Clinical trial NCT03971071
Conditions: Migraine Headache
Keywords: Chronic Migraine Medication Overuse Headache
Sponsor: Amgen
Start date: 2019-10-07; Completion date: 2023-06-13
Enrollment: 620 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study 20170703 is a phase 4, randomized, double-blind, parallel-group, placebo-controlled study to evaluate the efficacy and safety of erenumab against placebo in participants with chronic migraine (CM) who have a history of at least 1 preventive treatment failure and are diagnosed with medication overuse headache (MOH).

Detailed description:
Study 20170703 is a phase 4, randomized, double-blind, double-dummy, parallel-group, placebo-controlled study to evaluate the safety and efficacy of erenumab against placebo in a CM population with MOH and prior history of treatment failure. Participants will be enrolled based on fulfilment of the International Classification of Headache Disorders, 3rd Edition (ICHD-3) CM and MOH criteria and will not be advised to early discontinue acute medication.

Participants who successfully complete the 24-week double-blind treatment period (DBTP) of the study will be offered an opportunity to continue in an open-label treatment period (OLTP) of 28-weeks duration. Participants who received erenumab treatment during the DBTP will continue to receive the same erenumab dose during the OLTP. Participants who received placebo during the DBTP will be allocated in a 1:1 ratio to receive either erenumab 70 mg or 140 mg SC QM during the OLTP. All participants will remain blinded to their original DBTP treatment assignment.

Arms: arm 1: After participants complete the baseline period and are found eligible, they will be enrolled and randomized in a 1:1:1 ratio to either erenumab (70 mg or 140 mg) or placebo. arm 2: After participants complete the baseline period and are found eligible, they will be enrolled and randomized in a 1:1:1 ratio to either erenumab (70 mg or 140 mg) or placebo. arm 3: After participants complete the baseline period and are found eligible, they will be enrolled and randomized in a 1:1:1 ratio to either erenumab (70 mg or 140 mg) or placebo.
Interventions: intervention 1: Erenumab 70 mg intervention 2: Erenumab 140 mg intervention 3: Placebo
Intervention descriptions: intervention 1: Erenumab once every 4 weeks. Subcutaneous injection. intervention 2: Erenumab once every 4 weeks. Subcutaneous injection. intervention 3: Placebo once every 4 weeks. Subcutaneous injection.

Protocol documents:
Prot_002.pdf: 
Product:  Erenumab
Protocol Number:  20170703
Date:  27 May 2020
Page 1 of 144
CONFIDENTIAL
Title Page
Protocol Title:
A Phase 4, Randomized, Double-blind, 
Placebo-controlled, Parallel-group Study to 
Evaluate the Efficacy and Safety of Erenumab in 
Adults With Chronic Migraine and Medication 
Overuse Headache
Short Protocol Title:
A Phase 4 Randomized Controlled Study to 
Evaluate the Efficacy and Safety of Erenumab in 
Adults With Medication Overuse Headache
Protocol Number:
20170703
Investigational Product:
Erenumab
Trade Name:
AIMOVIG
Sponsor
Name of Sponsor:
Amgen Inc. 
Address:
One Amgen Center Drive 
Thousand Oaks, CA 91320
Telephone Number:
805-447-1000
Protocol 
Approver
Name:
Function:
Global Development Lead
Key 
Sponsor 
Contact
Name:
Address:
One Amgen Center Drive 
Thousand Oaks, CA 91320
Telephone Number:
Email Address:
EudraCT Number:
2018-003342-16
NCT Number:
NCT03971071
Protocol Date:
Document Version
Date
Approved


Product:  Erenumab
Protocol Number:  20170703
Date:  27 May 2020
Page 2 of 144
CONFIDENTIAL
Original
20 September 2018
Amendment 1 (v2.0)
19 April 2019
Amendment 2 (v3.0)
27 May 2020
Version/Date:
Data Element Standards Version
6.1 
Confidentiality Notice
This document contains confidential information of Amgen Inc.
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent.
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc.
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN; Canadian sites, 
1-866-50-AMGEN; for all other countries, insert the local toll-free Medical Information 
number; Amgen’s general number in the US, 1-805-447-1000.
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Product:  Erenumab
Protocol Number:  20170703
Date:  27 May 2020
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Investigator’s Agreement:
I have read the attached protocol entitled A Phase 4, Randomized, Double-blind, 
Placebo-controlled, Parallel-group Study to Evaluate the Efficacy and Safety of 
Erenumab in Adults With Chronic Migraine and Medication Overuse Headache, dated 
27 May 2020, and agree to abide by all provisions set forth therein.  
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP), Declaration of Helsinki, and applicable 
national or regional regulations/guidelines.   
I agree to ensure that Financial Disclosure Statements will be completed by: me 
(including, if applicable, my spouse or legal partner and dependent children) and my 
subinvestigators (including, if applicable, their spouses or legal partners and dependent 
children) at the start of the study and for up to 1 year after the study is completed, if 
there are changes that affect my financial disclosure status.
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc.
_______________________________
Signature
_______________________________
____________________________
Name of Investigator
Date (DD Month YYYY)
Approved


Product:  Erenumab
Protocol Number:  20170703
Date:  27 May 2020
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Table of Contents
Table of Contents............................................................................................................ 4
1.
Protocol Synopsis................................................................................................. 12
2.
Study Schema and Schedule of Activities.............................................................25
2.1
Study Schema...........................................................................................25
2.2
Schedule of Activities ................................................................................26
3.
Introduction...........................................................................................................35
3.1
Study Rationale.........................................................................................35
3.2
Background...............................................................................................36
3.2.1
Disease .....................................................................................36
3.2.2
Amgen Investigational Product Background:  
Erenumab .................................................................................38
3.3
Benefit/Risk Assessment...........................................................................38
4.
Objectives, Endpoints and Hypotheses................................................................. 39
4.1
Objectives and Endpoints..........................................................................39
4.2
Hypotheses...............................................................................................46
5.
Study Design ........................................................................................................47
5.1
Overall Design ..........................................................................................47
5.2
Number of Subjects...................................................................................47
5.2.1
Replacement of Subjects...........................................................48
5.2.2
Number of Sites.........................................................................48
5.3
End of Study .............................................................................................48
5.3.1
End of Study Definition..............................................................48
5.3.2
Study Duration for Subjects.......................................................49
5.4
Justification for Investigational Product Dose ............................................49
5.5
Patient Input on Study Design...................................................................49
6.
Study Population ..................................................................................................49
6.1
Inclusion Criteria Part 1.............................................................................50
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6.2
Exclusion Criteria Part 1............................................................................50
6.3
Inclusion Criteria Part 2.............................................................................57
6.4
Exclusion Criteria Part 2............................................................................58
6.5
Subject Enrollment....................................................................................62
6.6
Screen Failures.........................................................................................63
7.
Treatments ...........................................................................................................63
7.1
Treatment Procedures...............................................................................63
7.1.1
Investigational Products ............................................................63
7.1.2
Noninvestigational Products ......................................................65
7.1.3
Medical Devices ........................................................................65
7.1.4
Other Protocol-required Therapies ............................................65
7.1.5
Other Treatment Procedures.....................................................65
7.1.6
Product Complaints ...................................................................65
7.1.7
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ...............................................66
7.2
Method of Treatment Assignment .............................................................68
7.3
Blinding .....................................................................................................69
7.3.1
Site Personnel Access to Individual Treatment 
Assignments .............................................................................69
7.3.2
Access to Individual Subject Treatment Assignments 
by Amgen or Designees............................................................69
7.4
Dose Modification......................................................................................69
7.4.1
Dose-cohort Study Escalation/De-escalation and 
Stopping Rules..........................................................................70
7.4.2
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation .....................................70
7.4.2.1
Amgen Investigational Product:  
Erenumab or Matching Placebo ..............................70
7.4.3
Hepatotoxicity Stopping and Rechallenge Rules .......................70
7.5
Preparation/Handling/Storage/Accountability ............................................70
7.6
Treatment Compliance..............................................................................70
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7.7
Treatment of Overdose .............................................................................70
7.8
Prior and Concomitant Treatment .............................................................70
7.8.1
Prior Treatment .........................................................................70
For all other prior therapies that were being 
taken/used within 120 days prior to screening through 
the signing of the informed consent, therapy name, 
start and stop dates will be collected in the 
concomitant medication CRF. ..................................................71
7.8.2
Concomitant Treatment.............................................................71
8.
Discontinuation Criteria.........................................................................................71
8.1
Discontinuation of Study Treatment...........................................................71
8.2
Discontinuation From the Study ................................................................72
8.2.1
Reasons for Removal From Washout, Run-in or 
Invasive Procedures..................................................................73
8.2.2
Reasons for Removal From Study.............................................73
8.3
Lost to Follow-up.......................................................................................73
9.
Study Assessments and Procedures ....................................................................73
9.1
General Study Periods ..............................................................................74
9.1.1
Screening, Enrollment and/or Randomization............................74
9.1.1.1
Screening Period.....................................................74
9.1.1.2
Baseline Period.......................................................74
9.1.1.3
Randomization ........................................................75
9.1.2
Treatment Period.......................................................................75
9.1.3
Early Termination ......................................................................75
9.1.4
End of Study..............................................................................75
9.2
Description of General Study Assessments and Procedures.....................75
9.2.1
General Assessments ...............................................................75
9.2.1.1
Informed Consent....................................................75
9.2.1.2
Demographics.........................................................75
9.2.1.3
Medical History........................................................76
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9.2.1.4
Physical Examination ..............................................76
9.2.1.5
Physical Measurements ..........................................76
9.2.1.6
Performance Status.................................................76
9.2.2
Efficacy Assessments................................................................76
9.2.2.1
Clinical Outcome Assessments and 
Electronic Diaries (eDiaries)....................................76
9.2.2.2
Allodynia Symptoms Checklist 12 items 
(ASC-12)................................................................. 78
9.2.2.3
Beck Depression Inventory (BDI-II) .........................78
9.2.2.4
General Anxiety Disorder 7-item 
questionnaire (GAD-7) ............................................78
9.2.2.5
Headache Impact Test-6 (HIT-6).............................79
9.2.2.6
Migraine Disability Assessment 
Questionnaire (MIDAS) ...........................................79
9.2.2.7
Migraine Functional Impact Questionnaire 
(MFIQ).....................................................................80
9.2.2.8
Migraine Physical Function Impact Diary 
(MPFID) ..................................................................80
9.2.2.9
Patient Global Impression of Change 
(PGIC).....................................................................80
9.2.2.10
Sleep Questionnaire (ARMR sleep 
questionnaire) .........................................................81
9.2.2.11
Health Resource Utilization Resource 
Questionnaire (HRU)...............................................81
9.2.3
Safety Assessments..................................................................81
9.2.3.1
Adverse Events.......................................................82
9.2.3.2
Vital Signs...............................................................85
9.2.3.3
Electrocardiograms (ECGs).....................................85
9.2.3.4
Vital Status..............................................................85
9.2.3.5
Other Safety............................................................86
9.2.4
Clinical Laboratory Assessments...............................................86
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9.2.4.1
Pregnancy Testing ..................................................86
9.2.4.2
Prespecified Biomarker Assessments .....................87
9.2.5
Pharmacokinetic Assessments..................................................87
9.2.6
Pharmacodynamic Assessments...............................................87
9.2.7
Pharmacogenetic Assessments.................................................87
9.2.8
Antibody Testing Procedures.....................................................87
9.2.9
Biomarker Development ............................................................87
9.2.10
Clinical Outcome Assessments .................................................87
9.2.11
Health Economics OR Medical Resource Utilization 
and Health Economics ..............................................................88
9.2.12
Optional Substudies ..................................................................88
9.2.13
Other Assessments ...................................................................88
10.
