are highly recommended to remain on the week 12 erenumab 
dose for the rest of the study. Dose changes are permitted at the investigator’s 
discretion, but are not recommended unless medically necessary. 
8.5.7 
Substudy Data Analysis 
Audio recordings from the interviews will be transcribed for qualitative analyses.  Evidera 
will develop a separate data analysis plan that will detail how the qualitative data will be 
analyzed.  The analyses of interview data will help to illustrate subjects’ perceptions of 
meaningful change or difference, migraine functional impacts, and treatment efficacy or 
benefit.  Subjects will be grouped by migraine type, and other exploratory subgroups 
may be determined based on the characteristics of the final sample.  The qualitative 
report will discuss perceived treatment benefit and changes, if any, in relation to 
entry-interview discussion of the functional impacts of migraine.  
A qualitative content analysis approach will be used to analyze data collected from 
qualitative interviews using coding dictionaries and ATLAS.ti qualitative data analysis 
software.  The cleaned transcripts will be entered into ATLAS.ti qualitative analysis 
software version 7.0 or higher (Friese and Ringmayr, 2013).  Qualitative data coded in 
ATLAS.ti can be systematically organized into analysis outputs.  ATLAS.ti software is 
designed to facilitate the storage, coding, and retrieval of qualitative data.   
Coding will be an iterative process that marks the beginning of the qualitative analysis 
process.  Concept codes will be used to capture symptoms or impacts of the disease 
most important and relevant to participants.  Qualitative data will be coded according to 
the coding dictionary as outlined in the analysis plan.  The initial coding dictionary will be 
based on the structure of the main themes and content of the discussion guide to allow 
the text data to be coded with key concepts codes.  The coding dictionary will be 
iteratively updated with emerging themes and concepts from discussions.   
Evidera proposes to conduct longitudinal qualitative research analyses (Calman et al, 
2013; Saldana, 2003), which is distinguished from a traditional qualitative approach by 


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the fact that the key focus of analysis is on how and why the subject experiences/ 
perceptions change over time.  This innovative approach will be used to characterize 
changes in subjects’ perceptions and experiences over time, particularly in concepts the 
subjects perceive as most important.  
A list of each key concept identified at analysis of entry interviews will be provided to 
interviewers ahead of the follow-up interviews, so that these may be probed at the 
follow-up interviews.  For each concept, a category will be assigned to show changes in 
concepts that occurred between the 2 time points (newly emerged, not changed/stable, 
improved, worsened, not experienced anymore, and missing) in the concept tracker.  
Each of the concepts probed during the follow-up interviews will be categorized and 
compared to the entry interview.  An analysis will then be conducted on the data from 
groups of participants to document the changes observed over time.  
All analysis and reporting will be conducted by Evidera staff with experience in 
qualitative research.   
Subject characteristics collected in the clinical trial will be summarized for describing the 
sample.  Descriptive statistics (eg, n, mean, SD, and/or frequency) will be used to 
characterize the sample in terms of questionnaire data, sociodemographic, and clinical 
characteristics. 
The results of this sub-study will be reported separately from the main study. 
8.5.8 
Collection of Safety Information and Product Complaints  
There will be no substudy-specific safety database for collection, recording, and 
reporting of adverse events reported during the conduct of the substudy.  All safety data 
collection, recording, and reporting will be performed through the parent study and will 
follow the detailed procedures outlined in Study Protocol 20190389.  Adverse events, 
serious adverse events, or product complaints reported during the conduct of an 
interview will be reported to Amgen and to investigational sites within 1 business day of 
awareness. 
8.5.8.1 
Definition of Safety Events  
Refer to Section 11.4 for definition of safety events. 
8.5.8.2 
Safety Reporting Requirements  
The clinical site investigator is responsible for ensuring that safety events (adverse 
events, product complaints, and other safety findings) are reported in accordance with 
Amgen’s Study 20190389 protocol.  Evidera will report any adverse events to the clinical 


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site and Amgen within 1 business day of awareness; the site investigator will be 
responsible for reconciling the reporting to Amgen. 
Safety events must be submitted as individual case safety reports to Amgen via the 
applicable Amgen Safety Reporting Form (paper or electronic form) which will be the 
responsibility of the subject’s clinic site in accordance with the Study 20190389 protocol. 
9. 
Statistical Considerations 
9.1 
Statistical Hypotheses 
The study is descriptive in nature without a comparator arm, and as such no formal 
statistical hypothesis is defined. 
9.2 
Sample Size Determination 
The total sample size of approximately 322 subjects (effective sample size of 
289 assuming 10% dropout at week 24) is driven by the precision of the proportion 
estimates for the binary secondary endpoints, which targets a half-width of 95% 
confidence intervals (CIs) around 5%. The half-width of the 95% CI will be the widest 
when the estimated percentage is 50% given a fixed sample size and will become 
narrower if the percentage moves further away from 50% (see Table 9-1).   
Table 9-1.  Half-width of 95% CI for Various Estimated Percentages With Effective 
Sample Size of 289 Subjects  
Percentage  
estimate 
Half-width of 95% CI  
with effective sample 
size = 289 
50% 
5.8% 
60% 
5.6% 
70% 
5.3% 
80% 
4.6% 
 
 
 


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9.3 
Populations for Analysis 
The following populations are defined: 
Population 
Description 
Full Analysis Set  
The full analysis set (FAS) consists of all subjects enrolled 
in the study. Analysis of disposition, demographic and 
baseline characteristics, and important protocol deviations 
will utilize the FAS. 
Efficacy Analysis Set 
The respective efficacy analysis set consists of a subset of 
subjects from FAS who receive at least 1 dose of 
investigational product and have a baseline value and at 
least 1 post baseline value for the endpoint of interest. 
Analysis of the primary and secondary efficacy endpoints 
(except for the global impression Patient Reported 
Outcomes [PRO] endpoints) will utilize the respective 
efficacy analysis set. 
Global Impression PRO 
Analysis Set 
The global impression PRO analysis set consists of a 
subset of subjects from FAS who receive at least 1 dose of 
investigational product and have at least 1 post baseline 
value for the global impression PRO endpoints of interest. 
Analysis of each of the 3 global impression PRO endpoints 
will utilize this analysis set. 
Safety Analysis Set 
The safety analysis set (SAS) will consist of a subset of 
subjects from FAS who received at least 1 dose of 
investigational product. Analysis of safety endpoints and 
summary of investigational product administration will 
utilize the safety analysis set. 
 
9.3.1 
Covariates 
All model-adjusted analyses of primary and secondary efficacy endpoints will include the 
corresponding baseline value for the endpoint being analyzed, if applicable, and 
baseline MMD. 
9.3.2 
Subgroups 
The primary and secondary endpoints will be analyzed in the following subgroups: 
 
Whether remained on standard of care migraine preventive treatment throughout the 
study (yes vs no) 
 
Migraine type (EM vs CM) based on eDiary collection during baseline 
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 final analysis. 


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9.4 
Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock.  Below 
is a summary of the timing and methods for the planned statistical analyses. 
9.4.1 
Planned Analyses 
9.4.1.1 
Interim Analysis and Early Stopping Guidelines 
Not applicable. 
9.4.1.2 
Primary Analysis 
Not applicable. 
9.4.1.3 
Final Analysis 
The final analysis will be conducted when all enrolled subjects have completed the 
week 24/EOS visit and the data have been entered, cleaned, and locked. 
9.4.2 
Methods of Analyses 
9.4.2.1 
General Considerations 
Summary statistics will be computed at each timepoint of interest.  For continuous 
endpoints, the following descriptive statistics will be computed: number of observations, 
means, standard deviations, standard errors, medians, first and third quartiles, 
minimums and maximums.  For categorical endpoints, the summaries will contain the 
number and percentage of subjects in each category. 
Due to lack of a control arm, all analyses should be considered as descriptive in nature.  
Data on any endpoints collected after treatment discontinuation due to lack of efficacy or 
adverse event will be defined based on the worst observed value (for continuous 
endpoints) or non-response (for binary endpoints) using a composite strategy.  Data 
collected after treatment discontinuation due to other reasons will be censored based on 
a hypothetical strategy and not be used in efficacy analyses as described in 
Section 9.4.2.2. 
 
 


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9.4.2.2 
Efficacy Analyses 
 
Endpoint/ 
Estimand 
Statistical Analysis Methods 
Primary 
In the event of IP discontinuation due to lack of efficacy or adverse 
event, the TSQM overall satisfaction scale score after treatment 
discontinuation will be defined as the worst postbaseline value 
observed up to IP discontinuation (inclusive).  Any TSQM data 
collected after treatment discontinuation due to other reasons will be 
censored and not included in the analysis.  
The primary endpoint will be analyzed using a repeated measures 
mixed effects model, including baseline TSQM overall satisfaction 
scale score, visit, the prevailing erenumab dose from week 12 
onwards, and baseline MMD based on observed data.  The mean 
change from baseline in TSQM overall satisfaction scale score at 
week 24 will be estimated from the least-squares mean (LSM) of the 
mixed effects model, and the corresponding 95% CI will be provided.  
The nominal p-value will be reported by comparing the mean change 
from baseline in TSQM overall satisfaction scale score at week 24 to 
zero with a two-sided 5% significance level. 
Secondary 
In the event of IP discontinuation due to lack of efficacy or adverse 
event, the binary secondary endpoint after IP discontinuation will be 
classified as not achieving overall satisfaction or global impression on 
improvement; and the continuous MFIQ domain scores after treatment 
discontinuation will be defined as the worst postbaseline value 
observed before treatment discontinuation.  Data collected after IP 
discontinuation due to other reasons will be censored and not included 
in the analysis.   
A generalized linear mixed effects model with the appropriate link 
function will be used to analyze each secondary endpoint based on 
observed data.  The model will include the corresponding baseline 
value for the endpoint being analyzed (except for the global 
impression endpoints), visit, the prevailing erenumab dose from week 
12 onwards, and baseline MMD.   
For binary secondary endpoints, logit link function will be used, and 
the proportions and the corresponding 95% CI at week 24 will be 
estimated from the LSM (with inverse link function) of the mixed 
effects model.  
For the continuous MFIQ domain score endpoints, identity link function 
will be used, and mean change from baseline in each domain score at 
week 24 with the corresponding 95% CI will be estimated from the 
LSM of the mixed effects model, and p-values comparing with zero at 
a 2-sided 5% significance level will be reported. 
Exploratory 
Will be described in the statistical analysis plan (SAP) finalized before 
database lock 
 


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9.4.2.3 
Safety Analyses 
All safety analyses will be performed based on all subjects in the Safety Analysis Set, 
both overall and separately by migraine prevention therapy standard of care status 
(continuation vs discontinuation). 
9.4.2.3.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) will be used to code all 
adverse events. 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  Tables of fatal adverse events, serious adverse events, 
adverse events leading to discontinuation from investigational product and 
treatment-emergent adverse events of interest will also be provided.  Subject incidence 
of device-related events, if applicable, will be tabulated by system organ class and 
preferred term. 
9.4.2.3.2 
Exposure to Investigational Product 
The number and percentage of subjects with dose change, reason for dose change and 
duration of exposure to investigational product in days will be summarized over time. 
9.4.2.3.3 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving migraine preventive medications will be 
summarized by medication category.  Number and proportion of subjects who 
discontinue standard of care migraine prevention therapy will also be 
summarized.   
 