Statistical Considerations......................................................................................89
10.1
Sample Size Determination.......................................................................89
10.2
Analysis Sets, Subgroups, and Covariates................................................89
10.2.1
Analysis Sets.............................................................................89
10.2.1.1
Full Analysis Set......................................................89
10.2.1.2
Efficacy Analysis Set...............................................89
10.2.1.3
Safety Analysis Set .................................................90
10.2.1.4
Open-label Treatment Period Analysis Set..............90
10.2.2
Covariates .................................................................................90
10.2.3
Subgroups.................................................................................90
10.2.4
Handling of Missing and Incomplete Data..................................90
10.2.4.1
Missing and Incomplete Dates ................................91
10.3
Adaptive Design........................................................................................91
10.4
Statistical Analyses ...................................................................................91
10.4.1
Planned Analyses......................................................................92
10.4.1.1
Primary Analysis .....................................................92
10.4.1.2
Final Analysis..........................................................92
10.4.2
Methods of Analyses ................................................................. 92
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10.4.2.1
General Considerations...........................................92
10.4.2.2
Efficacy Analyses ....................................................93
10.4.2.3
Safety Analyses ......................................................94
10.4.2.4
Other Analyses........................................................95
11.
References ...........................................................................................................96
12.
Appendices...........................................................................................................99
12.1
Appendix 1.  List of Abbreviations and Definitions of Terms....................100
12.2
Appendix 2.  Clinical Laboratory Tests ....................................................105
12.3
Appendix 3.  Study Governance Considerations .....................................107
Independent Review Committee .............................................................107
Regulatory and Ethical Considerations....................................................107
Recruitment Procedures..........................................................................108
Informed Consent Process......................................................................108
Data Protection/Subject Confidentiality ...................................................109
Publication Policy....................................................................................110
Investigator Signatory Obligations...........................................................111
Data Quality Assurance...........................................................................111
Source Documents..................................................................................113
Study and Site Closure............................................................................114
Compensation.........................................................................................114
12.4
Appendix 4.  Safety Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting.....................................115
Definition of Adverse Event .....................................................................115
Definition of Serious Adverse Event ........................................................116
Definition of Adverse Device Effect .........................................................117
Recording Adverse Events and Serious Adverse Events ........................117
Evaluating Adverse Events and Serious Adverse Events........................118
Reporting of Serious Adverse Event........................................................119
Adverse Device Effects:  Recording, Evaluating and Reporting...............119
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12.5
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information......................................................125
Definition of Females of Childbearing Potential .......................................125
Collection of Pregnancy Information........................................................126
Collection of Lactation Information ..........................................................128
12.6
Appendix 6.  Sample Storage and Destruction........................................131
12.7
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions 
and Follow-up Assessments and Study Treatment Rechallenge 
Guidelines...............................................................................................133
Criteria for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other 
Protocol-required Therapies Due to Potential 
Hepatotoxicity..........................................................................133
Criteria for Rechallenge of Amgen Investigational Product and 
Other Protocol-required Therapies After Potential 
Hepatotoxicity..........................................................................134
Drug-induced Liver Injury Reporting and Additional 
Assessments...........................................................................135
12.8
Appendix 8.  Substudy:  Qualitative Interview Substudy to ‘A 
Phase 4, Randomized, Double-blind, Placebo-controlled, 
Parallel group Study to Evaluate the Efficacy and Safety of 
Erenumab in Adults With Chronic Migraine and Medication 
Overuse Headache.’ ...............................................................................137
List of Tables
Table 2-1.  Schedule of Activities - Study Visits Through Double-blind 
Treatment Period....................................................................................26
Table 2-2.  Schedule of Activities - Study Visits Through Open-label 
Treatment Period....................................................................................31
Table 2-3.  Schedule of Activities – Optional Interview-based Substudy 
(Selected US Sites Only) ........................................................................34
Table 7-1.  Study Treatments ........................................................................................64
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Table 12-1.  Analyte Listing .........................................................................................105
Table 12-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................134
List of Figures
Figure 2-1.  Study Schema............................................................................................25
Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Report 
Form.....................................................................................................120
Figure 12-2.  Pregnancy and Lactation Notification Worksheet....................................129
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1.
Protocol Synopsis
Protocol Title:  A Phase 4, Randomized, Double-blind, Placebo-controlled, 
Parallel-group Study to Evaluate the Efficacy and Safety of Erenumab in Adults With 
Chronic Migraine and Medication Overuse Headache
Short Protocol Title:  A Phase 4 Randomized Controlled Study to Evaluate the Efficacy 
and Safety of Erenumab in Adults With Medication Overuse Headache
Study Phase:  4 
Indication:  Preventive treatment of migraine in adults
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Rationale
In a prior study, erenumab 70 mg and 140 mg administered subcutaneously (SC) every 
4 weeks were superior to placebo in controlling monthly migraine days (MMD) in a 
chronic migraine (CM) population. A subgroup analysis revealed that CM subjects who 
met thresholds for medication overuse (CM-MO subjects) at baseline experienced 
significant reductions of their monthly headache days (MHD) and were able to revert 
medication overuse status more often than placebo-treated subjects. This benefit 
seemed to be heightened when the subgroup analysis was further refined to include 
CM-MO subjects with a history of at least 1 prior treatment failure due to lack of efficacy 
or tolerability issues. Based on these observations and the significant unmet medical 
need medication overuse headache (MOH) represents, Study 20170703 is being 
conducted to better understand the efficacy of erenumab in a dedicated MOH 
population.
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Product:  Erenumab
Protocol Number:  20170703
Date:  27 May 2020
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CONFIDENTIAL
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary
•
To evaluate the effect of 
erenumab compared with placebo 
on achieving MOH remission 
during the double-blind treatment 
period (DBTP)
•
Absence of MOH at month 6 as 
defined by mean monthly acute 
headache medication days 
(AHMD) < 10 days over 
months 4, 5, and 6 (week 13 
through 24) OR mean monthly 
headache days (MHD) < 14 days 
over months 4, 5, and 6 (week 13 
through 24) of the DBTP where 
AHMD include any eDiary day in 
which an acute headache 
medication intake is reported
Primary Estimand
The estimand for the primary efficacy endpoint consists of:
•
The target population, which includes subjects diagnosed with CM and MOH who 
have a history of at least 1 preventive treatment failure and do not use opioid 
medication for more than 4 days per month
•
The endpoint, which is the absence of MOH at month 6 as defined by mean 
monthly AHMD < 10 days over months 4, 5, and 6 (week 13 through 24) OR 
mean MHD < 14 days over months 4, 5, and 6 (week 13 through 24) of the DBTP
•
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of investigational product (IP), regardless of adherence to 
treatment.
•
The summary measure, which is the odds ratio of absence of MOH between each 
erenumab dose group (ie, 70 mg or 140 mg) and the placebo group
Secondary
•
To evaluate the effect of 
erenumab compared with placebo 
in reducing acute headache 
medication days (AHMD) during 
the DBTP
•
Change from baseline in mean 
monthly AHMD over months 4, 5, 
and 6 (week 13 through 24) of 
the DBTP
The estimand for the secondary objective on AHMD consists of:
•
The target population, which includes subjects diagnosed with CM and MOH who 
have a history of at least 1 preventive treatment failure and do not use opioid 
medication for more than 4 days per month.
•
The endpoint, which is the change from baseline in mean monthly AHMD over 
months 4, 5, and 6 (week 13 through 24) of the DBTP 
•
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of investigational product (IP) and have at least 1 change 
from baseline in MHD, regardless of adherence to treatment.
•
The summary measure, which is the difference in mean of the endpoint between 
each erenumab dose group (ie, 70 mg and 140 mg) and the placebo group
•
To evaluate the effect of 
erenumab compared with placebo 
•
Sustained MOH remission during 
DBTP, as defined by absence of 
MOH at months 3 (week 12) and 
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Product:  Erenumab
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Objectives
Endpoints
on sustaining MOH remission 
during the DBTP
6 (week 24) of the DBTP, and 
“absence of MOH” is achieved 
when mean monthly 
AHMD < 10 days OR mean 
MHD < 14 days over the 
respective 3-month period 
The estimand for the secondary objective on sustained absence of MOH consists of:
•
The target population, which includes subjects diagnosed with CM and MOH who 
have a history of at least 1 preventive treatment failure and do not use opioid 
medication for more than 4 days per month
•
The endpoint, which is the sustained MOH remission during DBTP, as defined by 
absence of MOH over months 1, 2, and 3 (week 1 through 12) AND over months 
4, 5, and 6 (week 13 through 24) of the DBTP.  Absence of MOH is achieved 
when mean monthly AHMD < 10 days OR mean MHD < 14 days over the 
respective 3-month period
•
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of investigational product (IP), regardless of adherence to 
treatment.
•
The summary measure, which is the odds ratio of sustained MOH remission 
between each erenumab dose group (ie, 70 mg and 140 mg) and the placebo 
group
•
To evaluate the effect of 
erenumab compared with placebo 
on reducing the impact of 
migraines on physical impairment 
and everyday activities as 
measured by the Migraine 
Physical Function Impact Diary 
(MPFID) during the DBTPa
•
Change from baseline in mean 
monthly average physical 
impairment domain scores as 
measured by the MPFID over 
months 4, 5, and 6 (week 13 
through 24) of the DBTP
•
Change from baseline in mean 
monthly average impact on 
everyday activities domain scores 
as measured by the MPFID over 
months 4, 5, and 6 (week 13 
through 24) of the DBTP
The estimand for the secondary objective on MPFID consists of:
•
The target population, which includes subjects diagnosed with CM and MOH who 
have a history of at least 1 preventive treatment failure and do not use opioid 
medication for more than 4 days per month
•
The endpoints, which include (1) the change from baseline in mean monthly 
average physical impairment domain scores and (2) the change from baseline in 
mean monthly average impact on everyday activities domain scores as measured 
by the MPFID over months 4, 5, and 6 (week 13 through 24) of the DBTP 
•
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of investigational product (IP) and have at least 1 change 
from baseline in the respective domain score, regardless of adherence to 
treatment.
•
The summary measure, which is the difference in mean of the endpoint between 
each erenumab dose group (ie, 70 mg and 140 mg) and the placebo group
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Objectives
Endpoints
•
To evaluate the effect of 
erenumab compared to placebo 
on change from baseline in 
headache impact scores as 
measured by the Headache 
Impact Test (HIT-6)a  
•
Change from baseline in mean 
HIT-6 score over months 4, 5, 
and 6 (week 13 through 24) of 
the DBTP
The estimand for the secondary objective on HIT-6 consists of:
•
The target population, which includes subjects diagnosed with CM and MOH who 
have a history of at least 1 preventive treatment failure and do not use opioid 
medication for more than 4 days per month 
•
The endpoint, which is the change from baseline in mean HIT-6 total score over 
months 4, 5, and 6 (week 13 through 24) of the DBTP 
•
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of investigational product (IP) and have at least 1 change 
from baseline in HIT-6 total score, regardless of adherence to treatment.
•
The summary measure, which is the difference in mean of the endpoint between 
each erenumab dose group (ie, 70 mg and 140 mg) and the placebo group
Safety
•
To evaluate the safety and 
tolerability of erenumab in 
subjects with CM-MOH
•
Adverse events
•
Vital signs
a In the EU region only, HIT-6 will replace MPFID as a secondary endpoint and MPFID will be evaluated as 
an exploratory endpoint.  In non-EU regions, MPFID will remain as a secondary endpoint while HIT-6 will be 
evaluated as an exploratory endpoint.
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Hypotheses
The primary clinical hypothesis of Study 20170703 is that preventive treatment with 
monthly injections of erenumab is superior to placebo in achieving MOH remission for 
subjects with CM-MOH in the nonopioid-treated cohort who have a history of at least 
1 preventive treatment failure as measured by the absence of the MOH status based on 
the mean over months 4, 5, and 6 (week 13 through 24) of the DBTP.  
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Overall Design
Study 20170703 is a phase 4, randomized, double-blind, parallel-group, 
placebo-controlled study to evaluate the efficacy and safety of erenumab against 
placebo in subjects with CM who have a history of at least 1 preventive treatment failure 
and are diagnosed with MOH.
Up to 20% of the total population will be composed by subjects with regular opioid 
medication use (ie, > 4 days/month).  Subjects in this cohort will be randomized and 
evaluated separately in an exploratory fashion for the efficacy and safety of erenumab 
against placebo in reducing opioid medication intake. 
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Product:  Erenumab
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Date:  27 May 2020
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Number of Subjects
Approximately 687 subjects (549 subjects in the nonopioid-treated cohort and up to
138 subjects in the opioid-treated cohort) will be randomized in a 1:1:1 fashion to either 
placebo, erenumab 70 mg SC every 4 weeks, or erenumab 140 mg SC every 4 weeks.  
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Summary of Subject Eligibility Criteria
Adults ≥18 years with a documented history of migraine without aura and/or migraine 
with aura and MOH according to the International Headache Society (IHS) Classification 
(International Classification of Headache Disorders, 3rd Edition [ICHD-3]) for 
≥12 months at screening. 
For a full list of eligibility criteria, please refer to Section 6.1 to Section 6.4. 
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Treatments
Subjects will receive 2 SC injections (in the upper arm, upper thigh, or abdomen) on  
day 1 and every 4 weeks until week 24 (DBTP). Subjects randomized to the erenumab 
70 mg group will get 1 injection of active (erenumab 70 mg/mL) and 1 injection of 
placebo, subjects in the erenumab 140 mg group will receive 2 injections of active, and 
subjects randomized to placebo will receive 2 injections of placebo.  Subjects who 
successfully complete the DBTP of the study will be given the option to continue in an 
open-label treatment period (OLTP) of 28-week duration.  Subjects who received 
placebo during the DBTP will be allocated to either erenumab 70 mg or 140 mg in a 1:1 
fashion. Subjects who received erenumab during the DBTP will receive the same 
erenumab dose in OLTP.  The same treatment allocation procedure will be done within 
the opioid-treated and nonopioid-treated cohorts for placebo-treated subjects as defined 
at the initial randomization.   
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Procedures
After signing informed consent, subjects will enter an up to 7-week screening period, 
which is composed of an initial screening period up to 3 weeks followed by a 4-week 
baseline period.  Subjects will be randomized/enrolled into the 24-week DBTP and will 
begin to receive double-blind investigational product SC every 4 weeks.  Subjects who 
successfully complete the DBTP will have the opportunity to enter a 28-week OLTP.  
Subjects will use an electronic diary (eDiary) everyday throughout the baseline period, 
DBTP, and during the last quarter of the OLTP (defined as starting at the week 40 visit 
through week 52/End of Study [EOS]) to report information about their migraine and 
nonmigraine headaches, other migraine-related symptoms, and acute headache 
medication use.  Subjects will have scheduled in-clinic study visits throughout the study.
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 9.2 and the Schedule of Activities in Table 2-1. 
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Statistical Considerations
The primary analysis will be performed when the last subject in the nonopioid-treated 
cohort completes the week 24 assessments or discontinues the DBTP.  The final 
analysis for the study will be performed after all subjects (nonopioid-treated and 
opioid-treated cohorts) complete the study through the OLTP last visit or discontinue 
from the study.
Formal statistical analyses using statistical models and hypothesis testing will be 
performed for the nonopioid-treated cohort only. 
For the primary and other dichotomous efficacy endpoints, a stratified 
Cochran-Mantel-Haenszel test will be used after the missing data is imputed as 
nonresponse.  Continuous secondary endpoints will be analyzed using a linear mixed 
effects model including treatment group, baseline value, stratification factor, scheduled 
visit, and the interaction of treatment group with scheduled visit, without any imputation 
for missing data.  The mean change from baseline for each treatment group, the 
treatment difference, 95% CI, and p-value will be reported. 
The 2 erenumab dose groups will be compared with placebo for the primary and 
secondary efficacy endpoints in the nonopioid-treated cohort using a simple fixed 
sequence procedure with a study-wise type I error rate α = 0.05.  The order of the 
endpoints to be tested is prespecified below. If any test is not significant at the α = 0.05
level, no further testing will be performed.  
Primary and secondary endpoints in erenumab 140 mg versus placebo:
1. 
Absence of MOH at month 6 (week 24) of the DBTP (140 mg)
2.
Change from baseline in mean monthly AHMD over months 4, 5, and 6 (week 13 
through 24) of the DBTP (140 mg)
3.
Sustained MOH remission during DBTP (140 mg)
Primary and secondary endpoints in erenumab 70 mg versus placebo:
4.
Absence of MOH at month 6 (week 24) of the DBTP (70 mg)
5.
Change from baseline in mean monthly AHMD over months 4, 5, and 6 (week 13 
through 24) of the DBTP (70 mg)
6.
Sustained MOH remission during DBTP (70 mg)
Patient-reported outcome-related secondary endpoints for the non-European Union (EU)
region: 
7.
Change from the baseline in mean monthly average physical impairment domain 
scores as measured by the MPFID over months 4, 5, and 6 (week 13 through 24) 
of the DBTP (140 mg) 
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8.
Change from the baseline in mean monthly average impact on everyday activities 
domain scores as measured by the MPFID over months 4, 5, and 6 (week 13 
through 24) of the DBTP (140 mg)
9.
Change from the baseline in mean monthly average physical impairment domain 
scores as measured by the MPFID over months 4, 5, and 6 (week 13 through 24) 
of the DBTP (70 mg) 
10.
Change from the baseline in mean monthly average impact on everyday activities 
domain scores as measured by the MPFID over months 4, 5, and 6 (week 13 
through 24) of the DBTP (70 mg) 
OR
Patient-reported outcome-related secondary endpoints for the EU region:
7. Change from baseline in mean HIT-6 score over months 4, 5, and 6 (week 13 
through 24) of the DBTP (140 mg) 
8. Change from baseline in mean HIT-6 score over months 4, 5, and 6 (week 13 
through 24) of the DBTP (70 mg) 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor Name:
Amgen Inc.  
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Product:  Erenumab
Protocol Number:  20170703
Date:  27 May 2020
Page 25 of 144
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2.
Study Schema and Schedule of Activities
2.1
Study Schema
Figure 2-1.  Study Schema
Treatment Period 
(up to 52 weeks)
Double-blind
Treatment Period
(24 weeks)
Open-label
Treatment Period
(28 weeks)
Placebo
SC QM
N = 229
Erenumab 70 mg SC QM
Erenumab 140 mg SC QM
Erenumab
70 mg SC QM
N = 229
Erenumab
140 mg SC QM
N = 229
Randomization 1:1:1
Baseline Period 
(4 weeks)
Initial Screening Period
(Up to 3 weeks)
Erenumab 70 mg SC QM
Erenumab 140 mg 
SC QM
End of Study
1: 1
-4 weeks
Day 1
Week 24
Week 52/EOS
SC = subcutaneous; QM = monthly; EOS = End of Study
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2.2
Schedule of Activities
Table 2-1.  Schedule of Activities - Study Visits Through Double-blind Treatment Period
Screening Period
Treatment Period
Initial Screening 
Period
Baseline Perioda
Double-blind Treatment Period (24 Weeks)
PROCEDURE
(up to 3 weeks before 
Baseline)
(4 weeks before 
Day 1)
Day 1b Wk 4 Wk 8 Wk 12 Wk 16 Wk 20
Wk 24/
ETc
Notes
Clinic Visit
X 
X 
X 
X 
X 
X 
X 
X 
X 
Informed consent
X 
IRT call
X 
X 
X 
X 
X 
X 
X 
X 
Part 1 inclusion and exclusion 
criteria
X 
Demographics
X 
Physical examination
X 
X 
Physical measurements
X 
X 
Medical history
X 
Neurological medical history
X 
Cardiovascular medical 
history
X 
Cardiac risk factors
X 
Headache and migraine 
frequency history
X
Migraine prevention 
medication history
X 
Vital signs
X 
X 
X 
X 
X 
X 
X 
X 
Pre-randomization on Day 1; BP, HR, 
RR, and temperature
Page 1 of 4
Footnotes after last page of table.
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Table 2-1.  Schedule of Activities - Study Visits Through Double-blind Treatment Period
Screening Period
Treatment Period
Initial Screening 
Period
Baseline 
Perioda
Double-blind Treatment Period (24 Weeks)
PROCEDURE
(up to 3 weeks
before Baseline)
(4 weeks
before Day 1)
Day 1b
Wk 4 Wk 8 Wk 12 Wk 16 Wk 20
Wk 24/
ETc
Notes
Electrocardiogram
X 
Part 2 inclusion and exclusion 
criteria
X 
Pre-randomization on Day 1
Randomization
X 
Adverse events
X 
X 
X 
X 
X 
X 
X 
Post-randomization on Day 1
Serious adverse events
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse device effectsd
X
X
X
X
X
X
X
Product complaints
X 
X 
X 
X 
X 
X 
X 
Concomitant therapies review
X 
X 
X 
X 
X 
X 
X 
X 
LABORATORY ASSESSMENTSe
Urine pregnancy test (females of 
childbearing potential only)f
X 
X 
X 
X 
X 
X 
X 
X 
A highly sensitive test at screening 
and at Day 1 pre-randomization of 
initiation of investigational product
Urine drug testing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Post-randomization on Day 1; 
Central laboratory
Hematology
X 
X (to be performed at the discretion of the investigator)
Central laboratory
After screening, hematology testing 
will be at the discretion of the 
investigator 
Page 2 of 4
Footnotes after last page of table.