 


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10. 
References 
Antonaci F, Dumitrache C, De Cillis I, et al. A review of current European treatment 
guidelines for migraine. J Headache Pain. 2010;11(1):13-19.  
Calman L, Brunton L, Molassiotis A. Developing longitudinal qualitative designs: lessons 
learned and recommendations for health services research. BMC Med Res Methodol. 
2013;13:14.  
Dodick DW, Ashina M, Brandes JL, et al. ARISE: A Phase 3 randomized trial of 
erenumab for episodic migraine.  Cephalalgia.  2018;38(6):1026-1037.  
Erenumab Investigator’s Brochure. Thousand Oaks, CA.  Amgen Inc.  
Evers S, Afra J, Frese A, et al. EFNS guideline on the drug treatment of migraine - report 
of an EFNS task force.  Eur J Neurol.  2006;13(6):560-572.  
Food and Drug Administration (FDA).  Plan for Issuance of Patient-Focused Drug 
Development Guidance. 2017. Available at: 
https://www.fda.gov/media/105979/download.  
Friese S, Ringmayr T. ATLAS.ti 7 User Guide and Reference.  Berlin:  ATLAS.ti 
Scientific Software Development GmBH; 2013.  
Goadsby PJ & Evers S.  International Classification of Headache Disorders – 
ICHD-4 alpha.  Cephalalgia.  2020;40(9):887-888.  
Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S.  
Pathophysiology of Migraine:  A Disorder of Sensory Processing.  Physiol Rev.  
2017;97(2):553-622.  
Goadsby PJ, Lipton RB, Ferrari MD.  Migraine—current understanding and treatment.  
N Engl J Med.  2002;346(4):257-270.  
Headache Classification Committee of the International Headache Society (IHS).  The 
International Classification of Headache Disorders, 3rd ed (ICHD-3).  Cephalalgia.  
2018;38(1):1-211.  
Headache: The Journal of Head and Face Pain, 2018.  The American Headache Society 
Position Statement On Integrating New Migraine Treatments Into Clinical Practice. 
Katsarava Z, Buse DC, Manack AN, Lipton RB.  Defining the differences between 
episodic migraine and chronic migraine.  Curr Pain Headache Rep.  2012;16:86-92.  
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.  
Robbins MS, Lipton RB. The epidemiology of primary headache disorders. Semin 
Neurol. 2010;30(2):107-119.  
Saldana J. Longitudinal Qualitative Research: Analyzing Change Through Time. 
AltaMira Press, US; 2003.  
Stovner LJ, Andree C. Prevalence of headache in Europe: a review for the Eurolight 
project. J Headache Pain. 2010;11(4):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.  


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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.  
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(6):425-434. 
 
 


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11. 
Appendices 
 
 


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11.1 
Appendix 1.  List of Abbreviations 
 
Abbreviation 
Explanation 
ACE 
angiotensin-converting enzyme 
AI 
autoinjector 
CBT 
cognitive behavioral therapy 
CFR 
U.S. Code of Federal Regulations 
CGRP 
calcitonin gene related peptide 
COA 
clinical outcomes assessment 
CM 
chronic migraine 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DILI 
drug induced liver injury 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
eCRF 
Electronic Case Report Form 
eDiary 
electronic diary 
EDC 
electronic data capture 
EM 
episodic migraine 
EOS 
end of study 
ETS 
Expectation of Treatment Scale 
FAS 
full analysis set 
FSH 
follicle stimulating hormone 
GAD 
general anxiety disorder 
GAD-7 
General Anxiety Disorder scale 
GCP 
Good Clinical Practice 
HCP 
healthcare practitioner 
HRT 
hormone replacement therapy 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICHD 
International Headache Classification Disorders 
IEC 
Independent Ethics Committee 
IHS 
International Headache Society 
IP 
investigational product 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
LSM 
least-squares mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFIQ 
Migraine Functional Impact Questionnaire 


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mGI-I 
Migraine Global Impression Item 
MIBS-4 
Migraine Interictal Burden Scale 
MMD 
monthly migraine days 
MSSS 
Migraine Symptom Severity Scale 
NCT 
National Clinical Trials 
QTL 
quality tolerance limit parameter 
PHQ-9 
Patient Health Questionnaire 
PRO 
patient reported outcome 
Q4W 
every 4 weeks 
QM 
once monthly 
SAP 
statistical analysis plan 
SAS 
safety analysis set 
SC 
subcutaneous 
TSQM-14 
Treatment Satisfaction Questionnaire for Medication 
US 
United States 
 
 
 


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11.2 
Appendix 2.  Clinical Laboratory Tests 
A urine pregnancy test will be performed locally for women of childbearing potential as 
specified in the Schedule of Activities (Table 1-1).  
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Sections 5.1 to 5.2 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
 
 


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


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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 
as patient advocacy groups. 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 participant population. 
The investigator or his/her delegated representative will explain to the participant (ie, 
study subject or key family member) the aims, methods, anticipated benefits, and 
potential hazards of the study and optional sub-study before any protocol-specific 
screening procedures or any investigational product(s) is/are administered, and answer 
all questions regarding the study and substudy.   
Participants must be informed that their participation is voluntary.  Participants will then 
be required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act requirements, where applicable, and the IRB/IEC or study site.  
The subject’s medical record must include a statement that written informed consent 
was obtained before the subject was enrolled in the study and the date the written 
consent was obtained.  The authorized person obtaining the informed consent must also 
sign the informed consent form. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study unless it is a local requirement.  The 
investigator shall then inform the primary care physician.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 


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The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject and by the person who conducted the informed consent discussion.  Subject 
withdrawal of consent or discontinuation from study treatment and/or procedures must 
also be documented in the subject’s medical records; refer to Section 7. 
Subjects must be re-consented to the most current version of the informed consent 
form(s) during their participation in the study.  
The original signed informed consent form is to be retained in accordance with 
institutional policy, and a copy of the informed consent form(s) must be provided to the 
subject or the subject’s legally authorized representative.  
Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
The 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 electronic Case Report Form (eCRF) 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. 
Subject data should be kept in a secure location.  Access to subject data will be limited 
to authorized individuals, 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 
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.   


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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. 
Amgen complies with all relevant and applicable laws and regulations that protect 
personal information in order to ensure subject confidentiality and privacy.  Subjects are 
designated by a unique subject identification number in the Sponsor’s systems.  The 
Sponsor uses access-controlled systems to house, review, and analyze subject data.  
These systems are backed up regularly to minimize the risk of loss of subject data; 
procedures are also defined for data recovery in the event of data loss.  The Sponsor 
has standard operating procedures in place that restrict access to subject data to those 
who require access to this data based on their role and have also completed the 
required training.  These procedures also outline the process for revoking access to 
such data when it is no longer needed.  In the event of a security breach, the Sponsor 
has procedures in place for notification of privacy incidents and to address these 
incidents, via its Business Conduct Hotline. 
Publication Policy 
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 
(eCRF) 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 eCRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
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 eCRF 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 eCRFs, 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, eCRFs 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. 
Quality tolerance limit parameters (QTLs) will be pre-defined in the QTL definitions table 
to identify possible systematic issues that can impact participant safety and/or reliability 
of the study results.  These pre-defined parameters will be monitored during the study.  
Important deviations from the QTL threshold limits for these parameters and remedial 
actions taken will be summarized in the clinical study report. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
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 eCRFs will be included on the Amgen Delegation of Authority Form. 
Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
Source documents are original documents, data, and records from which the subject’s 
eCRF 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) system (if used, such as subject ID and 
randomization number) and eCRF entries if the eCRF 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 or certain demographic information). 


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Data entered in the eCRF 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 eCRFs, informed consent forms, and subject 
identification list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
 
Investigational product-related correspondence including Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), and Final Investigational Product Reconciliation Statement, 
as applicable 
 
Non-investigational product(s), and/or medical device(s) or combination product(s) 
documentation, as applicable 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Study and Site Closure 
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP.  
Both Amgen and the Investigator reserve the right to terminate the Investigator’s 
participation in the study according to the Clinical Trial Agreement.  The investigator is to 
notify the IRB/IEC in writing of the study’s completion or early termination and send a 
copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by a separate protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
 


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


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


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


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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 6.1.3 for the list of Amgen medical devices). 
Adverse Device Effect Definition 
An adverse device effect is any adverse event related to the use of a combination 
product or medical device.  Adverse device effects include, but are not limited to, 
adverse events resulting from insufficient or inadequate instructions for use, adverse 
events resulting from any malfunction of the device, or adverse events resulting from 
use error or from intentional misuse of the device. 
A combination product is a product composed of any combination of a drug, a 
device, and a biological product.  Each drug, device, and biological product 
included in a combination product is referred to as a “constituent part” of the 
combination product.  
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 electronic case report form (eCRF). 
 
The investigator must assign the following mandatory adverse event attributes: 
 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms); 
 
Dates of onset and resolution (if resolved); 


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 
Did the event start prior to first dose of investigational product, other protocol-
required therapies; 
 
Assessment of seriousness; 
 
Severity (or toxicity defined below); 
 
Assessment of relatedness to investigational product, devices, and/or study-
mandated activity and/or procedures; 
 
Action taken; and 
 
Outcome of event. 
 
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 eCRF. 
 
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to the sponsor in lieu of completion of the Event eCRF page. 
 
If specifically requested, the investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the 
medical records.  In this case, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records before 
submission to Amgen. 
 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious 
adverse event. 
Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The investigator will make an assessment of severity for each adverse event and 
serious adverse event reported during the study.  The assessment of severity will be 
based on: 
The Common Terminology Criteria for Adverse Events, version 4.03, which is 
available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between investigational 
product, device(s), and/or study-mandated activity and/or procedure(s) and each 
occurrence of each adverse event/serious adverse event. 
 
Relatedness means that there are facts or reasons to support a relationship 
between investigational product and the event. 
 
The investigator will use clinical judgment to determine the relationship. 


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 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
 
The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 
 
For each adverse event/serious adverse event, the investigator must document in 
the medical notes that he/she has reviewed the adverse event/serious adverse 
event and has provided an assessment of causality. 
 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report.  However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the serious adverse event data. 
 
The investigator may change his/her opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated 
causality assessment. 
 
The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of Adverse Event and Serious Adverse Event 
 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 
Amgen to elucidate the nature and/or causality of the adverse event or serious 
adverse event as fully as possible.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 
care professionals. 
 
If a subject is permanently withdrawn from protocol-required therapies because of 
a serious adverse event, this information must be submitted to Amgen. 
 
If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Amgen with a copy of any post-mortem 
findings including histopathology. 
 
New or updated information will be recorded in the originally completed Event 
eCRF. 
 
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. 
 
If the EDC system is unavailable for more than 24 hours, then the site will report 
the information to Amgen using a paper-based Serious Adverse Event 
Contingency Report Form (see Figure 11-1) within 24 hours of the investigator’s 
awareness of the event. 


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 
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 system has been taken off-line, then the site can report this information on a 
paper Serious Adverse Event Contingency Report Form (see Figure 11-1). 
 
Once the study has ended, serious adverse event(s) suspected to be related 
to investigational product will be reported to Amgen if the investigator 
becomes aware of a serious adverse event.  The investigator should use the 
paper-based Serious Adverse Event Contingency Report Form to report the 
event.  
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 eCRF 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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Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Report Form 
(paper-based form) 
 
 
 


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11.5 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy 
and Lactation Information 
Study-specific contraception requirements for female subjects of childbearing potential 
are outlined in Section 5.2. 
Female subjects of childbearing potential must receive pregnancy prevention counseling 
and be advised of the risk to the fetus if they become pregnant during treatment and for 
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: 
o documented hysterectomy; 
o documented bilateral salpingectomy; or 
o documented bilateral oophorectomy. 
Note: Site personnel documentation from the following sources is acceptable:  
1) review of subject’s medical records; 2) subject’s medical examination; or 
3) subject’s medical history interview. 
 
premenarchal female 
 
postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormone replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
o Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
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 
 
Intrauterine hormonal-releasing system 
 
Bilateral tubal ligation/occlusion 


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 
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, postovulation 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 protocol-required therapies. 
 
Information will be recorded on the Pregnancy Notification Form (see Figure 11-2).  
The form must be submitted to Amgen Global Patient Safety within 24 hours of the 
site’s awareness of a subject’s pregnancy.  (Note: Sites are not required to provide 
any information on the Pregnancy Notification Form that violates the country or 
regions local privacy laws). 
 
After obtaining the female subject’s signed consent 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 IP through 16 weeks after the last dose of the study 
drug.  This information will be forwarded to Amgen Global Patient Safety.  Generally, 
infant follow-up will be conducted up to 12 months after the birth of the child (if 
applicable). 
 
Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.  
 
While pregnancy itself is not considered to be an adverse event or serious adverse 
event, any pregnancy complication or report of a congenital anomaly or 
developmental delay, fetal death, or suspected adverse reactions in the neonate will 
be reported as an adverse event or serious adverse event.  Note that an elective 
termination with no information on a fetal congenital malformation or maternal 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389 
Date:  18 March 2022 
Page 88 of 91 
CONFIDENTIAL  
 
 
complication is generally not considered an adverse event, but still must be reported 
to Amgen as a pregnancy exposure case. 
 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a serious adverse event. 
 
Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Section 11.4.  While the 
investigator is not obligated to actively seek this information in former study subjects, 
he or she may learn of a serious adverse event through spontaneous reporting.  
 