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Table 2-1.  Schedule of Activities - Study Visits Through Double-blind Treatment 
Screening Period
Treatment Period
Initial Screening
Period
Baseline 
Perioda
Double-blind Treatment Period (24 Weeks)
PROCEDURE
(up to 3 weeks
before Baseline)
(4 weeks
before Day 1)
Day 1b
Wk 4 Wk 8 Wk 12
Wk 16
Wk 20
Wk 24/
ETc
Notes
Chemistry
X 
X (to be performed at the discretion of the investigator)
Central laboratory
After screening, chemistry testing will 
be at the discretion of the investigator 
HIV, Hepatitis B and C 
screening
X 
Central laboratory
BIOMARKER DEVELOPMENT
Blood sample
X 
X 
X 
PHARMACOGENETIC ASSESSMENTS
Pharmacogenetic sampling 
(optional)g
X 
Post-randomization on Day 1; central 
laboratory
STUDY TREATMENT
Amgen investigational product
X 
X 
X 
X 
X 
X 
Pre-filled syringes
CLINICAL OUTCOME ASSESSMENTS/PATIENT-REPORTED OUTCOMES
Assign eDiary to subject
X 
Subject brings eDiary to center 
for use during visit or to return
X 
X 
X 
X 
X 
X 
X 
Sites retain eDiary at week 24/ET 
visit
eDiary
X (Daily)
Daily
MPFID
X (Daily)
Daily
HIT-6 
X 
X 
X 
X 
X 
X 
X 
Post-randomization on Day 1; 
eDiary in clinic
MFIQ
X 
X 
X 
X 
X 
X 
X 
Post-randomization on Day 1; 
eDiary in clinic
ASC-12
X 
X 
X 
Post-randomization on Day 1; 
eDiary in clinic
Page 3 of 4
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Product:  Erenumab
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Date:  27 May 2020
Page 29 of 144
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Table 2-1.  Schedule of Activities - Study Visits Through Double-blind Treatment 
Screening Period
Treatment Period
Initial Screening 
Period
Baseline 
Perioda
Double-blind Treatment Period (24 Weeks)
PROCEDURE
(up to 3 weeks
before Baseline)
(4 weeks
before Day 1)
Day 1b
Wk 4 Wk 8 Wk 12 Wk 16 Wk 20
Wk 24/
ETc
Notes
MIDAS
X 
X 
X 
Post-randomization on Day 1; eDiary 
in clinic
BDI-IIh
X
Xi
X
X
eDiary; in clinic
GAD-7 
X 
X 
X 
Post-randomization on Day 1; eDiary 
in clinic
Sleep Questionnaire 
X 
X 
X 
Post-randomization on Day 1; eDiary 
in clinic
PGIC
X 
eDiary in clinic
HRU Questionnairej
X 
X 
Post randomization on Day 1; in clinic
Page 4 of 4 
ASC-12 = Allodynia Symptoms Checklist-12; BDI-II = Beck Depression Inventory-II; BP = blood pressure; DBTP = double-blind treatment period; eDiary = electronic 
diary; ET = early termination; GAD-7 = Generalized Anxiety Disorder 7-item Scale; HIT-6 = Headache Impact Test-6; HIV = human immunodeficiency virus; HR = heart 
rate; HRU = Health Resource Utilization; IRT = Interactive Response Technology; MFIQ = Migraine Functional Impact Questionnaire; MIDAS = Migraine Disability 
Assessment; MPFID = Migraine Physical Function Impact Diary; OLTP = open-label treatment period; PGIC = Patient Global Impression of Change; RR = respiratory 
rate 
a The baseline period ends when either a subject is screen failed or randomized into the study. Randomization occurs at the Day 1 visit which must occur 
between 29 to 35 days after baseline entry (inclusive of the first day that eDiary device is assigned to subject). 
b On Day 1, all study assessments should be completed prior to subject’s first dose of investigational product. 
c A subject who discontinues the study during the DBTP will complete the assessments of the week 24/ET visit approximately 28 (+3) days after the last dose of 
investigational product. 
d Including pre-filled syringe in DBTP and autoinjector during OLTP. 
e All clinical laboratory testing at screening (except pregnancy testing) will be performed at a central laboratory.
f Additional on-treatment local laboratory 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. 
g For subjects who provided informed consent for the pharmacogenetic studies, DNA will be obtained from residual cells from the biomarker blood sample.  Therefore, 
additional sampling is not required.
h The BDI-II will be collected via paper CRF during screening and eDiary thereafter.
i The Baseline Period BDI-II will be completed at the end of the Baseline Period using the eDiary, after at least 28 days of data has been entered in the 
eDiary.
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j The baseline HRU questionnaire will have a 24-week recall of prior utilization.  The HRU questionnaire assessed at the ET visit before week 24 should only include 
HRU recalled since the previous assessment to avoid collecting duplicate information.  For example, the 24-week HRU questionnaire assessed at week 20 as the ET 
visit should only include HRU recalled since the previous assessment at day 1 (ie, 20-week recall).
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Table 2-2.  Schedule of Activities - Study Visits Through Open-label Treatment Period  
Treatment Period
Open-label Treatment Period (28 Weeks)
PROCEDURE
Wk 24
(OLTP
Entry Visit)
Wk 28
Wk 32
Wk 36
Wk 40
Wk 44
Wk48
Wk 52/ 
EOSa
Notes
GENERAL AND SAFETY ASSESSMENTS
Clinic Visit
X 
X 
X 
X 
Telephone Contact
X 
X 
X 
X 
IRT callb
X 
X 
X 
X 
Physical examination
X 
X 
X 
Vital signs
X 
X 
X 
BP, HR, RR, 
and 
temperature
Adverse events
X 
X 
X 
X 
X 
X 
X 
X 
Serious adverse events
X 
X 
X 
X 
X 
X 
X 
X 
Adverse device effectsc
X 
X 
X 
X 
X 
X 
X 
X 
Product complaints
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapies review
X 
X 
X 
X 
X 
X 
X 
X 
Page 1 of 3 
Footnotes after last page of table.
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Table 2-2.  Schedule of Activities - Study Visits Through Open-label Treatment Period
Treatment Period
Open-label Treatment Period (28 Weeks)
PROCEDURE
Wk 24
(OLTP
Entry Visit)
Wk 28
Wk 32
Wk 36
Wk 40
Wk 44
Wk 48
Wk 52/ 
EOSa
Notes
LABORATORY ASSESSMENTS
Urine pregnancy test (females of 
childbearing potential only)d
X 
X 
X 
X 
Urine drug test
X (to be performed at the discretion of the investigator)
Chemistry
X (to be performed at the discretion of the investigator)
X 
CLINICAL OUTCOME ASSESSMENTS/PATIENT-REPORTED OUTCOMES
Site re-assigns eDiary to subject
X 
eDiary
X (Daily)
Daily during 
assessment 
study months
Subject brings eDiary to center for 
use during visit or to return
X 
Sites should 
retain eDiary at 
EOS visit
MPFID 
X (Daily)
Daily during 
assessment
study months
HIT-6 
X 
eDiary in clinic
MFIQ
X 
eDiary in clinic
MIDAS
X 
eDiary in clinic
Page 2 of 3 
Footnotes after last page of table.
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Table 2-2.  Schedule of Activities - Study Visits Through Open-label Treatment Period
Treatment Period
Open-label Treatment Period (28 Weeks)
PROCEDURE
Wk 24
(OLTP
Entry Visit)
Wk 28
Wk 32
Wk 36
Wk 40
Wk 44
Wk48
Wk 52/ 
EOSa
Notes
STUDY TREATMENT
Subject receives training on usage 
of autoinjector
X 
Self-administration of 
investigational product at clinic
X 
X 
X 
Self-administration of 
investigational product at home
X 
X 
X 
X 
Study staff dispenses and/or 
reconciles investigational product
X 
X 
X 
Amgen investigational producte
X 
X 
X 
X 
X 
X 
X 
Autoinjectors
Page 3 of 3 
BP = blood pressure; DBTP = double-blind treatment period; eDiary = electronic diary; EOS = end of study; ET = early termination; HIT-6 = Headache Impact Test-6; 
HR = heart rate; IRT = Interactive Response Technology; MFIQ = Migraine Functional Impact Questionnaire; MIDAS = Migraine Disability Assessment; 
MPFID = Migraine Physical Function Impact Diary; OLTP = open-label treatment period; RR = respiratory rate 
a A subject who discontinues investigational product during the OLTP or who completes the study will perform the week 52/EOS visit assessments. Subjects who early 
terminate will complete the assessments approximately 28 (+3) days after the last dose of investigational product.
b All subjects will be enrolled via IRT in the OLTP to maintain the initial treatment blinding in DBTP.  Subjects who received active treatment during the DBTP will 
remain on the same dose.  Subjects who received placebo will receive either 70 mg or 140 mg in a 1:1 ratio.  
c Including pre-filled syringe in DBTP and autoinjector during OLTP.
d Additional on-treatment local laboratory 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.
e Study drug supply ceases at week 48.   
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Table 2-3.  Schedule of Activities – Optional Interview-based Substudy (Selected US Sites Only)
Treatment Period
Screening
Period
Baseline
Period
Double-blind Treatment Period (24 Weeks)
PROCEDURE
(up to 
3 weeks
before 
Baseline)
(4 weeks
before 
Day 1)
Day 1 
(post-rand)
Wk 4 
Wk 8 
Wk 12
Wk 16
Wk 20
Wk 24/
ET
Notes
INTERVIEW-BASED SUBSTUDY
Substudy informed consent
Xa
Substudy Eligibility Requirements
X 
Interviewb
Xc
Xd
DBTP = double-blind treatment period; ET = early termination; US = United States.
a The Substudy subject informed consent can also be obtained at the same time as the main study informed consent during Screening instead of after 
randomization.
b The first interview (Interview 1) will be conducted within the first week after randomization, the second interview (Interview 2) will be conducted within 1 week after the 
subject’s last visit during the DBTP. 
c The entry interview will be conducted within 7 days from first investigational product dose.
d The exit interview will be conducted in close proximity with the week 24 or early termination visits (within 7 days prior to week 24 visit or within 
approximately 14 days post early termination visit.  If possible within 7 days post early termination will be targeted).
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3.
Introduction
3.1
Study Rationale
Preclinical models of migraine suggest that prolonged exposure to commonly used 
migraine-specific (ie, triptans) and nonmigraine specific (ie, opioids, nonsteroidal 
anti-inflammatory drugs [NSAIDs]) medication may produce long-lasting, pronociceptive 
neuroplastic changes in the trigeminal system including peripheral nerves, dorsal root 
ganglion, and nucleus caudalis (Meng et al, 2011). The reduction in pain-eliciting stimuli 
thresholds induced by acute medication appears to be temporally associated with 
increased release of calcitonin gene-related peptide (CGRP) on the circulatory system 
and was successfully abolished by a CGRP receptor antagonist in a triptan-induced 
medication overuse headache (MOH) rodent model (Meng et al, 2011;
De Felice et al, 2010).  