Any female subject who becomes pregnant while participating will discontinue study 
treatment (see Section 7.1 for details). 
Male Subjects With Partners Who Become Pregnant 
 
In the event a male subject fathers a child during treatment, and for an additional 
16 weeks after discontinuing protocol-required therapies, the information will be 
recorded on the Pregnancy Notification Form.  The form (see Figure 11-2) 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 Form that violates the country or regions local privacy laws). 
 
The investigator will attempt to obtain a signed consent 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 consent 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 study 
drug. 
 
Information will be recorded on the Lactation Notification Form (see below) and 
submitted to Amgen Global Patient Safety within 24 hours of the investigator’s 
awareness of the event. 
 
Study treatment will be discontinued if female subject breastfeeds during the study 
as described in exclusion criterion 218. 
 
With the female subjects signed consent for release of mother and infant health 
information, the investigator will collect mother and infant health information and 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389 
Date:  18 March 2022 
Page 89 of 91 
CONFIDENTIAL  
 
 
complete the lactation questionnaire on any female subject who breastfeeds while 
taking protocol-required therapies through 16 weeks after discontinuing IP. 
 
 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389 
Date:  18 March 2022 
Page 90 of 91 
CONFIDENTIAL  
 
 
Figure 11-2.  Pregnancy and Lactation Notification Forms 
 
 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389 
Date:  18 March 2022 
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CONFIDENTIAL  
 
 
 
 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389 
Date:  18 March 2022 
Page 1 of 17 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 2 
Protocol Title:  Phase 4, Open-label Study to Evaluate Treatment Satisfaction With 
Erenumab in Patients With Migraine 
 
Amgen Protocol Number 20190389 
 
Amendment Date: 
18 March 2022 
 
Rationale: 
This protocol is being amended to remove restrictions to inclusion criteria and to update 
the list of excluded medications in order to encourage study enrolment.  
Amendments to the protocol include:  
 
Removal of the prior anti-calcitonin gene related peptide exposure exclusion 
 
Removal of the restriction of the use of concomitant botulinum toxin 
 
Clarification of the definition of episodic migraine in the protocol 
 
Clarification of the excluded medications in the protocol 
 
Update to the safety reporting language in the protocol based on the protocol 
template.  
 
Update of administrative details, correction of formatting and typographical errors 
throughout the document 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389 
Date:  18 December 2020 
Page 1 of 22 
Amgen Proprietary - Confidential 
Amendment 1 
Protocol Title:  Phase 4, Open-label Study to Evaluate Treatment Satisfaction With 
Erenumab in Patients With Migraine 
 
Amgen Protocol Number 20190389 
 
Amendment Date: 
18 December 2020 
 
Rationale: 
The protocol is being amended to: 
 
Remove Schedule of Activities for clinicians as it no longer applies 
 
Clarify scale of measurement for migraine Global Impression Item (mGI-I) 
 
Remove references to clinician consent as consent is not required 
 
Clarify consent requirements for subjects and key family members 
 
Clarify on-study exclusionary procedure requirements 
 
Clarify how medications will be recorded 
 
Clarify local lab requirements 
 
Correct grammatical and typographical errors throughout 
 
 
 


Product:  Erenumab-aooe (AMG 334) 
Protocol Number:  20190389 
Date:  20 November 2020 
Page 1 of 1 
Amgen Proprietary - Confidential 
Superseding Original Amendment 
Protocol Title:  Phase 4, Open-label Study to Evaluate Treatment Satisfaction With 
Erenumab in Patients With Migraine 
 
Amgen Protocol Number 20190389 
 
Amendment Date: 
20 November 2020 
 
Rationale: 
Clarify the intent of exclusion criterion 204 
 
Description of Changes  
Section 5.2, Exclusion Criterion 204 
Replace:   
Malignancy (except non-melanoma skin cancers, cervical or breast ductal carcinoma in 
situ within the last 5 years) 
With:   
Malignancy (except non-melanoma skin cancers, cervical or breast ductal carcinoma in 
situ) within the last 5 years) 
 
 
 

SAP_001.pdf: 
Product:  Erenumab (AMG 334) 
Protocol Number:  20190389 
Date:  16 October 2023 
Page 1 of 48 
CONFIDENTIAL  
 
 
Internal Use Only General and Administrative 
Statistical Analysis Plan 
Protocol Title: 
Phase 4, Open-label Study to Evaluate Treatment 
Satisfaction With Erenumab in Patients With 
Migraine 
Short Protocol Title: 
Erenumab Treatment Satisfaction Study 
Protocol Number: 
20190389 
NCT Number: 
NCT04825678 
Authors: 
 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
SAP Date: 
 
 
 
Document Version 
Date 
Original (v1.0) 
26 May 2021 
Amendment 1 (v2.0) 
16 October 2023 
 
 
 
 


Product:  Erenumab (AMG 334) 
Protocol Number:  20190389 
Date:  16 October 2023 
Page 2 of 48 
CONFIDENTIAL  
 
 
Internal Use Only General and Administrative 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
26MAY2021 
Not applicable 
Amendment 1 (v2.0) 
16OCT2023 
 
Section 1 protocol version date 
updated to newest one 
 
Section 3.2 updated to add 
description and table 3-2 for 240 
enrolled subject due to study early 
termination  
 
Section 4.2 updated to including 
screening period 
 
Section 5.1 updated to add 
treatment-related TEAE definition 
 
Section 5.3 updated to add 
enrollment date as Day 1 if no IP 
received 
 
Section 5.1.1 updated the 
definition of migraine type to 
account for headache days and 
migraine days collected during 
screening period 
 
Section 5.4.2 updated to >= 156 
days for week 24 windows 
 
Section 6.3.1 deleted baseline 
value and at least 1 post baseline 
value 
 
Section 6.3.2 deleted Global 
Impression Pro Analysis set  
 
Section 7 updated to all the 240 
enrolled subjects due to early 
termination 
 
Section 9.2 deleted summary of IP 
dose adjustment due to medical 
necessity after week 12 as only 
one subject changed dose after 
week 12 visit; deleted subject 
disposition summary due to 
COVID-19 
 
Section 9.4 updated to 
o Prior migraine preventive 
medication by categories 
o Reasons for stopping of 
prior migraine preventive 
medication by categories 
o General medical history 


Product:  Erenumab (AMG 334) 
Protocol Number:  20190389 
Date:  16 October 2023 
Page 3 of 48 
CONFIDENTIAL  
 
 
Internal Use Only General and Administrative 
o Type of SOC for 
dissatisfaction with SOC 
o Targeted neurological 
medical history 
 
Section 9.5.1 updated to delete 
the request to report treatment 
difference with 95% CI and P-
value for primary endpoint; 
subgroup includes screening 
period 
 
Section 9.5 updated to use 
efficacy analysis set for secondary 
endpoint mGI-I; added summary 
of TSQM item 14 at w12, w16 and 
w20 
 
Section 9.6.1 updated to newest 
MeDRA version 26.0 
 
Section 9.6.1 new EOIs that 
summaries across other studies 
under A334 are added for s389 
 
Section 9.6.2 is deleted due to no 
lab need to be analyzed 
 
Section 9.6.2 updated to 
summarize number, percentage 
and reason for both doses 
adjusted and none or partial dose 
 
Section 9.6.3 updated to be the 
same as protocol language 
 
Section 9.7 updated to NA as 
COID-19 control measure protocol 
deviations not collected 
 
Section 13 updated to data 
collected for the qualitative 
interviewed-based sub-study is 
not covered by this analysis plan 
 
Section 14 updated to add “Not 
applicable” 
 
 
 
 
 


Product:  Erenumab (AMG 334) 
Protocol Number:  20190389 
Date:  16 October 2023 
Page 4 of 48 
CONFIDENTIAL  
 
 
Internal Use Only General and Administrative 
Table of Contents 
1. 
Introduction ............................................................................................................. 8 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 8 
2.1 
Objectives and Endpoints/Estimands .......................................................... 8 
2.2 
Hypotheses and/or Estimations ................................................................. 15 
3. 
Study Overview .................................................................................................... 16 
3.1 
Study Design ............................................................................................. 16 
3.2 
Sample Size .............................................................................................. 18 
3.3 
Adaptive Design ........................................................................................ 18 
4. 
Covariates and Subgroups ................................................................................... 19 
4.1 
Planned Covariates ................................................................................... 19 
4.2 
Subgroups ................................................................................................. 19 
5. 
Definitions ............................................................................................................. 19 
5.1 
Definition of Terms Included in Study Endpoints ....................................... 19 
5.1.1 
Efficacy Endpoints Based on Monthly Collection ....................... 19 
5.1.2 
Efficacy Endpoints Based on Clinical Outcome 
Assessments ............................................................................. 22 
5.1.3 
Safety Analysis .......................................................................... 25 
5.2 
Study Dates .............................................................................................. 25 
5.3 
Study Points of Reference ......................................................................... 26 
5.4 
Study Time Intervals ................................................................................. 27 
5.4.1 
Monthly Intervals for Efficacy Endpoints Derived From 
Daily Diary Collection ................................................................ 27 
5.4.2 
Analysis Visits for Endpoints Derived Based on 
Monthly Data Collection ............................................................ 27 
5.4.3 
Subject Disposition .................................................................... 29 
5.5 
Arithmetic Calculations .............................................................................. 30 
5.6 
Disease Characteristics ............................................................................. 30 
6. 
Analysis Sets ........................................................................................................ 31 
6.1 
Full Analysis Set........................................................................................ 31 
6.2 
Efficacy Analysis Set ................................................................................. 31 
6.3 
Safety Analysis Set ................................................................................... 31 
7. 
Planned Analyses ................................................................................................. 31 
7.1 
Final Analysis ............................................................................................ 31 
8. 
Data Screening and Acceptance ........................................................................... 31 
8.1 
General Principles ..................................................................................... 31 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 31 
8.3 
Handling of Missing and Incomplete Data ................................................. 32 
8.4 
Detection of Bias ....................................................................................... 33 


Product:  Erenumab (AMG 334) 
Protocol Number:  20190389 
Date:  16 October 2023 
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CONFIDENTIAL  
 
 
Internal Use Only General and Administrative 
8.5 
Outliers ..................................................................................................... 33 
8.6 
Distributional Characteristics ..................................................................... 34 
8.7 
Validation of Statistical Analyses ............................................................... 34 
9. 
Statistical Methods of Analysis.............................................................................. 34 
9.1 
General Considerations ............................................................................. 34 
9.2 
Subject Accountability ............................................................................... 35 
9.3 
Important Protocol Deviations ................................................................... 35 
9.4 
Demographic and Baseline Characteristics ............................................... 36 
9.5 
Efficacy Analyses ...................................................................................... 37 
9.5.1 
Analyses of Primary Efficacy Endpoint(s)/Estimand(s) .............. 43 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 44 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 45 
9.6 
Safety Analyses ........................................................................................ 45 
9.6.1 
Adverse Events ......................................................................... 45 
9.6.2        Enter Analyses Laboratory Test Results .................................... 46 
9.6.3 
Exposure to Investigational Product .......................................... 46 
9.6.4 
Exposure to Concomitant Medication ........................................ 46 
9.7 
Other Analyses ......................................................................................... 46 
10. 
Changes From Protocol-specified Analyses.......................................................... 46 
11. 
Literature Citations / References ........................................................................... 46 
12. 
Prioritization of Analyses....................................................................................... 46 
13. 
Data Not Covered by This Plan............................................................................. 47 
14. 
Appendices ........................................................................................................... 48 
 
 
List of Table 
Table 3-1.  Half-width of 95% CI for Various Estimated Percentages With Effective 
Sample Size of 289 Subjects….……………………………....………..…...18 
Table 3-2.  Half-width of 95% CI for Various Estimated Percentages With Effective 
Sample Size of 216 Subjects….……………………………....………….…18 
Table 5-1.  Definitions of Migraine Day, Headache Day, and Acute Migraine-specific 
Medication Day ……………….…………………………………....…………20 
Table 5-2.  Monthly Intervals for Efficacy Endpoints Derived From Daily Diary 
Data Collection ....................................................................................... 27 
Table 5-3.  MFIQ, MSSS, and MIBS-4 Analysis Visit Windows ...................................... 29 
Table 5-4.  mGI-I Analysis Visit Windows ...................................................................... 29 
Table 5-5.  GAD-7 and PHQ-9 Analysis Visit Windows .................................................. 29 


Product:  Erenumab (AMG 334) 
Protocol Number:  20190389 
Date:  16 October 2023 
Page 6 of 48 
CONFIDENTIAL  
 
 
Internal Use Only General and Administrative 
Table 5-6.  TSQM Version 1.4 Analysis Visit Windows .................................................. 29 
Table 8-1.  Handling of Missing and Incomplete eDiary Data……………….…...……..…32 
Table 8-2.  Imputation for Incomplete Start Date of an Adverse Event or Concomitant 
Medication …………………..….……………………………....………..…...33 
Table 9-1.  Primary Efficacy Endpoint and analysis Summary Table ............................. 37 
Table 9-2.  Secondary Efficacy Endpoint Summary Table ............................................. 38 
Table 9-3.  Exploratory Efficacy Endpoint Summary Table ............................................ 40 
 
 List of Figures 
Figure 1 1.  Study Schema…………………………………………………………………….17 
 


Product:  Erenumab (AMG 334) 
Protocol Number:  20190389 
Date:  16 October 2023 
Page 7 of 48 
CONFIDENTIAL  
 
 
Internal Use Only General and Administrative 
List of Abbreviations 
 
Abbreviation 
Explanation 
COA 
Clinical Outcomes Assessment 
COVID-19 
Coronavirus Disease 2019 
CM 
Chronic Migraine 
CTCAE 
Common Terminology Criteria for Adverse Events 
eCRF 
electronic Case Report Form 
eDiary 
electronic Diary 
EM 
Episodic Migraine 
EOS 
End of Study 
FAS 
Full Analysis Set 
GAD-7 
General Anxiety Disorder scale 
IP 
Investigational Product 
LSM 
Least-squares Mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFIQ 
Migraine Functional Impact Questionnaire 
mGI-I 
Migraine Global Impression Item 
MIBS-4 
Migraine Interictal Burden Scale 
MMD 
Monthly Migraine Days 
MSSS 
Migraine Symptom Severity Scale 
PHQ-9 
Patient Health Questionnaire 
Q4W 
Every 4 Weeks 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
TSQM-14 
Treatment Satisfaction Questionnaire for Medication 
 


Product:  Erenumab (AMG 334) 
Protocol Number:  20190389 
Date:  16 October 2023 
Page 8 of 48 
CONFIDENTIAL  
 
 
Internal Use Only General and Administrative 
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 2 for study 
20190389, Erenumab (AMG 334) dated 18 March 2022. The scope of this plan includes 
the final 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/Estimands 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the effect of 
erenumab on medication-specific 
treatment satisfaction 
 
Change from baseline in the 
Treatment Satisfaction 
Questionnaire for Medication 
(TSQM) overall satisfaction scale 
score at week 24, as measured by 
items 12 to 14 of the TSQM 
version 1.4  
Primary Estimand 
The estimand for the primary efficacy objective consists of: 
 The target population, which includes subjects with Episodic Migraine (EM) or 
Chronic Migraine (CM) currently on 1 standard of care migraine prevention 
therapy 
 The endpoint, which is the change from baseline in TSQM overall satisfaction 
scale score at week 24, as measured by items 12 to 14 of the TSQM 
 There are 2 intercurrent events, discontinuation of investigational product (IP) 
due to lack of efficacy or adverse event, and discontinuation of IP due to other 
reasons.  The treatment effect of interest will be assessed for all subjects who 
receive least 1 dose of IP and have a baseline score and at least 1 post-
baseline score on the TSQM overall satisfaction scale.  A composite strategy 
will be used for subjects who discontinued IP due to lack of efficacy or adverse 
event with data after IP discontinuation, defined by the worst postbaseline 


Product:  Erenumab (AMG 334) 
Protocol Number:  20190389 
Date:  16 October 2023 
Page 9 of 48 
CONFIDENTIAL  
 
 
Internal Use Only General and Administrative 
value observed up to IP discontinuation (inclusive).  A hypothetical strategy will 
be used for those subjects who discontinued IP due to other reasons with data 
collected after IP discontinuation censored. 
 The treatment, which is erenumab 70 or 140 mg every 4 weeks 
 The summary measure, which is the mean change from baseline in TSQM 
overall satisfaction scale score at week 24, as measured by items 12 to 14 of 
the TSQM 
The primary estimand for the primary efficacy objective is the mean change from 
baseline in TSQM overall satisfaction scale score at week 24 in subjects with EM or 
CM who are currently on 1 standard of care migraine prevention therapy and who 
receive at least 1 dose of IP and have a baseline and at least 1 post-baseline TSQM 
overall satisfaction scale score, and a composite strategy will be used for subjects 
who discontinued IP due to lack of efficacy or adverse event with data after IP 
discontinuation defined by the worst postbaseline value observed up to IP 
discontinuation (inclusive), while a hypothetical strategy will be used for those subjects 
who discontinued IP due to other reasons with data collected after IP discontinuation 
censored. 
Secondary 
 
To assess the effect of erenumab 
on medication-specific treatment 
satisfaction 
 
Achievement of overall 
satisfaction at week 24 as defined 
by subject reporting of satisfied, 
very satisfied, or extremely 
satisfied on Item 14 of the TSQM 
version 1.4 
The estimand for the secondary efficacy objective on treatment satisfaction consists 
of: 
 
The target population, which includes subjects with EM or CM currently on 1 
standard of care migraine prevention therapy 
 
The endpoint, which is achievement of overall satisfaction at week 24 as 
defined by subject reporting of satisfied, very satisfied, or extremely satisfied 
on Item 14 of the TSQM 


Product:  Erenumab (AMG 334) 
Protocol Number:  20190389 
Date:  16 October 2023 
Page 10 of 48 
CONFIDENTIAL  
 
 
Internal Use Only General and Administrative 
 
There are 2 intercurrent events, discontinuation of IP due to lack of efficacy or 
adverse event, and discontinuation of IP due to other reasons.  The treatment 
effect of interest will be assessed for all subjects who receive at least 1 dose of 
IP and have a baseline value and at least 1 post-baseline value for Item 14 of 
the TSQM.  A composite strategy will be used for subjects who discontinued IP 
due to lack of efficacy or adverse event where they will be defined as not 
satisfied after IP discontinuation.  A hypothetical strategy will be used for those 
subjects who discontinued IP due to other reasons with data collected after IP 
discontinuation censored. 
 
The treatment, which is erenumab 70 or 140 mg every 4 weeks 
 
The summary measure, which is the proportion of subjects who achieves 
overall satisfaction at week 24 
The estimand for the secondary efficacy objective on treatment-related satisfaction is 
the proportion of subjects who achieves overall satisfaction at week 24 as defined by 
subject reporting of satisfied, very satisfied, or extremely satisfied on Item 14 of the 
TSQM version 1.4, in subjects with EM or CM who are currently on 1 standard of care 
migraine prevention therapy and who receive at least 1 dose of IP and have a 
baseline value and at least 1 post-baseline value for Item 14 of the TSQM.  A 
composite strategy will be used for subjects who discontinued IP due to lack of 
efficacy or adverse event where they will be defined as not satisfied after IP 
discontinuation, while a hypothetical strategy will be used for those subjects who 
discontinued IP due to other reasons with data collected after IP discontinuation 
censored. 
 
To assess the effect of erenumab 
on global impression of change in 
migraine (by subject, treating 
clinician, and key family member) 
 
Improvement in subject global 
impression at week 24, as defined 
by subject reporting of much 
improved or a little improved on 
the migraine Global Impression 
Item (mGI-I)  
 
Improvement in treating clinician’s 
global impression at Week 24, as 
defined by treating clinician’s 
reporting of much improved or a 


Product:  Erenumab (AMG 334) 
Protocol Number:  20190389 
Date:  16 October 2023 
Page 11 of 48 
CONFIDENTIAL  
 
 
Internal Use Only General and Administrative 
little improved on the mGI-I for 
each individual subject  
 
Improvement in key family 
member’s impression at week 24, 
as defined by key family member’s 
reporting of much improved or a 
little improved on the mGI-I for 
each individual subject 
The estimand for the secondary efficacy objectives on impression of change in 
migraine consists of: 
 The target population, which includes subjects with EM or CM currently on 1 
standard of care migraine prevention therapy 
 The endpoints, which include: 
 Improvement in subject global impression at week 24, as defined by 
subject reporting of much improved or a little improved on the mGI-I 
 Improvement in treating clinician’s global impression at week 24, as defined 
by the clinician’s reporting of much improved or a little improved on the 
mGI-I for each individual subject  
 Improvement in key family member’s global impression at week 24, as 
defined by family member’s reporting of much improved or a little improved 
on the mGI-I for each individual subject 
 There are 2 intercurrent events, discontinuation of IP due to lack of efficacy or 
adverse event, and discontinuation of IP due to other reasons.  The treatment 
effect of interest will be assessed for all subjects who receive at least 1 dose of 
IP and have at least 1 post-baseline value of each respective mGI-I item.  A 
composite strategy will be used for subjects who discontinued IP due to lack of 
efficacy or adverse event where they will be defined as not improved after IP 
discontinuation.  A hypothetical strategy will be used for those subjects who 
discontinued IP due to other reasons with data collected after IP 
discontinuation censored. 
 The treatment, which is erenumab 70 or 140 mg every 4 weeks 


Product:  Erenumab (AMG 334) 
Protocol Number:  20190389 
Date:  16 October 2023 
Page 12 of 48 
CONFIDENTIAL  
 
 
Internal Use Only General and Administrative 
 The summary measure, which is the proportion of subjects who achieves 
impression of improvement at week 24.   
The estimand for the secondary efficacy objective on impression of change in 
migraine is the proportion of subjects who achieves global impression of migraine 
improvement at week 24 as defined by subject, treating clinician, or family member 
reporting of much improved or a little improved on the mGI-I, in subjects with EM or 
CM who are currently on 1 standard of care migraine prevention therapy and who 
receive at least 1 dose of IP and have at least 1 post-baseline value of the respective 
mGI-I, and a composite strategy will be used for subjects who discontinued IP due to 
lack of efficacy or adverse event where they will be defined as not improved after IP 
discontinuation, while a hypothetical strategy will be used for those subjects who 
discontinued IP due to other reasons with data collected after IP discontinuation 
censored. 
 
To assess the effect of erenumab 
on subject functional impairment 
 
Change from baseline in physical 
function domain score at week 24, 
as measured by the Migraine 
Functional Impact Questionnaire 
(MFIQ) 
 
Change from baseline in usual 
activities domain score at week 24 
as measured by MFIQ 
 
Change from baseline in 
emotional function domain score 
at week 24 as measured by MFIQ 
 
Change from baseline in social 
function domain score at week 24 
as measured by MFIQ 
The estimand for the secondary efficacy objective on subject functional impairment 
consists of: 
 
The target population, which includes subjects with EM or CM currently on 1 
standard of care migraine prevention therapy 
 
The endpoints, which include: 
 
Change from baseline in MFIQ physical function domain score at week 24 


Product:  Erenumab (AMG 334) 
Protocol Number:  20190389 
Date:  16 October 2023 
Page 13 of 48 
CONFIDENTIAL  
 
 
Internal Use Only General and Administrative 
 
Change from baseline in MFIQ usual activities domain score at week 24 
 
Change from baseline in MFIQ emotional function domain score at week 24 
 
Change from baseline in MFIQ social function domain score at week 24 
 
There are 2 intercurrent events, discontinuation of IP due to lack of efficacy or 
adverse event, and discontinuation of IP due to other reasons.  The treatment 
effect of interest will be assessed for all subjects 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 scores.  A composite strategy will be used for 
subjects who discontinued IP due to lack of efficacy or adverse event with 
data after IP discontinuation defined by the worst postbaseline value observed 
up to IP discontinuation (inclusive).  A hypothetical strategy will be used for 
those subjects who discontinued IP due to other reasons with data collected 
after IP discontinuation censored. 
 
The treatment, which is erenumab 70 or 140 mg every 4 weeks 
 
The summary measure, which is change from baseline in each MFIQ domain 
score at week 24  
The estimand for the secondary efficacy objective on subject functional impairment is 
the change from baseline at week 24 in each MFIQ domain score, in subjects with EM 
or CM who are currently on 1 standard of care migraine prevention therapy and who 
receive at least 1 dose of IP and have a baseline value and at least 1 post-baseline 
value in each MFIQ domain score, and a composite strategy will be used for subjects 
who discontinued IP due to lack of efficacy or adverse event with data after IP 
discontinuation defined by the worst postbaseline value observed up to IP 
discontinuation (inclusive), while a hypothetical strategy will be used for those subjects 
who discontinued IP due to other reasons with data collected after IP discontinuation 
censored. 
 