In Study 20120295, erenumab 70 mg and 140 mg subcutaneously (SC) every 4 weeks
were superior to placebo in reducing monthly migraine days (MMD) from baseline to the 
last study month of the double-blind treatment period (DBTP) in subjects with chronic 
migraine (CM) with or without medication overuse status at baseline. In a prespecified 
subgroup analysis including subjects with CM with medication overuse (CM-MO 
subjects), both doses of erenumab achieved numerical and nominal superiority to 
placebo in reducing MMD (least-squares mean [LSM]: -3.1 days for both 70 mg and 
140 mg versus placebo, p < 0.001), achieving ≥50% reduction in MMD at month 3 (odds 
ratio: 2.67 and 2.51 for 70 mg and 140 mg, respectively; p = -0.004 and 0.007, 
respectively) and acute headache medication days (AHMD) (LSM: -3.3 and -2.8 for 
70 mg and 140 mg, respectively; p < 0.001) (Tepper et al, 2017).  A subsequent 
post hoc subgroup analysis including CM-MO subjects who had failed 1 or more 
migraine preventive treatment further confirmed this observation with numerically 
superior reductions for both erenumab doses as compared with placebo in MMD (LSM:  
2.54 and 4.44 for 70 mg and 140 mg, respectively), moderate to severe headache days 
(LSM:  1.81 and 3.82 for 70 mg and 140 mg, respectively) and AHMD (LSM:  2.61 and 
4.26 for 70 mg and 140 mg, respectively). In addition, more subjects treated with 
erenumab (47% and 52% in 70 mg and 140 mg, respectively) met medication 
overuse-free status at the end of DBTP as compared with placebo (29%).   
The safety profile of subjects included in the CM-MO stratum was consistent with that of 
the 12-week integrated safety analysis set for the erenumab clinical development 
program. Overall, at least 1 treatment emergent adverse event was reported for 46.2%, 
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48.7%, and 34.2% of subjects in the erenumab 70 mg, erenumab 140 mg, and placebo 
groups in the CM-MO stratum, respectively. Majority of treatment-emergent adverse 
events (TEAEs) were categorized CTCAE grade 1 or 2 with CTCAE grade 3 TEAEs only 
reported for 6.4%, 1.3%, and 5.3% of subjects in the erenumab 70 mg, erenumab 
140 mg, and placebo groups. There were no CTCAE category 4 or deaths reported and 
serious adverse events (SAEs) were observed in 3.8%, 1.3%, and 1.8% of subjects in 
the erenumab 70 mg, erenumab 140 mg, and placebo groups, respectively.
Given the unmet medical need that MOH represents, and based on preliminary 
information obtained from Study 20120295, Study 20170703 is being conducted to 
confirm the efficacy of erenumab in a dedicated MOH population.
3.2
Background
3.2.1
Disease
In patients with migraine, frequent intake of acute pain medication can yield a 
paradoxical effect and contribute to increased pain severity and frequency of days with 
headache (May and Schulte, 2016). This phenomenon is often met with a cyclic pattern 
of further increase in acute pain medication intake and consequential clinical 
deterioration which may lead to “chronification” (May and Schulte, 2016) of headache 
attacks. 
Metabolic, functional, and structural brain imaging studies involving subjects without 
migraine and subjects with CM with or without MOH have provided further evidence that 
the observed clinical deterioration associated with overuse of acute headache 
medication is possibly grounded on maladaptive neuroplasticity.  Volume-based
magnetic resonance imaging (MRI), stimulus-induced functional MRI, resting-state MRI, 
and positron emission tomography studies have reported changes in volume, 
connectivity, and metabolism in areas of the lateral pain system (the right supramarginal 
gyrus, right inferion and superior parietal cortex) and other encephalic areas associated 
with pain processing (ie, thalamus, insula, ventromedial prefrontal cortex) and the 
reward system (substantia nigra/ventral tegmentum, striatum, orbitofrontal cortex)  
(Lai et al, 2016; Riederer et al, 2013; Riederer et al, 2012; Ferraro et al, 2012a; 
Ferraro et al, 2012b; Grazzi et al, 2010; Chiapparini et al, 2009; Fumal et al, 2006). 
These functional anatomical changes appeared to be distinctive of MOH irrespective of 
headache frequency and have been reported to improve upon successful treatment of 
MOH (Schwedt and Chong, 2017).
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Longitudinal epidemiological studies have also strengthened the association between
medication overuse and migraine chronification.  In the American Migraine Prevalence 
and Prevention study, high frequency episodic migraine (EM) subjects (ie, 10 to 
14 headache days/month) who reported medication overuse had a 12-month conversion 
to CM risk that was several fold higher than those who reported no medication overuse  
(Bigal et al, 2008).
In recognition of the potential to accompany and complicate primary headache 
disorders, the International Classification of Headache Disorders (ICHD) has recognized 
chronification of a primary headache that is associated with excessive and sustained 
overuse of acute medication as a secondary headache disorder termed MOH, a term 
that, in line with preclinical observations, implies a potential causative role for acute 
medication overuse in peripheral and central pain sensitization. 
Medication overuse headache is believed to be a highly pervasive and underrecognized 
condition. Prevalence estimates in an adult Western population have been reported to 
range from 1% to 2% with majority of cases (ie, from 80% to 100%) having migraine as 
an underlying primary headache disorder either isolated or in association with another 
primary headache (Kristoffersen and Lundqvist, 2014).  Known risk factors to date for 
the development of MOH include a diagnosis of migraine, high frequency of headache 
attacks, female gender, psychiatric comorbidity, pre-existing pain, and acute pain 
medication use (migraine-specific [triptans, ergotamines] or nonspecific [eg, NSAIDs, 
opioids], or combinations thereof), allodynia, lower socioeconomic status, and 
lifestyle-related factors (Diener et al, 2016).
Clinically, the association of medication overuse headache with CM has been linked to 
an increased risk of preventive treatment failure, stronger association with psychiatric 
comorbidities (ie, mood disorders, substance-related disorders), increased 
migraine-related disability, higher levels of health care utilization, and overall decreased 
quality of life (Diener et al, 2016; Raggi et al, 2015; Kristoffersen and Lundqvist, 2014). 
Economically, MOH places a high burden on society with the per-person annual costs 
being estimated to be approximately 10 times greater than those of tension-type 
headache and 3 times greater than those of migraine without MOH in Europe
(Linde et al, 2012). 
Recommended treatment options for MOH include early discontinuation of the overused 
acute medication, initiation or optimization of a preventive intervention, or a combination 
of both. Evidence to support efficacy of each 1 of these treatment modalities in isolation 
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or combined is limited by the lack of large randomized controlled trials in MOH 
(Chiang et al, 2016).  A summary of current standard-of-care options and their 
evidentiary basis is presented in . 
3.2.2
Amgen Investigational Product Background:  Erenumab
Erenumab is a human immunoglobulin G2 (IgG2) that is directed against the CGRP 
receptor complex and inhibits the action of CGRP. 
Calcitonin gene-related peptide belongs to the calcitonin family of peptides and is 
expressed in both the central and peripheral nervous systems.  It is prominently involved 
in the pathophysiology of migraine through nociceptive modulation, in the 
trigeminovascular system (Goadsby et al, 2002; Tajti et al, 1999).  Nonclinical studies 
with erenumab demonstrated that it binds to and antagonizes both human and 
cynomolgus monkey CGRP receptors with high affinity and potency.  Erenumab has 
been developed for the prevention of migraine in adults based on the observed long 
serum half-life in humans (28 days), clinical data demonstrating that small molecule 
CGRP receptor antagonists are effective in acute migraine reversal (Ho et al, 2008a;
Ho et al, 2008b), prevention (Ho et al, 2014), and the strong rationale for CGRP’s 
association with migraine pathophysiology (Goadsby et al 2017; Sun et al, 2016;
Bellamy et al, 2006; Sarchielli et al, 2006; Juhasz et al, 2005; Petersen et al, 2005; 
Lassen et al, 2002; Tajti et al, 1999; Gallai et al, 1995; Goadsby et al 1990; 
Goadsby et al, 1988).
As of the date of approval of this protocol, erenumab 70 mg and 140 mg SC QM have 
been approved in the United States, European Union (EU), and other regions for the 
prevention of migraine in adults. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of erenumab 
is provided in the Investigator’s Brochure and regional label. 
3.3
Benefit/Risk Assessment
The identified risks for AMG 334 are documented in Appendix A of the currently 
approved IB (Edition  11:  February 2020).  A limited number of adverse drug 
reactions (injection site reactions, constipation, muscle spasm, and pruritis) have 
been identified at low frequencies (< 5%) in clinical trials.  In post-marketing 
settings, hypersensitivity reactions (including rash, angioedema and 
anaphylactoid reactions) and constipation with serious complications have been 
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reported.  Available safety data for the clinical trials with AMG 334 are summarized 
in Section 6.3 of the AMG 334 Investigator’s Brochure, Annex 2.
4.
Objectives, Endpoints and Hypotheses
4.1
Objectives and Endpoints
Objectives
Endpoints
Primary
•
To evaluate the effect of 
erenumab compared with placebo 
on achieving MOH remission
during the double-blind treatment 
period (DBTP)
•
Absence of MOH at month 6 as 
defined by mean monthly acute 
headache medication days 
(AHMD) < 10 days over 
months 4, 5, and 6 (week 12 
through 24) OR mean monthly 
headache days (MHD) < 14 days 
over months 4, 5, and 6 (week 12 
through 24) of the DBTP where 
AHMD include any eDiary day in 
which an acute headache 
medication intake is reported
Primary Estimand
The estimand for the primary efficacy endpoint consists of:
•
The target population, which includes subjects diagnosed with CM and MOH who 
have a history of at least 1 preventive treatment failure and do not use opioid 
medication for more than 4 days per month
•
The endpoint, which is the absence of MOH at month 6 as defined by mean 
monthly AHMD < 10 days over months 4, 5, and 6 (week 13 through 24) OR 
mean MHD < 14 days over months 4, 5, and 6 (week 13 through 24)of the DBTP
•
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of investigational product (IP), regardless of adherence to 
treatment.
•
The summary measure, which is the odds ratio of absence of MOH between each 
erenumab dose group (ie, 70 mg or 140 mg) and the placebo group
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Objectives
Endpoints
Secondary
•
To evaluate the effect of 
erenumab compared with placebo 
in reducing acute headache 
medication days (AHMD) during 
the DBTP
•
Change from baseline in mean 
monthly AHMD over months 4, 5, 
and 6 (week 13 through 24) of 
the DBTP
The estimand for the secondary objective on AHMD consists of:
•
The target population, which includes subjects diagnosed with CM and MOH who 
have a history of at least 1 preventive treatment failure and do not use opioid 
medication for more than 4 days per month.
•
The endpoint, which is the change from baseline in mean monthly AHMD over 
months 4, 5, and 6 (week 13 through 24) of the DBTP 
•
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of investigational product (IP) and have at least 1 change 
from baseline in MHD, regardless of adherence to treatment.
•
The summary measure, which is the difference in mean of the endpoint between 
each erenumab dose group (ie, 70 mg and 140 mg) and the placebo group
•
To evaluate the effect of 
erenumab compared with placebo 
on sustaining MOH remission 
during the DBTP
•
Sustained MOH remission during 
DBTP, as defined by absence of 
MOH at months 3 (week 12) and 
6 (week 24) of the DBTP, and 
“absence of MOH” is achieved 
when mean monthly 
AHMD < 10 days OR mean 
MHD < 14 days over the 
respective 3-month period 
The estimand for the secondary objective on sustained absence of MOH consists of:
•
The target population, which includes subjects diagnosed with CM and MOH who 
have a history of at least 1 preventive treatment failure and do not use opioid 
medication for more than 4 days per month
•
The endpoint, which is the sustained MOH remission during DBTP, as defined by 
absence of MOH over months 1, 2, and 3 (week 1 through week 12) AND over 
months 4, 5, and 6 (week 13 through 24) of the DBTP.  Absence of MOH is 
achieved when mean monthly AHMD < 10 days OR mean MHD < 14 days over 
the respective 3-month period
•
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of investigational product (IP), regardless of adherence to 
treatment.