 
 
Exploratory 
 
To explore the effect of 
erenumab on the change 
from baseline in monthly 
 
Change from baseline in TSQM overall 
satisfaction scale score at weeks 12, 16, and 
20 and mean over weeks 16, 20, and 24 


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medication-specific 
treatment satisfaction 
 
Change from baseline in TSQM sub-scale 
domain scores at weeks 12, 16, 20 and 24 and 
mean over weeks 16, 20, and 24: 
‒ effectiveness  
‒ side effects  
‒ convenience 
 
To explore the effect of 
erenumab on monthly 
global impression of 
improvement in migraine 
 
Improvement in subject global impression at 
weeks 12, 16, and 20, as defined by subject 
reporting of much improved or a little improved 
on the mGI-I 
 
Improvement in treating clinician’s global 
impression at weeks 12, 16, and 20, as 
defined by treating clinician’s reporting of 
much improved or a little improved on the 
mGI-I 
 
Improvement in key family member’s global 
impression at weeks 12, 16, and 20, as 
defined by key family member’s reporting of 
much improved or a little improved on the 
mGI-I 
 
To explore the effect of 
erenumab on the change 
from baseline in monthly 
functional impairment 
 
Change from baseline in MFIQ functional 
impairment domain scores, at weeks 12, 16, 
and 20, and mean over weeks 16, 20, and 24: 
‒ Impact on physical function  
‒ Impact on usual activities  
‒ Impact on emotional function  
‒ Impact on social function  
 
To explore the effect of 
erenumab on the change 
from baseline in the burden 
of migraine 
 
Change from baseline in the Migraine 
Symptom Severity Scale (MSSS) total score at 
weeks 12, 16, 20, and 24 and mean over 
weeks 16, 20, and 24 


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 
Change from baseline in the Migraine Interictal 
Burden Scale (MIBS-4) total score at weeks 
12, 16, 20, and 24 and mean over weeks 16, 
20, and 24 
 
To explore the effect of 
erenumab on the change 
from baseline in number of 
monthly migraine days 
(MMD) 
 
Change from baseline in mean MMD over 
weeks 16, 20, and 24  
 
Change from baseline in MMD at weeks 16, 
20, and 24 
 
Achievement of at least a 50% reduction from 
baseline in mean MMD over weeks 16, 20, 
and 24 
 
Achievement of at least a 50% reduction from 
baseline in MMD at weeks 16, 20, and 24 
 
To explore the effect of 
erenumab on the change 
from baseline in acute 
migraine-specific 
medication use 
 
Change from baseline in mean monthly acute 
migraine-specific medication days over weeks 
16, 20, and 24 
 
Change from baseline in monthly acute 
migraine-specific medication days at weeks 16, 
20, and 24 
 
To explore the effect of 
erenumab on the change 
from baseline in anxiety 
and depression 
 
Change from baseline in General Anxiety 
Disorder scale (GAD-7) total score at weeks 
12 and 24 
 
Change from baseline in Patient Health 
Questionnaire (PHQ-9) total score at weeks 12 
and 24 
 
2.2 
Hypotheses and/or Estimations 
The study is descriptive in nature without a comparator arm, and as such no formal 
statistical hypothesis is defined. 


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3. 
Study Overview 
3.1 
Study Design 
Study 20190389 is a phase 4 open-label study that will enroll subjects with EM or CM in 
an approximately 1:1 ratio. The study will comprise the following periods:  
 
A combined screening/baseline period consisting of the following:  
- A screening visit (which may coincide with the first day of the baseline period) for 
the assessment of eligibility criteria  
- A baseline period of approximately 4 weeks (no less than 28 days; up to 35 days) 
to collect data on migraine headaches and acute headache medication use using 
electronic diary (eDiary) and to assess compliance in eDiary usage  
 
A 24-week open-label treatment period 
Eligible subjects may enter the baseline period at the same visit or may delay baseline 
procedures up to 3 weeks after the screening visit.  At completion of the baseline period, 
those who meet eligibility criteria and choose to proceed will be enrolled and will enter 
the open-label treatment period to receive erenumab 70 or 140 mg once every 4 weeks 
(Q4W) by subcutaneous (SC).  All subjects will be started on a 70 mg dose of erenumab 
at day 1 with provider discretion for dose optimization (either 70 mg or 140 mg), which is 
recommended to be completed by week 12. All subjects will be required to enter the 
study on 1 standard of care preventive medication for their migraine, whose dose then 
can be adjusted by the investigator’s discretion and must be stable by week 12. The 
treating clinician and a key family member (if available) for each participating subject will 
be invited to complete an mGI-I at weeks 12, 16, 20, and 24/End of Study (EOS) for the 
mGI-I endpoints. 


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Figure 1 1.  Study Schema 
 
* All subjects will be started on a 70 mg dose of erenumab at day 1 with provider discretion for dose optimization.  Dose optimization will allow patients to remain on 70 
mg, increase the dose from 70 mg to 140 mg, and if needed decrease the dose back down from 140 mg to 70 mg.  It is highly recommended that all erenumab dose 
adjustments be completed by week 12, after which all subjects should remain on the week 12 erenumab dose for the rest of the study.  Additional dose adjustments 
after week 12 are not recommended and must only be made if deemed medically necessary by the investigator. 
** Baseline may begin on the same day as screening 
 


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3.2 
Sample Size 
The total sample size of approximately 322 subjects (effective sample size of 
289, assuming 10% dropout at week 24) is driven by the precision of the proportion 
estimates for the binary secondary endpoints, which targets a half-width of 95% 
confidence intervals (CIs) around 5%. The half-width of the 95% CI will be the widest 
when the estimated percentage is 50%, given a fixed sample size, and will become 
narrower if the percentage moves further away from 50% (see Table 3-1). 
Table 3-1.  Half-width of 95% CI for Various Estimated Percentages With Effective 
Sample Size of 289 Subjects  
Percentage  
Estimate 
Half-width of 95% CI  
With Effective Sample Size = 289 
50% 
5.8% 
60% 
5.6% 
70% 
5.3% 
80% 
4.6% 
Given the evolving landscape of migraine preventive trials and treatment 
paradigm, the exploratory design of this trial, and the descriptive nature of the 
study objectives and endpoints, it had been understood that prolonging screening 
and enrollment efforts beyond this point would be of little additional value, thus, it 
has been decided to terminate study 20190389 early to enroll only 240 subjects. 
Table 3-2 is the updated half-width of 95% CI based on the sample size of 240 
subjects (effective sample size of 216, assuming 10% dropout at week 24). 
 
Table 3-2. Half-width of 95% CI for Various Estimated Percentages With Effective 
Sample Size of 216 Subjects 
Percentage  
Estimate 
Half-width of 95% CI  
With Effective Sample Size = 
216 
50% 
6.7% 
60% 
6.5% 
70% 
6.1% 
80% 
5.3% 
 
3.3 
Adaptive Design 
The adaptive design is not applicable for this study. 


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4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
All model-adjusted analyses of primary and secondary efficacy endpoints will include the 
corresponding baseline value for the endpoint being analyzed if applicable, visit, the 
prevailing erenumab dose from week 12 onwards, and baseline MMD in the model. 
4.2 
Subgroups 
The primary and secondary endpoints will be analyzed in the following subgroups: 
 
Whether remained on standard of care migraine preventive treatment throughout the 
study (yes vs no) 
 
Migraine type (EM vs CM) based on both CRF data collected on form “Headache 
and Migraine Frequency Medical History” during screening and eDiary 
collection during baseline 
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 final analysis. 
5. 
Definitions 
5.1 
Definition of Terms Included in Study Endpoints 
5.1.1 
Efficacy Endpoints Based on Monthly Collection 
The daily eDiary collection will occur during the baseline period and months 4, 5, and 6. 
Subjects’ daily headache information will be collected through the following questions. 
Possible outcomes on migraine-related endpoints are summarized below:


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Table 5-1.  Definitions of Migraine Day, Headache Day, and Acute Migraine-specific Medication Day 
 
Scenarios 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
eDiary data collection 
 
 
 
 
 
 
 
 
 
 
Headache (Y/N) 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
No 
No 
No 
No 
If Y, (a) Pain intensity (1 to 10) 
1 to 10 
1 to 10 
1 to 10 
1 to 10 
1 to 10 
1 to 10 
NA 
NA 
NA 
NA 
        (b) Migraine (Y/N) 
Yes 
Yes 
Yes 
No 
No 
No 
NA 
NA 
NA 
NA 
        (c) Acute medication for headache (Y/N) 
Yes 
Yes 
No 
Yes 
Yes 
No 
NA 
NA 
NA 
NA 
                If Y, Triptan (Y/N) 
Yes 
No 
NA 
Yes 
No 
NA 
NA 
NA 
NA 
NA 
If N, Aura (Y/N) 
NA 
NA 
NA 
NA 
NA 
NA 
Yes 
Yes 
Yes 
No 
        If Y, acute medication for aura (Y/N) 
NA 
NA 
NA 
NA 
NA 
NA 
Yes 
Yes 
No 
NA 
                If Y, Triptan (Y/N) 
NA 
NA 
NA 
NA 
NA 
NA 
Yes 
No 
NA 
NA 
Endpoint definition 
 
 
 
 
 
 
 
 
 
 
Headache Day 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
No 
No 
No 
Migraine Day 
Yes 
Yes 
Yes 
Yes 
No 
No 
Yes 
No 
No 
No 
Acute Migraine-specific Medication Day 
Yes 
No 
No 
Yes 
No 
No 
Yes 
No 
No 
No 


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Internal Use Only General and Administrative 
Migraine Type 
CM is defined as subjects with ≥ 15 headache days per month of which ≥ 8 
headache days meet criteria as migraine on either CRF data collected on form 
“Headache and Migraine Frequency Medical History” during screening or eDiary 
collection during baseline; EM is defined as subjects who does not fulfill criteria 
for CM. 
Diary Day  
A calendar day (00:00 to 23:59) with complete migraine headache, aura, and acute 
migraine headache medication data recorded in the eDiary device 
Headache Day 
A calendar day (00:00 to 23:59) in which the subject reports a headache (ie, Scenarios 1 
to 7 in Table 5-1) 
Migraine Day  
A calendar day (00:00 to 23:59) in which the subject reports a migraine (ie, Scenarios 1 
to 4 in Table 5-1) or takes a migraine-specific medication (ie, Scenario 7 in Table 5-1) 
Acute Migraine-specific Medication Day  
A calendar day (00:00 to 23:59) in which the subject takes a migraine-specific 
medication (ie, Scenarios 1, 4, and 7 in Table 5-1). 
Monthly Frequency Variable in Days  
Number of days of interest during one monthly interval as defined in Table 5-2. Monthly 
frequency variables include  
 
Monthly Migraine Days (MMD)  
 
Monthly Acute Migraine-specific Medication Days  
 
The following proration rule will be applied to all monthly frequency variables for each 
monthly interval. 