•
The summary measure, which is the odds ratio of sustained MOH remission
between each erenumab dose group (ie, 70 mg and 140 mg) and the placebo 
group
•
To evaluate the effect of 
erenumab compared with placebo 
on reducing the impact of 
migraines on physical impairment 
and everyday activities as 
measured by the Migraine 
•
Change from baseline in mean 
monthly average physical 
impairment domain scores as 
measured by the MPFID over 
months 4, 5, and 6 (week 13 
through 24) of the DBTP
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Objectives
Endpoints
Physical Function Impact Diary 
(MPFID) during the DBTPa
•
Change from baseline in mean 
monthly average impact on 
everyday activities domain scores 
as measured by the MPFID over 
months 4, 5, and 6 (week 13 
through 24) of the DBTP
The estimand for the secondary objective on MPFID consists of:
•
The target population, which includes subjects diagnosed with CM and MOH who 
have a history of at least 1 preventive treatment failure and do not use opioid 
medication for more than 4 days per month
•
The endpoints, which include (1) the change from baseline in mean monthly 
average physical impairment domain scores and (2) the change from baseline in 
mean monthly average impact on everyday activities domain scores as measured 
by the MPFID over months 4, 5, and 6 (week 13 through 24) of the DBTP 
•
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of investigational product (IP) and have at least 1 change 
from baseline in the respective domain score, regardless of adherence to 
treatment.
•
The summary measure, which is the difference in mean of the endpoint between 
each erenumab dose group (ie, 70 mg and 140 mg) and the placebo group
•
To evaluate the effect of 
erenumab compared to placebo 
on change from baseline in 
headache impact scores as 
measured by the Headache 
Impact Test (HIT-6)a  
•
Change from baseline in mean 
HIT-6 score over months 4, 5, 
and 6 (week 13 through 24) of 
the DBTP
The estimand for the secondary objective on HIT-6 consists of:
•
The target population, which includes subjects diagnosed with CM and MOH who 
have a history of at least 1 preventive treatment failure and do not use opioid 
medication for more than 4 days per month 
•
The endpoint, which is the change from baseline in mean HIT-6 total score over 
months 4, 5, and 6 (week 13 through 24) of the DBTP 
•
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of investigational product (IP) and have at least 1 change 
from baseline in HIT-6 total score, regardless of adherence to treatment.
•
The summary measure, which is the difference in mean of the endpoint between 
each erenumab dose group (ie, 70 mg and 140 mg) and the placebo group
Safety
•
To evaluate the safety and 
tolerability of erenumab in 
subjects with CM-MOH
•
Adverse events
•
Vital signs
a In the EU region only, HIT-6 will replace MPFID as a secondary endpoint and MPFID will be evaluated as 
an exploratory endpoint.  In non-EU regions, MPFID will remain as a secondary endpoint while HIT-6 will be 
evaluated as an exploratory endpoint.
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Objectives
Endpoints
Exploratory (Double-blind treatment period) 
•
To explore the effect of erenumab 
compared with placebo in 
promoting conversion to EM
•
Achievement of conversion to 
episodic migraine (EM) at
month 3 defined as mean MHD 
< 14 days over months 1, 2, and 
3 (week 1 through 12) of the 
DBTP
•
Achievement of conversion to EM 
at month 6, defined as mean 
MHD < 14 days over months 4, 5, 
and 6 (week 13 through 24) of 
the DBTP
•
Achievement of conversion to EM 
over 6 months, defined as mean 
MHD < 14 days over months 1 
through 6 (week 1 through 24) of 
the DBTP
•
To explore the effect of erenumab 
compared with placebo on the 
change of at least moderate pain 
intensity MHD from baseline to 
the DBTP 
•
Change from baseline in  MHD of 
at least moderate pain intensity 
at monthly assessment time 
points  
•
Change from baseline in mean at 
least moderate pain intensity
MHD over months 4, 5, and 6
(week 13 through 24) of the 
DBTP
•
Achievement of at least 30%, 
50%, and 75% reductions from 
baseline in at least moderate 
pain intensity MHD at monthly 
assessment time points
•
Achievement of at least 30%, 
50%, and 75% reduction from 
baseline in mean at least 
moderate pain intensity MHD 
over months 4, 5, and 6 (week 13 
through 24) of the DBTP 
•
To explore the effect of erenumab 
compared with placebo on the 
change from baseline in monthly 
migraine days (MMD) during the 
DBTP
•
Change from baseline in MMD at 
monthly assessment time points  
•
Change from baseline in mean 
MMD over months 4, 5, and 6 
(week 13 through 24) of the 
DBTP
•
Achievement of at least a 30%, 
50%, and 75% reductions from 
baseline in MMD at monthly 
assessment time points 
•
Achievement of at least 30%, 
50%, and 75% reductions from 
baseline in MMD mean over 
months 4, 5, and 6 (week 13 
through 24) of the DBTP
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Objectives
Endpoints
•
To explore the effect of erenumab 
compared with placebo on the 
change from baseline in average 
headache pain severity during the 
DBTP
•
Change from baseline in the 
monthly average pain severity 
score of qualified headache days 
at monthly assessment time 
points
•
Change from baseline in the 
mean monthly average pain 
severity score of qualified 
headache days over months 4, 5, 
and 6 (week 13 through 24) of 
the DBTP
•
To explore the effect of erenumab 
compared with placebo on the 
change from baseline in migraine-
free days during the DBTP
•
Change from baseline in monthly
migraine-free days at monthly 
assessment time points of the 
DBTP
•
Change from baseline in mean 
monthly migraine-free days over 
months 4, 5, and 6 (week 13 
through 24) of the DBTP
•
To explore migraine-related 
disability metrics as measured by 
the migraine functional impact 
questionnaire (MFIQ) 
•
Change from baseline in MFIQ 
domain scores and overall impact 
on usual activities global item 
score at assessment time points
•
To explore migraine-related 
disability and productivity as 
measured by the Migraine 
Disability Assessment (MIDAS) 
Questionnaire
•
Change from baseline in 
MIDAS total score, absenteeism 
score and presenteeism score at 
assessment time points during 
DBTP 
•
Cumulative (sum of) changes 
from baseline in MIDAS total 
score, absenteeism score and 
presenteeism score over 
6 months during DBTP
•
To explore the effect of erenumab 
compared with placebo on the 
change from baseline in health 
resource utilization (HRU)
•
Occurrence of at 
least 1 headache-related 
hospitalization or outpatient HRU 
during the DBTP
•
Occurrence of at 
least 1 headache-related 
hospitalization during the DBTP
•
Occurrence of at 
least 1 headache-related
outpatient HRU during the DBTP
•
Occurrence of at least 
1 headache-related outpatient 
emergency room visit during the 
DBTP
•
Occurrence of at least 
1 headache-related outpatient 
urgent care visit during the DBTP
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Objectives
Endpoints
•
Occurrence of at least 
1 headache-related outpatient 
clinic visit during the DBTP
•
To explore the effect of erenumab 
compared with placebo on the 
change from baseline in 
depression and anxiety 
symptoms
•
Change from baseline in 
Generalized Anxiety Disorder 
7-item scale (GAD-7) score at 
assessment time points
•
Change from baseline in Beck 
Depression Inventory-II (BDI-II) 
score at assessment time points
•
To explore the effect of erenumab 
compared with placebo on the 
change from baseline in 
measures of sleep quality
•
Change from baseline in each of 
the sleep questionnaire domain 
scores at assessment time points
•
To explore the effect of erenumab 
compared with placebo on the 
subject’s assessment of the 
change in clinical status since the 
start of treatment
•
Change in clinical status as 
measured by the Patient’s Global 
Impression of Change (PGIC) as 
assessed by the subject at 
month 6 of the DBTP
•
To explore the effect of erenumab 
compared to placebo on the 
change from baseline in allodynia 
symptoms
•
Change from baseline in
Allodynia Symptoms Checklist-12 
(ASC-12) score at assessment 
time points
Exploratory (Open-label treatment period) 
•
To explore the rate of MOH 
relapse in the end of open-label 
treatment period (OLTP)
•
MOH relapse at year 1, defined 
as both mean monthly 
AHMD ≥ 10 days over months 11, 
12, and 13 (week 41 through 52)
AND mean MHD ≥ 14 days over 
months 11, 12, and 13 (week 41 
through 52) in subjects who 
achieved MOH remission at 
month 6 of the DBTP
Note:  This endpoint will be 
analyzed among subjects who 
were treated with erenumab 
throughout the entire study
•
To explore absence of MOH at 
end of OLTP
•
Absence of MOH at end of study
as defined by mean monthly 
AHMD < 10 days over months 11, 
12, and 13 (week 41 through 52) 
OR mean MHD < 14 days over 
months 11, 12, and 13 (week 41 
through 52)  
•
To explore sustainability of MOH 
remission during OLTP
•
Sustained absence of MOH over 
1 year as defined by absence of 
MOH over the DBTP (months 1, 
2, and 3 [week 1 through 12], 
OR months 4, 5, and 6 [week 13 
through 24]) AND OLTP (months 
11, 12, and 13 [week 41 through 
52]).
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Objectives
Endpoints
Note:  “Absence of MOH” is achieved 
when mean monthly AHMD < 10 days 
OR mean MHD < 14 days over the 
respective 3-month period
This endpoint will be analyzed 
among subjects who were treated 
with erenumab throughout the 
entire study
•
To explore change in AHMD, 
MMD, and MHD of at least 
moderate pain intensity
•
Change from baseline in mean 
AHMD, MMD and MHD of at 
least moderate pain intensity at 
assessment time points  
•
Change from week 24 (OLTP 
baseline) in mean AHMD, MMD, 
and MHD of at least moderate 
pain intensity at assessment 
time points during OLTP 
•
To explore everyday activities as 
measured by the MPFID
•
Change from baseline in monthly 
average impact on everyday 
activities score as measured by 
the MPFID at assessment time 
points
•
Change from week 24 (OLTP 
baseline) in monthly average 
impact on everyday activities 
score as measured by the MPFID 
at assessment time points during 
OLTP
•
To explore physical impairment 
as measured by the MPFID
•
Change from baseline in monthly 
average physical impairment 
score as measured by the MPFID 
at assessment time points
•
Change from week 24 (OLTP 
baseline) in monthly average 
physical impairment score as 
measured by the MPFID at 
assessment time points during 
OLTP
•
To explore the daily activity 
impact of headache as measured 
by the HIT-6 
•
Change from baseline in HIT-6 
total score at week 52
•
Change from week 24 (OLTP 
baseline) in HIT-6 total score at 
week 52
•
To explore migraine-related 
disability metrics as measured by 
MFIQ
•
Change from baseline in MFIQ 
domain scores and overall impact 
on usual activities global item 
score at week 52
•
Change from week 24 (OLTP 
baseline) in MFIQ domain scores 
and overall impact on usual 
activities global item score at 
week 52
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Objectives
Endpoints
•
To explore migraine-related 
disability and productivity as 
measured by the MIDAS 
Questionnaire
•
Change from baseline in MIDAS 
total score, absenteeism score 
and presenteeism score at 
week 52
•
Change from week 24 (OLTP 
baseline) in MIDAS total score, 
absenteeism score, and 
presenteeism score at week 52
Exploratory (Opioid-treated Cohort Only)a 
•
To explore the effect of erenumab 
compared with placebo in 
reducing consumption of opioids 
in subjects stratified to the 
opioid-treated cohort during 
DBTP
•
Change from baseline in monthly 
opioid/opioid-containing 
medication days at assessment 
time points during DBTP
•
Change from baseline in mean 
monthly 
opioid/opioid-containing 
medication days over months 
4, 5, and 6 (week 13 through 24)
of the DBTP
•
To explore the effect of erenumab 
compared with placebo in 
reducing consumption of opioids 
in subjects stratified to the 
opioid-treated cohort during 
OLTP  
•
Change from baseline in monthly 
opioid/opioid-containing 
medication days at assessment 
time points during OLTP
a In addition to these objectives/endpoints, all primary, secondary, and exploratory objectives and endpoints
will be evaluated for the opioid-treated cohort. 
4.2
Hypotheses
The primary clinical hypothesis of Study 20170703 is that preventive treatment with 
monthly injections of erenumab is superior to placebo in achieving MOH remission for 
subjects with CM-MOH in the nonopioid-treated cohort who have a history of at least 
1 preventive treatment failure as measured by the absence of the MOH status based on 
the mean over months 4, 5, and 6 (week 13 through 24) of the DBTP. 
The secondary clinical hypotheses of Study 20170703 are that preventive treatment with 
monthly injections of erenumab is superior to placebo in reducing AHMDs over months 4 
to 6 (week 13 through 24) of the DBTP; sustaining MOH remission during the entire 
DBTP; reducing migraine-related impact on physical functioning and everyday activities 
as measured by Migraine Physical Function Impact Diary (MPFID) physical function and 
everyday activities domains (non-EU) or migraine-related impact on physical functioning 
as measured by the Headache Impact Test 6 (HIT-6) (EU only).
For subjects with CM-MOH allocated to the opioid-treated cohort, an additional 
exploratory clinical hypothesis of Study 20170703 is that preventive treatment with 
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monthly injections of erenumab could help reduce opioid use as measured by the mean 
change in monthly opioid medication days from baseline over months 4, 5, and 6
(week 13 through 24) of the DBTP.  Formal statistical testing does not apply to this 
exploratory clinical hypothesis.
5.
Study Design
5.1
Overall Design
Study 20170703 is a phase 4, randomized, double-blind, double-dummy, parallel-group, 
placebo-controlled study to evaluate the safety and efficacy of erenumab against 
placebo in a CM population with MOH and prior history of treatment failure. Subjects will 
be enrolled based on fulfilment of the International Classification of Headache Disorders, 
3rd Edition (ICHD-3) CM and MOH criteria and will not be advised to early discontinue 
acute medication. During randomization, subjects will be separated into 2 distinct 
cohorts based on their opioid medication use at baseline.  Subjects with an opioid 
medication use > 4 days per month during the baseline period will be allocated to the 
opioid-treated cohort.  Subjects with an opioid medication use of ≤4 days per month
during the baseline period will be allocated to the nonopioid-treated cohort.  The 
randomization process on the nonopioid-treated cohort will be balanced based on the 
following stratum: 
•
Concomitant oral migraine preventive treatment initiated before screening and 
taken during baseline (Yes or No). 
Subjects allocated to the opioid-treated cohort will be analyzed separately as an 
exploratory cohort. 
Subjects who successfully complete the 24-week DBTP of the study will be offered an 
opportunity to continue in an OLTP of 28-weeks duration. Subjects who received 
erenumab treatment during the DBTP will continue to receive the same erenumab dose 
during the OLTP.  Subjects who received placebo during the DBTP will be allocated in a 
1:1 ratio to receive either erenumab 70 mg or 140 mg SC QM during the OLTP.  All 
subjects will remain blinded to their original DBTP treatment assignment. 
The overall study design is described by a study schema in Section 2.1. The endpoints 
are defined in Section 4.1. 
5.2
Number of Subjects
Approximately 687 subjects (549 subjects in the nonopioid-treated cohort and up to
138 subjects in the opioid-treated cohort) will be enrolled in the study. Subjects with a 
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baseline intake of opioid/opioid-containing medication that exceeds 4 days per month 
during the baseline period will be allocated to the opioid-treated cohort. 
The opioid-treated cohort will be capped at no more than 20% of the total randomized 
population to improve study feasibility. 
Subjects in this clinical investigation shall be referred to as “subjects”.  For the sample 
size justification, see Section 10.1. 
5.2.1
Replacement of Subjects
Subjects who are withdrawn or removed from treatment or the study will not be replaced.
5.2.2
Number of Sites
Approximately 80 investigative sites in 12 countries are expected to participate in 
Study 20170703. Additional sites and/or countries within North America, Europe, or 
Asia Pacific may be added as deemed necessary by the study management team.  
Sites that do not enroll subjects within 3 study months of site initiation may be closed.
5.3
End of Study
5.3.1
End of Study Definition
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s), for the purposes of conducting the primary analysis, whether the 
study concluded as planned in the protocol or was terminated early.
For this study, the primary completion date is the date when the last subject in the 
nonopioid-treated cohort has completed the assessments for week 24 (month 6) 
or discontinues study.
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, ET of the study), then the primary completion will be the date when the last 
subject is assessed or receives an intervention for evaluation in the study (ie, last 
subject last visit).
End of Study:  The end of study date is defined as the date when the last subject 
across all sites is assessed or receives an intervention for evaluation in the study (ie, last 
subject last visit), following any additional parts in the study (eg, long-term follow-up), as 
applicable.
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5.3.2
Study Duration for Subjects
The total study duration for subjects who successfully complete the study will be 
approximately 59 weeks. Total study duration includes: 
• 
An up to 3-week initial screening period
•
A 4-week baseline period
•
An up to 52-week treatment period comprised of a 24-week DBTP and a 
28-week OLTP
5.4
Justification for Investigational Product Dose
Erenumab 70 mg and 140 mg SC every 4 weeks are approved in Europe, US, and other 
regions for the prevention of migraine in adults. Regulatory approval was based on 
established superiority against placebo for each dose in 4 independent randomized 
clinical studies (1 CM and 3 EM).  Based on treatment response observed in subjects 
with medication overuse enrolled in Study 20120295, dose response in this study is 
expected to be comparable to migraine. In addition, data from the CM study (Study 
20120295) indicated that erenumab 140 mg SC every 4 weeks may provide incremental 
benefit in inducing MOH remission as compared with 70 mg in subjects with CM, 
medication overuse, and prior treatment failure. Consequently, the adoption of 2 active 
dose levels in this study is justified to further inform on efficacy and safety of the 
2 approved doses in a dedicated MOH population. 
5.5
Patient Input on Study Design
Patient input was not collected during study design. 
6.
Study Population
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).  
Eligibility criteria will be evaluated during the up to 3-week screening period (part 1) and 
a 4-week baseline period (part 2). At the end of baseline period, subjects who 
successfully met eligibility criteria will be randomized on study. 
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Section 12.3).
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be provided. 
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6.1
Inclusion Criteria Part 1
To be assessed during the 3-week screening period, prior to the baseline period. 
Subjects are eligible to be included in the study only if all of the following criteria apply:
101.
Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures
102.
Age ≥18 years on entry into the study
103.
Documented history of migraine without aura and/or migraine with aura 
according to the ICHD-3 Classification for ≥12 months at screening
104.
Documented history of CM (refer to Section 12.1 for definition of CM) for a 
minimal duration of 6 months before screening
105.
Current diagnosis of MOH (refer to Section 12.1 for ICHD-3 definition of MOH)
106.
History of treatment failure with at least 1 preventive treatment as defined as 
treatment discontinuation due to lack of efficacy, adverse event or general poor 
tolerability
6.2
Exclusion Criteria Part 1
Subjects are excluded from the study if any of the following criteria apply: 
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Disease Related
201.
Age > 50 years at migraine onset or > 65 years at CM onset
202.
History of hemiplegic migraine, cluster headache or other trigeminal autonomic 
cephalalgia
203.
Current concomitant diagnosis of a secondary type of headache other than 
MOH
204.
History of clinically significant orofacial pain (eg, painful cranial neuropathies, 
temporomandibular disorder) that in the opinion of the investigator or Amgen's 
physician, if consulted, could interfere with the study evaluation, procedures or 
completion 
205.
Chronic headache with continuous pain, in which the subject does not 
experience headache-free periods of any duration
206.
No therapeutic response in prevention of migraine after an adequate therapeutic 
trial of > 3 of the following medication categories. These medication categories 
include:
• Category 1: Topiramate
• Category 2: Other antiepileptics (eg, divalproex sodium, sodium valproate, 
carbamazepine)
• Category 3: Beta blockers
• Category 4: Tricyclic antidepressants 
• Category 5: Other antidepressants (eg, serotonin-norepinephrine reuptake 
inhibitors, selective serotonin-reuptake inhibitors)
•
Category 6: Calcium channel blockers (eg, verapamil, amlodipine, 
cinnarizine, lomerizine) or calcium antagonists (eg, flunarizine)
• Category 7: Angiotensin receptor blockers (eg, candesartan) or 
angiotensin-converting enzyme (ACE) inhibitors (eg, lisinopril)
• Category 8: Botulinum toxin
• Category 9: Other drugs used for migraine prevention
Note: no therapeutic response is defined as no reduction in headache frequency, 
duration or severity after administration of the medication for at least 6 weeks at the 
generally accepted therapeutic dose(s) and is based on the investigator's 
assessment.  Subjects do not meet this exclusion criteria if:
1.  The subject discontinued the medication prior to achieving a therapeutic 
response due to adverse events related to the medication
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2.  Based on investigator opinion, the subject did not receive an adequate dose 
of the medication for at least 6 weeks
235.
Changes in drug regimen (ie, changes in dose or frequency of use) of an allowed 
migraine preventive medication within 2 months prior to start of baseline (refer 
to Section 7.1.7 for the list of these medications)
208.
Received botulinum toxin in the head and/or neck region within 4 months prior to 
screening
236.
Documented history of treatment with an anti-CGRP preventive treatment
210.
Anticipated to require any excluded medication/device or procedure during the 
study (Refer to Section 7.1.7 for the list of excluded medications, devices or 
procedures)
211.
Subject likely to not be available to complete all protocol required study visits or 
procedures, and/or to comply with all required study procedures (eg, Clinical 
Outcome Assessments [COAs]) to the best of the subject’s and investigator's 
knowledge. 
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Other Medical Conditions
212.
History or evidence of unstable or clinically significant medical condition that, in 
the opinion of the investigator or Amgen's physician, if consulted, would pose a 
risk to subject safety or interfere with the study evaluation, procedures or 
completion
237.
Excluded medical conditions include:
•
Currently diagnosed with fibromyalgia and/or chronic pelvic pain; 
•
Currently diagnosed with a clinically significant cervical or intracranial disease (eg,
chronic cervical radiculopathy, space-occupying lesions, intracranial aneurysms) 
that, in the opinion of the investigator, might confound or mimic migraine 
symptomatology; 
•
History of major psychiatric disorder (such as schizophrenia or other psychotic 
disorders, bipolar disorder, obsessive-compulsive disorder, post-traumatic stress 
disorder), or current evidence of depression based on a BDI-II total score > 24 at 
screening. 