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Within Each 
Monthly Interval 
Monthly Frequency Variable  
≥ 14 diary days 
Prorate to 28-day equivalent without rounding 
 
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑓𝑟𝑒𝑞𝑢𝑒𝑛𝑐𝑦 𝑑𝑎𝑦𝑠 𝑤𝑖𝑡ℎ𝑖𝑛 𝑒𝑎𝑐ℎ 𝑚𝑜𝑛𝑡ℎ𝑙𝑦 𝑖𝑛𝑡𝑒𝑟𝑣𝑎𝑙
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑖𝑎𝑟𝑦 𝑑𝑎𝑦𝑠 𝑤𝑖𝑡ℎ𝑖𝑛 𝑒𝑎𝑐ℎ 𝑚𝑜𝑛𝑡ℎ𝑙𝑦 𝑖𝑛𝑡𝑒𝑟𝑣𝑎𝑙
∗28 
 
< 14 diary days 
Set to missing 
 
 
5.1.2 
Efficacy Endpoints Based on Clinical Outcome Assessments 
 
Treatment Satisfaction Questionnaire for Medication (TSQM) 
The Treatment Satisfaction Questionnaire for Medication (TSQM) version 1.4 is a 14-
item instrument designed to measure important dimensions of patients' experiences with 
their medication.  It has 4 domains: effectiveness, side effects, convenience, and global 
satisfaction.  Scores range from 0 to 100, with higher scores indicating greater 
satisfaction.  The recall period is the last two to three weeks, or since the medication 
was last used. 
Scoring Algorithm: TSQM Scale scores range from 0 to 100 and no computed score 
should be lower or higher than these limits. 
Effectiveness: Effectiveness domain contains Item 1 to Item 3 
𝐸𝑓𝑓𝑒𝑐𝑡𝑖𝑣𝑒𝑛𝑒𝑠𝑠= [(𝐼𝑡𝑒𝑚 1 + 𝐼𝑡𝑒𝑚 2 + 𝐼𝑡𝑒𝑚 3) −3]
18
 × 100 
Side Effects: Side effects domain contains Item 5 to Item 8 
𝑆𝑖𝑑𝑒 𝐸𝑓𝑓𝑒𝑐𝑡𝑠= [(𝐼𝑡𝑒𝑚 5 + 𝐼𝑡𝑒𝑚 6 + 𝐼𝑡𝑒𝑚 7 + 𝐼𝑡𝑒𝑚 8) −4]
16
 × 100 
Convenience: Convenience contains Item 9 to Item 11 
𝐶𝑜𝑛𝑣𝑒𝑛𝑖𝑒𝑛𝑐𝑒= [(𝐼𝑡𝑒𝑚 9 + 𝐼𝑡𝑒𝑚 10 + 𝐼𝑡𝑒𝑚 11) −3]
18
 × 100 
Overall satisfaction: Overall satisfaction domain contains Item 12 to Item 14 
First recode Item14, recode Item 14 = (Item14 − 1) × 5/6  
Then 
𝑂𝑣𝑒𝑟𝑎𝑙𝑙 𝑠𝑎𝑡𝑖𝑠𝑓𝑎𝑐𝑡𝑖𝑜𝑛 = [(𝐼𝑡𝑒𝑚 12 + 𝐼𝑡𝑒𝑚 13 + 𝐼𝑡𝑒𝑚 14) −3]
12
 × 100 


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 
Migraine Global Impression Item (mGI-I) 
The mGI-I is a single item instrument designed to measure improvement/worsening in 
migraine. The 3 versions of the instrument include the perspective of study subjects, key 
family members, and treating clinicians measured on the following scale: much 
improved; a little improved; no change; a little worse; or much worse. The recall period is 
the past 7 days. 
 
Migraine Functional Impact Questionnaire (MFIQ) 
The Migraine Functional Impact Questionnaire (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 (items 1 to 5), Impact on Usual Activities 
(items 6 to 15), Impact on Social Functioning (items 17 to 21), and Impact on Emotional 
Functioning (items 22 to 26).  In addition, there is 1 stand-alone global item (item 16) 
assessing the overall impact on usual activities.  Subjects respond to each item 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 (ie, raw score) 
and rescaled to a 0-100 scale according to the formula below, with higher scores 
representing greater burden.  No total score is created for the MFIQ.  The recall period is 
the past 7 days. 
𝐷𝑜𝑚𝑎𝑖𝑛 𝑆𝑐𝑜𝑟𝑒=
(𝑅𝑎𝑤 𝑠𝑐𝑜𝑟𝑒−𝐿𝑜𝑤𝑒𝑠𝑡 𝑝𝑜𝑠𝑠𝑖𝑏𝑙𝑒 𝑟𝑎𝑤 𝑠𝑐𝑜𝑟𝑒)
(𝐻𝑖𝑔ℎ𝑒𝑠𝑡 𝑝𝑜𝑠𝑠𝑖𝑏𝑙𝑒 𝑟𝑎𝑤 𝑠𝑐𝑜𝑟𝑒−𝐿𝑜𝑤𝑒𝑠𝑡 𝑝𝑜𝑠𝑠𝑖𝑏𝑙𝑒 𝑟𝑎𝑤 𝑠𝑐𝑜𝑟𝑒) ∗100 
For the purposes of domain scoring, “does not apply” will be imputed with the mean of 
other items in the domain. 
 
Migraine Symptom Severity Scale (MSSS) 
The Migraine Symptom Severity Scale (MSSS) is a 7-item questionnaire that assesses 
frequency of pain and other symptoms associated with migraines.  Responses are as 
follows: “never”, “rarely”, “less than half the time”, “half the time or more”, and “all or 
nearly all of the time”.  The responses are given a value from 1 to 3 as follows: Never = 
0, Rarely = 1, Less Than Half the Time = 2, Half the Time or More = 3, and All or Nearly 
All of the time = 3.  The MSSS score is the sum of the 7 items, and has a range from 0 to 
21. 
 
Migraine Interictal Burden Scale (MIBS-4)  
The Migraine Interictal Burden Scale (MIBS-4) measures interictal migraine-related 
burden with 4 questions that assess impairment in work or school, impairment in family 


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and social life, difficulty making plans or commitments, and emotional/affective and 
cognitive distress.  Each of the 4 questions is responded to using 1 of 6 response 
categories: “Don’t know/NA” (Score = 0), “Never” (Score = 0), “Rarely” (Score = 1), 
“Some of the time” (Score = 2), “Much of the time” (Score = 3) or “Most or all of the time” 
(Score = 3).  Each question is multiplied with its score and summed up to produce total 
score ranges from 0 to 12.  The MIBS-4 total scores are categorized into 4 level of 
interictal burden: None (0), Mild (1 to 2), Moderate (3 to 4) and Severe (5 or higher).  
Total Score = {[(Number of responses for ‘Don't Know’ for Item 1 to Item 4)* 0] +  
  
 
[(Number of responses for ‘Never’ for Item 1 to Item 4)* 0] +  
[(Number of responses for ‘Rarely’ for Item 1 to Item 4)* 1] +  
[(Number of responses for ‘Some of the time’ for Item 1 to Item 4)* 2] +  
[(Number of responses for ‘Much of the time’ for Item 1 to Item 4)* 3] +  
                         [(Number of responses for ‘Most or all of the time’ for Item 1 to Item 4)* 3]} 
 
Generalized Anxiety Disorder Scale (GAD-7) 
The Generalized Anxiety Disorder Scale (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.  
 
Patient Health Questionnaire (PHQ-9) 
The Patient Health Questionnaire (PHQ-9) is a self-administered questionnaire, widely 
used for diagnosis and severity assessment of depression in primary care settings. 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 


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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. 
5.1.3 
Safety Analysis 
Serious Adverse Event (SAE) 
An event categorized as “Adverse Event” with the indicator flag “Serious” equal to “Yes” 
on the Events Case Report Form (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 Events 
A TEAE with the indicator flag “Serious” equal to “Yes” on the Events eCRF. 
Treatment-emergent Adverse Device Effect 
A TEAE with the indicator flag “Is there a reasonable possibility that the event may have 
been caused by the investigational device” equal to “Yes” on the Events eCRF. 
Treatment-related Treatment-emergent Adverse Event 
A treatment-emergent adverse event with the indicator flag “Is there a reasonable 
possibility that the event may have been caused by Investigational Medicinal 
Product” 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 data entry after completion of the eDiary 
training module. 


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Enrollment Date 
Enrollment Date is the day a subject has met all eligibility criteria and is enrolled. 
First IP Dose Date 
First Dose Date is the date on which a subject is administered the first dose of IP 
following completion of the Baseline period as recorded on the IP Administration eCRF. 
End of IP Administration Date 
The end of IP admin date for each subject is defined as the date the decision was made 
to end IP as recorded on the End of IP 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 
eDiary collection during baseline period) before the first dose of investigational product. 
In cases where baseline measurements are taken on the same day as IP, it will be 
assumed that these measurements are taken prior to IP being administered.  
Study Day 1 
Study Day 1 is defined as the first IP dose date or enrollment date if no IP received. 
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. 
Treatment Discontinuation Visit 
Treatment discontinuation visit is defined as the earliest visit on or after the date when 
the decision to discontinue treatment is made. 


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5.4 
Study Time Intervals 
5.4.1 
Monthly Intervals for Efficacy Endpoints Derived From Daily Diary 
Collection 
The (4-week) monthly intervals for efficacy endpoints derived from eDiary collection will 
be determined based on each subject’s monthly IP dosing dates. When an IP is missed, 
discontinued, or no longer required, a 28-day monthly interval will be used.   
Applicable efficacy endpoints utilizing the monthly intervals in Table 5-2 includes: 
 
Monthly Migraine Days (MMD)  
 
Monthly Acute Migraine-specific Medication Days  
 
Table 5-2.  Monthly Intervals for Efficacy Endpoints Derived From Daily Diary  
Data Collection 
Study 
Period 
Assessment 
Timepoint 
Monthly Interval 
Start Date (Day) a 
End Date (Day) b 
Baseline 
Period 
Baseline 
Date of Device Ready for 
Entry 
Day prior to study day 1 
Open-
label 
Treatment 
Period 
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 24 visit date – 1 
a Start Date (Day) = End date (day) of previous monthly interval + 1 if IP dose date is not available 
b End Date (Day) = Start date (day) of current monthly interval + 27 if IP dose date is not available,  
unless stated otherwise 
5.4.2 
Analysis Visits for Endpoints Derived Based on Monthly Data 
Collection 
Since the actual visit for a subject may not exactly coincide with their targeted visit date, 
the actual visit date is mapped to the analysis visit as in Table 5-3, Table 5-4, Table 5-5, 
and Table 5-6.  
For by-visit summaries, if more than one visit with non-missing measurement (including 
the unscheduled visits, ie, CPEVENT = ‘UNSCHED’) fall within the same visit window, 
the following rules will be applied according to the order described below for selecting 
one visit per visit window for summary: 


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1. Scheduled visit will be used regardless of the distance from the target day.  
Unscheduled visit will only be used when there is no measurement from 
scheduled visit in the visit window. 
2. The visit closest to the target day among visits of the same type (all scheduled 
visits or all unscheduled visits) will be considered for analysis. 
3. If two assessment dates are equidistant from the target date, the latter visit will 
be considered for analysis.


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Table 5-3.  MFIQ, MSSS, and MIBS-4 Analysis Visit Windows 
Study Period 
Analysis Visit 
Target Day 
Visit Window (Study Day) 
Baseline Period 
Day 1 (Baseline) 
1 
Last measurement ≤ Day 1 
 
Open-label 
Treatment Period 
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 
Table 5-4.  mGI-I Analysis Visit Windows 
Study Period 
Analysis Visit 
Target Day 
Visit Window (Study Day) 
 
Open-label 
Treatment Period 
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 
Table 5-5.  GAD-7 and PHQ-9 Analysis Visit Windows 
Study Period 
Analysis Visit 
Target Day 
Visit Window (Study Day) 
Baseline Period 
Day 1 (Baseline) 
1 
Last measurement ≤ Day 1 
Open-label 
Treatment Period 
Week 12 (Month 3) 
85 
72 to 99 
Week 24 (Month 6) 
169 
≥ 156 
Table 5-6.  TSQM Version 1.4 Analysis Visit Windows 
Study Period 
Analysis Visit 
Target Day 
Visit Window (Study Day) 
Baseline Period 
Day 1 (Baseline) 
1 
Last measurement ≤ Day 
1 
 
Open-label 
Treatment Period a 
 
Week 12 (Month 3) 
85 
79 to 106 
Week 16 (Month 4) 
113 
107 to 134 
Week 20 (Month 5) 
141 
135 to 162 
Week 24 (Month 6) 
169 
≥ 163 
a The recall period for TSQM Version 1.4 is the last 2 to 3 weeks. 
5.4.3 
Subject Disposition 
Exposed to Investigational Product 
Subjects are defined as exposed if they receive at least one dose of investigational 
product. 
Completing the Investigational Product 


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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 are enrolled and have not yet completed their 
EOS visit. 
5.5 
Arithmetic Calculations 
Duration of IP Exposure (Days) 
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. 
Percent Change From Baseline  
The change from baseline divided by baseline and multiplied by 100: 
𝑃𝑒𝑟𝑐𝑒𝑛𝑡 𝐶ℎ𝑎𝑛𝑔𝑒 𝐹𝑟𝑜𝑚 𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒= 
(𝑃𝑜𝑠𝑡𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒−𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒)
𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒
 × 100 
If the baseline value is 0 and the postbaseline value is also 0, the percent change from 
baseline is set to 0. If the baseline value is 0 and the postbaseline value is non-zero, the 
percent change from baseline is set to missing. 
Mean Monthly Change From Baseline Over Multiple Months 
Arithmetic Mean monthly change from baseline is the arithmetic mean of the observed 
monthly change from baseline values for the months with non-missing change from 
baseline values. 
5.6 
Disease Characteristics 
Treatment Failure of Prior Migraine Preventive Medications 
Treatment failure of prior migraine preventive medications is determined by the 
medications marked as “Prior Migraine Prophylactic” with “Reason for Stopping” being 
“Lack of Efficacy” or “Adverse reaction” or “Intolerance” on the Prior Migraine 
Prophylactic And Ongoing Migraine Prophylactic eCRF.  


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6. 
Analysis Sets 
The following analysis sets are defined for this study. 
6.1 
Full Analysis Set 
The full analysis set (FAS) consists of all subjects enrolled in the study. Analysis of 
disposition, demographic and baseline characteristics, important protocol deviations, and 
protocol deviations related to COVID-19 control measures will utilize the FAS. 
6.2 
Efficacy Analysis Set 
The efficacy analysis set consists of a subset of subjects from FAS who receive at 
least 1 dose of investigational product. Analysis of efficacy endpoints will utilize 
the efficacy analysis set. 
6.3 
Safety Analysis Set 
The safety analysis set (SAS) will consist of a subset of subjects from FAS who 
received at least 1 dose of investigational product. Analysis of safety endpoints 
and summary of investigational product administration will utilize the safety 
analysis set. 
7. 
Planned Analyses 
There is only one milestone analysis to be conducted for this study once all the 240 
enrolled subjects have completed the week 24/EOS visit. The data will be cleaned, and 
the database will be locked for the final analysis. 
7.1 
Final Analysis 
The final analysis will be conducted when all enrolled subjects have completed the week 
24/EOS visit. 
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 electronic Clinical Outcome Assessments (eCOAs) data including eDiary, 
GAD-7, MFIQ, mGI-I, MIBS-4, MSSS, PHQ-9, TSQM version 1.4 questionnaires data 
will be stored outside of RAVE database. The database is subject to edit check outlined 
in the Data Management Plan (DMP). 


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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, inability to 
evaluate an endpoint at a particular point in time, and treatment discontinuation due to 
lack of efficacy, adverse event, or non-response. The efficacy endpoints will be collected 
via daily eDiary and monthly eCOA assessments device. Subjects could miss entering 
several days of daily migraine data or an eCOA assessment in each monthly interval.  
The general procedures outlined below describe how missing data will be handled. 
For the eDiary data collected daily, if at least 14 days of eDiary are collected in the 
monthly interval, then the monthly frequency measurements (eg, headache days, 
migraine days or acute migraine-specific medications days [AMSMD]) will be prorated 
based on the number of days with available information. If less than 14 days of eDiary 
are collected in the monthly interval, then the monthly frequency measurements will be 
set to missing (Table 8-1). For the descriptive summary of the mean monthly value 
calculated using the monthly value from each of months 4, 5, and 6, if a subject has at 
least one monthly value at months 4, 5, and 6, then the subject contributes to the 
summary statistics. 
For the endpoints derived from the daily diary data, please refer to proration approach 
specified in Section 5.1.1. On handling missing daily diary data. Missing monthly 
measurement after proration will be handled by statistical analysis approaches listed in 
Section 9.5. 
Table 8-1.  Handling of Missing and Incomplete eDiary Data 
Monthly 
Frequency 
Endpoint  
Condition  
Proration Method (Without 
Rounding)  
Monthly 
frequency 
measurements 
(migraine days 
and  acute 
migraine-specific 
medication days)  
A diary day is a day with all 
headache-related questions 
completed in eDiary.  
If diary days in baseline or each 
post-baseline interval ≥ 14, apply 
proration for that monthly interval;  
Else monthly frequency 
measurement is set to missing  
Number of event days of interest in 
a monthly interval* 28/ Number of 
diary days in the monthly interval  
 
Note: Event days of interest is 
referred to migraine days and 
acute migraine-specific medication 
days  


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Missing or incomplete dates will be listed as reported, except for incomplete start date of 
an adverse event or concomitant medication (Table 8-2). 
Table 8-2.  Imputation for Incomplete Start Date of an Adverse Event or 
Concomitant Medication 
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  
—  
eCRF = electronic case report form 
Missing data will not be imputed for safety endpoints. 
8.4 
Detection of Bias 
The below mentioned factors that may bias the results of the study: 
 
Important protocol deviations likely to impact the analysis and interpretation of the 
efficacy endpoints 
 
Investigational product dosing non-compliance 
 
The timing of and reasons for early withdrawal from study treatment and from study 
The incidence of these factors may be assessed. Important protocol deviations will be 
listed and/or tabulated in the clinical study report (CSR). If necessary, the incidence of 
other factors will be tabulated. 
The reasons for early withdrawal from study 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.  


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Outliers will be queried 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 presented in this statistical 
analysis plan unless there is sufficient justification to exclude them. However, ad-hoc 
sensitivity analyses may be conducted to evaluate the influence of extreme values in the 
data. 
8.6 
Distributional Characteristics 
Continuous endpoints of change from baseline value will be analyzed under normality 
assumption.  
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.   
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Summary statistics will be computed at each timepoint of interest.  For continuous 
endpoints, the following descriptive statistics will be computed: number of observations, 
means, standard deviations, standard errors, medians, first and third quartiles, 
minimums and maximums.  For categorical endpoints, the summaries will contain the 
number and percentage of subjects in each category. 
Due to lack of a control arm, all analyses should be considered as descriptive in nature. 
If a subject discontinued treatment due to lack of efficacy or adverse event, data on 
primary and secondary efficacy endpoints collected after treatment discontinuation will 
be defined based on the worst post-baseline value observed (for continuous endpoints) 
up to IP discontinuation (inclusive) or non-response (for binary endpoints) using a 
composite strategy. If a subject discontinued treatment due to other reasons, data 
collected after treatment discontinuation visit will be censored based on a hypothetical 
strategy and not be used in efficacy analyses as described in Section 9.5. 


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Analysis for primary and secondary endpoints will be using observed data with 
intercurrent event handling; analysis for exploratory endpoints will be using 
observed data without intercurrent event handling. A sensitivity analysis using 
observed data without any intercurrent event handling will also be performed for 
primary endpoint. 
9.2 
Subject Accountability 
The disposition of all enrolled subjects will be tabulated based on two migraine types 
(EM vs CM) separately and overall population using FAS.  
The number and percentage of subjects who were enrolled, received investigational 
product, completed investigational product, discontinued investigational product and 
reasons for discontinuing, completed study, discontinued study and reasons for 
discontinuing will be summarized by the two migraine types (EM vs CM) separately, and 
the overall population. Summary of subjects who discontinue investigational 
product/study due to COVID-19 control measures will be included. 
In addition, the descriptive summaries listed below will be done by the two migraine 
types (EM vs CM) separately and overall population using safety analysis set. 
 
At week 12, the number and percentage of subjects who remained on 70 mg and 
did not receive any 140 mg dose, who increased the dose to 140 mg, and who 
received 70 mg at week 12 and have received at least one dose of 140 mg 
previously. 
 
At week 12, the number and percentage of subjects who continued or 
discontinued SOC 
The summary of the study reporting phase including a description of key dates such as 
the first subject enrolled, last subject enrolled, last subject's end of investigational 
product, last subject's end of study will also be provided using FAS by the two migraine 
types (EM vs CM) separately and overall population. 
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to database lock. These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the course of the study. Eligibility deviations are defined 
in the protocol. 


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The final IPD list will be used to produce the Summary of IPDs table and the list of 
subjects with IPDs using the FAS. 
Protocol deviations related to COVID-19 control measures will be summarized 
separately. 
9.4 
Demographic and Baseline Characteristics 
Subject demographic and baseline disease characteristics will be summarized using 
descriptive statistics separately for the two migraine types and overall study population 
using FAS. If multiple races have been reported for a subject, the subject will be 
categorized as multiple race. 
The following demographics and baseline disease characteristics will be summarized: 
 
Age 
 
Sex 
 
Ethnicity 
 
Race 
 
Height (cm) 
 
Weight (kg) 
 
Body Mass Index (BMI, kg/m2) 
 
Overall Migraine 
 
Prior migraine preventive medication by categories 
 
Reasons for stopping of the prior migraine preventive medication by 
categories 
 
General medical history 
 
Type of SOC for dissatisfaction with SOC 
 
Summary of prior migraine preventive medication and reasons for discontinuation 
 
PRO (TSQM 1.4, MFIQ, MSSS, MIBS-4, GAD-7, PHQ-9, and ETS) at baseline 
 
Targeted neurological medical history 
 
Disease duration of migraine 
 
Age at onset of migraine 
 
Monthly headache days during baseline period 
 
Monthly migraine days during baseline period 
 
Monthly acute migraine-specific medication days during baseline period 


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9.5 
Efficacy Analyses 
The final analysis of primary, secondary and exploratory endpoints will utilize the efficacy 
analysis set.  
The primary and secondary endpoints will be analyzed in the following subgroups:  
 
Whether remained on standard of care migraine preventive treatment throughout 
the study (yes vs no)  
 
Migraine type (EM vs CM)  
Detailed analysis methods and covariates included in the models are summarized in the 
table below. The value for the covariate “prevailing dose from week 12 onwards” will be 
the prevailing dose if all three planned doses are administered, or the last dose if two or 
fewer doses are administered from week 12 to week 20 or last observed dose prior to 
week 12 if none of three doses are administered. 
Table 9-1.  Primary Efficacy Endpoint and analysis Summary Table 
Endpoint 
Primary Summary and Analysis Method  
Change from baseline in the 
Treatment Satisfaction Questionnaire 
for Medication (TSQM) overall 
satisfaction scale score at week 24, 
as measured by items 12 to 14 of the 
TSQM version 1.4 
(Note: Results from individual time 
point and mean over time points will 
also be generated in the same 
repeated measures mixed effects 
model.) 
1. Summary statistics using observed data 
(after intercurrent event handling) 
2. The change from baseline in the TSQM 
overall satisfaction scale score at week 24, 
as measured by items 12 to 14 of the 
TSQM version 1.4 will be analyzed using a 
repeated measures mixed effects model, 
including baseline TSQM overall 
satisfaction scale score, visit, the prevailing 
erenumab dose from Week 12 onwards, 
and baseline MMD based on observed 
data. The mean change from baseline in 
TSQM overall satisfaction scale score at 
week 24 will be estimated from the least-
squares mean (LSM) of the mixed effects 
model, and the corresponding 95% CI will 
be provided. The nominal p-value will be 
reported by comparing the mean change 


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Endpoint 
Primary Summary and Analysis Method  
from baseline in TSQM overall satisfaction 
scale score at week 24 to zero with a two-
sided 5% significance level. 
3. The efficacy analysis set will be used for 
this endpoint analysis. 
Table 9-2.  Secondary Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis Method 
Achievement of overall satisfaction at 
week 24 as defined by subject 
reporting of satisfied, very satisfied, 
or extremely satisfied on Item 14 of 
the TSQM version 1.4 
1. Summary statistics using observed data 
(after intercurrent event handling);  
2. The achievement of overall satisfaction at 
week 24 as defined by subject reporting of 
satisfied, very satisfied, or extremely 
satisfied on Item 14 of the TSQM version 
1.4 will be analyzed using a generalized 
linear mixed effects model with the logit 
link function. The model will include 
baseline achievement of overall 
satisfaction, visit, the prevailing erenumab 
dose from Week 12 onwards, and baseline 
MMD based on observed data. The 
proportions and the corresponding 95% CI 
at week 24 will be estimated from the LSM 
(with inverse link function) of the mixed 
effects model. 
3. The efficacy analysis set will be used for 
this endpoint analysis. 
Improvement in subject global 
impression at week 24, as defined by 
subject reporting of much improved 
or a little improved on the mGI-I 
Improvement in treating clinician’s 
global impression at week 24, as 
1. Summary statistics using observed data 
(after intercurrent event handling); 
2. The Improvement in global impression at 
week 24, as defined by subject’s, 
clinician’s, and key family member’s 
reporting of much improved or a little 


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Endpoint 
Primary Summary and Analysis Method 
defined by treating clinician’s 
reporting of much improved or a little 
improved on the mGI-I 
Improvement in key family member’s 
global impression at week 24, as 
defined by key family  member’s 
reporting of much improved or a little 
improved on the mGI-I 
improved on the migraine Global 
Impression Item (mGI-I) will be analyzed 
separately using a generalized linear 
mixed effects model with the logit link 
function.  The model will include the visit, 
the prevailing erenumab dose from Week 
12 onwards, and baseline MMD based on 
observed data. The proportions and the 
corresponding 95% CI at week 24 will be 
estimated from the LSM (with inverse link 
function) of the mixed effects model. 
3. The efficacy analysis set will be used for 
this endpoint analysis. 
 
Change from baseline in subject 
functional impairment domain score 
at week 24, as measured by the 
Migraine Functional Impact 
Questionnaire (MFIQ) 
‒ Physical function domain score 
‒ Usual activities domain score 
‒ Emotional function domain score 
‒ Social function domain score 
 
1. Summary statistics using observed data 
(after intercurrent event handling); 
2. The change from baseline in subject 
functional impairment domain score at 
week 24, as measured by the MFIQ will be 
analyzed using a generalized linear mixed 
effects model with the identity link function. 
The model will include baseline subject 
functional impairment domain score, visit, 
the prevailing erenumab dose from Week 
12 onwards, and baseline MMD based on 
observed data. The mean change from 
baseline in subject functional impairment 
domain score at week 24 with the 
corresponding 95% CI will be estimated 
from the LSM of the mixed effects model, 
and p-values comparing with zero at a two-
sided 5% significance level will be 
reported. 


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Endpoint 
Primary Summary and Analysis Method 
3. The efficacy analysis set will be used for 
this endpoint analysis. 
4. This endpoint will be analyzed separately 
for each functional domain. 
Table 9-3.  Exploratory Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis Method  
Change from baseline in TSQM 
overall satisfaction scale score at 
weeks 12, 16, and 20 and mean over 
weeks 16, 20, and 24 
This endpoint will be analyzed same as 
primary efficacy endpoint. 
Achievement of overall 
satisfaction as defined by subject 
reporting of satisfied, very 
satisfied, or extremely satisfied on 
item 14 of the TSQM version 1.4 at 
weeks 12, 16, and 20. 
This endpoint will be analyzed same as 
primary efficacy endpoint. 
Change from baseline in TSQM sub-
scale domain scores at weeks 12, 
16, 20 and 24 and mean over weeks 
16, 20, and 24: 
‒ effectiveness 
‒ side effects 
‒ convenience 
This endpoint will be analyzed same as 
primary efficacy endpoint. 
Note: Use baseline value covariate as a 
“Baseline TSQM sub-scale domain score” 
Improvement in subject global 
impression at weeks 12, 16, and 20, 
as defined by subject reporting of 
much improved or a little improved on 
the mGI-I  
Improvement in treating clinician’s 
global impression at weeks 12, 16, 
and 20, as defined by treating 
This endpoint will be analyzed same as above 
mentioned mGI-I endpoint. 


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Endpoint 
Primary Summary and Analysis Method  
clinician’s reporting of much 
improved or a little improved on the 
mGI-I 
Improvement in key family member’s 
global impression at weeks 12, 16, 
and 20, as defined by key family 
member’s reporting of much 
improved or a little improved on the 
mGI-I 
 
Change from baseline in MFIQ 
functional impairment domain scores, 
at weeks 12, 16, and 20, and mean 
over weeks 16, 20, and 24: 
‒ Impact on physical function  
‒ Impact on usual activities  
‒ Impact on emotional function  
‒ Impact on social function 
 
1. Summary statistics by visit using observed 
data at each visit, and the calculated mean 
MFIQ physical function impairment domain 
score over weeks 16, 20, and 24. 
2. The change from baseline in physical 
function impairment domain score at 
weeks 12, 16, and 20, and mean over 
weeks 16, 20, and 24, as measured by the 
MFIQ will be analyzed using a generalized 
linear mixed effects model with the identity 
link function. The model will include 
baseline MFIQ physical function domain 
score, visit, the prevailing erenumab dose 
from Week 12 onwards, and baseline 
MMD based on observed data. The 
mean change from baseline in physical 
function impairment domain score at 
weeks 12, 16, and 20, and mean over 
weeks 16, 20, and 24 with the 
corresponding 95% CI will be estimated 
from the LSM of the mixed effects model. 
3. The efficacy analysis set will be used for 
this endpoint analysis. 


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Endpoint 
Primary Summary and Analysis Method  
Achievement of at least a 50% 
reduction from baseline in mean 
MMD over weeks 16, 20, and 24 
 
1. Summary statistics by visit using observed 
data at each visit, and at least a 50% 
reduction from baseline in mean MMD over 
weeks 16, 20, and 24. 
2. The achievement of at least a 50% 
reduction from baseline in mean MMD over 
weeks 16, 20, and 24 will be analyzed 
using a generalized linear mixed effects 
model with the logit link function. The 
model will include the prevailing erenumab 
dose from Week 12 onwards, and baseline 
MMD.  
The probabilities and the corresponding 
95% CI for 50% reduction from baseline 
MMD in mean MMD over months 4 to 6 will 
be estimated using the mixed effects 
model. 
3. The efficacy analysis set will be used for 
this endpoint analysis. 
Achievement of at least a 50% 
reduction from baseline in MMD at 
weeks 16, 20, and 24 
o Summary statistics by visit using observed 
data at each visit, and at least a 50% 
reduction from baseline in MMD at weeks 
16, 20, and 24. 
o The change from Achievement of at least a 
50% reduction from baseline in MMD at 
weeks 16, 20, and 24 will be analyzed 
using a generalized linear mixed effects 
model with the logit link function. The 
model will include achievement of at least 
a 50% reduction from baseline in MMD, 
visit, the prevailing erenumab dose from 
Week 12 onwards, and baseline MMD. 


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Endpoint 
Primary Summary and Analysis Method  
The probabilities and the corresponding 
95% CI for at least 50% reduction from 
baseline MMD at weeks 16, 20, and 24 will 
be estimated using the mixed effects 
model. 
o The efficacy analysis set will be used for 
this endpoint analysis. 
The same analysis methods will be applied to the below exploratory endpoints: 
Change from baseline in the Migraine Symptom Severity Scale (MSSS) total score at weeks 12, 16, 20, and 
24 and mean over weeks 16, 20, and 24 
Change from baseline in the Migraine Interictal Burden Scale (MIBS-4) total score at weeks 12, 16, 20, and 
24 and mean over weeks 16, 20, and 24 
Change from baseline in mean MMD over weeks 16, 20, and 24  
Change from baseline in MMD at weeks 16, 20, and 24 
Change from baseline in mean monthly acute migraine-specific medication days over weeks 16, 20, and 24 
Change from baseline in monthly acute migraine-specific medication days at weeks 16, 20, and 24 
Change from baseline in General Anxiety Disorder scale (GAD-7) total score at weeks 12 and 24 
Change from baseline in Patient Health Questionnaire (PHQ-9) total score at weeks 12 and 24 
9.5.1 
Analyses of Primary Efficacy Endpoint(s)/Estimand(s) 
The primary endpoint, the change from baseline in the TSQM overall satisfaction scale 
score at week 24, as measured by items 12 to 14 of the TSQM version 1.4 will be 
analyzed using a repeated measures mixed effects model, including baseline TSQM 
overall satisfaction scale score, visit, the prevailing erenumab dose from Week 12 
onwards, and baseline MMD based on observed data. 
The mean change from baseline in TSQM overall satisfaction scale score at week 24 will 
be estimated from the least-squares mean (LSM) of the mixed effects model, and the 
corresponding 95% CI will be provided. The nominal p-value will be reported by 
comparing the mean change from baseline in TSQM overall satisfaction scale score at 
week 24 to zero with a two-sided 5% significance level. 
This endpoint will be analyzed using the following subgroups respectively: 
 
Whether remained on standard of care migraine preventive throughout the study 
(yes vs. no) 
 
Migraine type (EM vs. CM) 


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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 final analysis. 
The purpose of the subgroup analyses is to explore if the treatment effect varies across 
subgroups of interest. Subgroup analyses will be performed using the same method as 
primary analysis method but within level of each subgroup of interest. 
The efficacy analysis set will be used for this endpoint analysis. 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
The secondary efficacy endpoints calculated by the methods as specified detailed in 
Table 9-2. Secondary Efficacy Endpoint Summary Table, column Primary Summary and 
Analysis Method.  
For continuous secondary endpoints, a generalized linear mixed effects model with the 
identity link function will be used. The model will include the corresponding baseline 
value for the endpoint being analyzed, visit, the prevailing erenumab dose from Week 12 
onwards, and baseline MMD. The corresponding 95% CI will be estimated from the LSM 
of the mixed effects model, and p-values comparing with zero at a two-sided 5% 
significance level will be reported. 
For binary secondary endpoints, a generalized linear mixed effects model with the logit 
link function will be used. The model will include the corresponding baseline value for the 
endpoint being analyzed (except for the global impression endpoints), visit, the 
prevailing erenumab dose from Week 12 onwards, and baseline MMD. The proportions 
and the corresponding 95% CI will be estimated from the LSM (with inverse link function) 
of the mixed effects model and will be reported. 
The secondary endpoints will be analyzed in the following subgroups: 
 
Whether remained on standard of care migraine preventive treatment throughout 
the study (yes vs. no) 
 
Migraine type (EM vs. CM)  
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 final analysis. 


Product:  Erenumab (AMG 334) 
Protocol Number:  20190389 
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The purpose of the subgroup analyses is to explore if the treatment effect varies across 
subgroups of interest. Subgroup analyses will be performed using the same method as 
primary analysis method but within level of each subgroup of interest. 
The efficacy analysis set will be used for this endpoints analyses. 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 
The exploratory efficacy endpoints calculated by the method as specified in Table 9-3.   
All the exploratory endpoints will be analyzed the same way as that for the primary and 
secondary endpoints without any intercurrent event handling. 
The subgroup analysis is not applicable for exploratory endpoints.  
The efficacy analysis set will be used for all the exploratory endpoint analyses. 
9.6 
Safety Analyses 
All safety analyses will be performed based on all subjects in the Safety Analysis Set, 
both overall and separately by migraine prevention therapy standard of care status 
(continuation vs discontinuation).  
The safety analysis will includes the adverse events, serious adverse events, and 
adverse device effects. 
No formal hypothesis testing will be performed for this study. 
9.6.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 26.0 or later will be 
used to code all adverse events. 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class (SOC) and preferred term (PT).  Tables of fatal adverse events, serious 
adverse events, adverse events leading to discontinuation from investigational product 
or other protocol-required therapies, 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) 
 
COVID-19 SMQ (Narrow) 


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Subject incidence of device-related events, if applicable, will be tabulated by system 
organ class and preferred term. 
In addition, summaries of treatment-emergent and serious adverse events will be 
tabulated by SOC, PT, and grade.  
The adverse event grading scale to be used for this study will be the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
9.6.2 
Laboratory Test Results 
Not applicable. 
9.6.3 
Exposure to Investigational Product 
The number and percentage of subjects with dose change, reason for dose change for 
both dose adjustment and none or partial dose, and duration of exposure to 
investigational product in days will be summarized over time. 
Descriptive statistics will be produced to describe the exposure to investigational product 
by migraine types (EM/CM) separately and overall population.  
9.6.4 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving migraine preventive medications will 
be summarized by medication category. Number and proportion of subjects who 
discontinue standard of care migraine prevention therapy will also be 
summarized. 
9.7 
Other Analyses 
Not applicable. 
10. 
Changes From Protocol-specified Analyses 
Frequency of headache and migraine days collected on CRF “Headache and 
Migraine Frequency Medical History” at screening period will be included to 
derive migraine type, in addition to eDiary at baseline. 
The definition of efficacy analysis set stated in the protocol is not applicable to all 
efficacy endpoints and has been corrected in Section 6.3 to what was intended. 
These changes will also be documented in the clinical study report. 
11. 
Literature Citations / References 
NA 
12. 
Prioritization of Analyses 
Prioritization of analyses has not been identified at this time. 


Product:  Erenumab (AMG 334) 
Protocol Number:  20190389 
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13. 
Data Not Covered by This Plan 
There are no plans to specifically analyze or summarize the following substudy outcome 
variables.   
 
Migraine impact 
 
Treatment efficacy 
 
Migraine experience 
Qualitative data on changes resulting from treatment received in the open-label 
treatment period will be collected via telephone interview. 
Data will be analyzed to achieve the study objectives, using qualitative data analysis 
software (ie, ATLAS.ti). 


Product:  Erenumab (AMG 334) 
Protocol Number:  20190389 
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14. 
Appendices 
Not applicable.