•
History of malignancy within the past 5 years, with the following exception[s]: 
−
Malignancy treated with curative intent and with no known active disease present 
for ≥5 years before screening and felt to be at low risk for recurrence by the 
treating physician
−
Adequately treated nonmelanoma skin cancer or lentigo maligna without 
evidence of disease
−
Prostatic intraepithelial neoplasia without evidence of prostate cancer
−
Adequately treated urothelial papillary noninvasive carcinoma or carcinoma 
in situ
•
Known human immunodeficiency virus (HIV) infection
•
Known hepatic disease with potential for hepatic function impairment or evidence of 
acute or chronic hepatitis B or hepatitis C (hepatitis status will be evaluated by 
testing for hepatitis B surface antigen [HepBsAg], total hepatitis B core antibody 
[HepBcAb] and hepatitis C antibody at screening) 
•
Total bilirubin ≥2.0x upper limit of normal (ULN) or alanine aminotransferase (ALT) 
or aspartate aminotransferase (AST) ≥3.0 x ULN, as assessed by the central 
laboratory at screening
214.
Myocardial infarction, stroke, transient ischemic attack, unstable angina, or 
coronary artery bypass surgery, or other revascularization procedures within 
6 months prior to screening
215.
Any known history of substance-related disorders (eg, abuse, misuse or 
addiction) or addictive disorders (eg, pathological gambling)
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216.
Evidence of "recreational use" of illicit drugs within 12 months prior to screening, 
based on medical records, self-report, or a positive drug test performed during 
screening. 
−
Note: positivity for some prescribed substances such as opioids may not be 
exclusionary. (Refer to Section 7.1.7) 
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Prior/Concomitant Therapy
218.
Used an excluded concomitant medication, procedure or device as outlined in 
Section 7.1.7
238.
Exceeded 15 days per month of a short-acting opioid/opioid-containing 
medication during any of the 2 months prior to screening
239.
Had a concomitant use of a short-acting opioid/opioid-containing medication in a 
frequency that exceeds 4 days per month with any of the following prescribed 
psychoactive substances:
• Regular use of barbiturates as defined as any use that exceeds 4 days per 
month during any of the 2 months prior to screening
• Regular use of central nervous system sedative-hypnotic drugs or drugs that 
may increase opioid risk such as benzodiazepines, z-drugs, gabapentinoids, 
tricyclic antidepressants, butyrophenones, phenothiazines, anticonvulsants, and 
muscle relaxants as defined as any use that exceeds 15 days per month during 
any of the 3 months prior to screening. 
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Prior/Concurrent Clinical Study Experience
240.
Currently receiving treatment in another investigational device or drug study, or 
< 30 days or 5 half-lives (whichever is longer) since ending treatment on 
another investigational device or drug study(ies).  Other investigational 
procedures while participating in this study are excluded.
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Other Exclusions
241.
Subject has known hypersensitivity to any of the components to be administered 
during dosing.
223.
Subject is likely to not be able or 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.
6.3
Inclusion Criteria Part 2
To be assessed at the end of the baseline period and prior to enrolment into DBTP. 
Based on information collected through the electronic diary (eDiary) during the baseline
period, the following requirements must be met:
107.
≥14 headache days during the 28-day baseline period out of which ≥8 
headache days meet criteria as migraine days (refer to Section 12.1 for a 
definition of migraine days)
108.
Observation of acute migraine medication overuse during the baseline period.  
Medication overuse at baseline is defined as:
−
≥10 days of combination treatment OR
−
≥10 days of short-acting opioids/opioid-containing medication OR
−
≥10 days of triptans, ergots, OR
−
≥15 days of NSAIDs or simple analgesics intake
109.
At least 2 acute headache medication days per week for each week with at least 
5 diary days
110.
Demonstrated at least 80% compliance with the eDiary (eg, must complete 
eDiary items on at least 23 out of 28 days during the baseline period) 
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6.4
Exclusion Criteria Part 2
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Study procedures
224.
Likely to not be able or available to complete all protocol required study visits or 
procedures, and/or comply with all required study procedures (eg independent 
completion of eDiary items) to the best of the subject's and investigator's 
knowledge
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Concomitant treatment at baseline
242.
Taken a short-acting opioid or opioid-containing analgesic for any indication for
> 15 days during baseline period
243.
Short-acting opioid use during baseline period that in the opinion of the 
investigator or Amgen's physician, if consulted, constitutes any of the following:
−
misuse (use that is contrary to the prescriber's directions, eg, unsolicited 
dose escalation) 
−
abuse (use for nonmedical intention, eg, euphoria or altered consciousness) 
−
dependence (use that is compulsive or potentially harmful)
−
diversion (transfer of a legally prescribed controlled substance from the 
individual for whom it was prescribed to another person for any illicit use)
227.
Changed or planning to change the dose of an allowed concomitant medication 
that may have migraine preventive effect during baseline period or 
postrandomization 
228.
Use of any of the excluded concomitant medications, procedures or devices as 
outlined in Section 7.1.7. 
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Medical conditions newly diagnosed during baseline
229.
Unstable or clinically significant medical condition 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
244.
At risk of self-harm or harm to others as evidenced by scoring ≥1 point in BDI-II 
item 9 (Suicidal Thoughts or Wishes) and concomitant demonstration of strong 
suicidal ideation (ie, presence of suicidal planning)
231.
Evidence of drug or alcohol abuse or dependence or "recreational use" of illicit 
drugs as demonstrated by subject self-report, medical records or a positive drug 
screen test at baseline 
232.
Newly diagnosed substance-related disorder as assessed by the investigator 
and/or an addiction specialist
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Contraception, pregnancy or breastfeeding
233.
Unwillingness to maintain acceptable contraception method, when applicable
234.
Evidence of pregnancy or breastfeeding per subject self-report, medical records 
or positivity on baseline pregnancy screening tests, through end of study
6.5
Subject Enrollment
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form, and all other 
subject information and/or recruitment material, if applicable (see Section 12.3). 
The subject must personally sign and date the IRB/IEC and Amgen-approved informed 
consent before commencement of study-specific procedures.
After signing informed consent, subjects will be evaluated for eligibility criteria during an 
up to 3-week screening period (part 1), and a 4-week baseline period (part 2).  Once the 
subject is determined by the investigator to meet part 1 eligibility criteria as part of the 
screening period, the subject will be evaluated for part 2 eligibility under the baseline 
period.
Upon completion of screening period procedures, the subject is evaluated by the 
investigator, and if the subject meets all Part 1 and Part 2 eligibility criteria he/she is 
subsequently randomized to a treatment regimen.  The investigator is to document this 
decision and date, in the subject’s medical record and in/on the enrollment case report 
form (CRF).  The subject is considered enrolled when the subject is randomized.
Subjects who do not meet either Part 1 or Part 2 eligibility criteria will be considered 
screen failures. 
Each subject who enters into the screening period for the study (screening period starts 
when the subject signs and dates the informed consent form) receives a unique subject 
identification number before any study-related activities/procedures are performed.  The 
subject identification number will be assigned via interactive response technology 
(IRT).  This number will be used to identify the subject throughout the clinical study and 
must be used on all study documentation related to that subject.
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.  This number will not necessarily be the same as the randomization number 
assigned for the study. 
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6.6
Screen Failures
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled/randomized in the study.  A minimal set of screen 
failure information will be collected that includes demography, screen failure details, 
eligibility criteria, and any serious adverse events.
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened once if the condition that led to screen failure is expected to be transient.  
Refer to Section 9.1.1. 
A subject who is determined to be ineligible must be registered as a screen fail in the 
IRT. 
7.
Treatments
Study treatment is defined as any investigational product(s), noninvestigational 
product(s), placebo, or medical device(s) intended to be administered to a study subject 
according to the study protocol.
Note that in several countries, investigational product and noninvestigational product are 
referred to as investigational medicinal product and noninvestigational medicinal 
product, respectively.
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of each treatment shown in Table 7-1 below.
7.1
Treatment Procedures
7.1.1
Investigational Products
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Table 7-1.  Study Treatments
Study Treatment Name
Amgen Investigational Product:a
Erenumab
Placebo
Dosage Formulation
• 
DBTP - Erenumab will be packaged in single prefilled 
syringes containing 1 mL of 70 mg/mL of erenumab.
•
OLTP - Erenumab will be packaged in an autoinjector 
containing 1 mL of 70 mg/mL or 140 mg/mL of erenumab.
•
Placebo will be presented in identical devices, and 
stored/packaged the same as erenumab
Unit Dose Strength(s)/
Dosage Level(s) and Dosage 
Frequency
•
Erenumab 70 mg and 140 mg will be administered every 
4 weeks during DBTP and OLTP. 
• 
To preserve blinding integrity during the DBTP, the 70 mg 
dose level will be composed of one 1 mL injection of 
erenumab 70 mg and one 1 mL injection of matching 
placebo, and the 140 mg dose level will be composed of 
two 1 mL injections of erenumab 70 mg.  
•
During OLTP, subjects will be maintained on their original 
dose assignment and receive IP as an autoinjector device.
•
Placebo will be administered every 4 weeks during 
the 24-week DBTP (ie, at day 1 and visit weeks 4, 8, 
12, 16, and 20).   
•
To preserve blinding integrity during the DBTP, there 
will be two 1 mL injections of matching placebo for 
placebo assigned subjects.
•
Upon completion of DBTP, placebo-treated subjects 
will be allocated to an active dose arm by IRT to
receive either 70 mg or 140 mg of erenumab every 
4 weeks. 
Route of Administration
•
Subcutaneous administration.
•
The anatomical sites for administration of investigational product are the upper arm, upper thigh or abdomen, Refer to the 
IPIM for investigational product details.
Accountability
•
The quantity, start date, start time, injection site, and box number(s) of investigational product are to be recorded on each
subject’s CRF.  During OLTP, start date, start time and injection site are to be recorded by the subject for at-home IP 
administrations. 
Dosing Instructions
•
Treatment doses to be administered at clinic visits by authorized investigational site study staff during the DBTP. During 
OLTP, subjects will be trained to self-administer with an autoinjector device in the clinic and are expected to self-
administer at home or in clinic during OLTP. 
•
Investigational product doses are fixed and cannot be adjusted
•
Erenumab dose received during DBTP will be maintained the same during OLTP for subjects assigned to active treatment 
during DBTP.  Subjects assigned to placebo during DBTP will be allocated in a 1:1 fashion to either dose of erenumab 
during OLTP.  
•
The anatomical sites for administration of investigational product are the upper arm, upper thigh, or abdomen.  Overdose 
with this product has not been reported.
CRF = case report form; DBTP = double-blind treatment period; IPIM = investigational product instruction manual; IRT = Interactive Response Technology; 
OLTP = open-label treatment period
a Erenumab will be manufactured and packaged by Amgen and distributed using Amgen clinical study drug distribution procedures.
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7.1.2
Noninvestigational Products
Not applicable.
7.1.3
Medical Devices
The following investigational medical device(s) provided by Amgen for use in this study 
are the prefilled syringe (PFS) during the DBTP and the autoinjector (AI) during OLTP
(Table 7-1). 
The erenumab PFS is a single-use, disposable, handheld manual injection device for 
fixed dose SC injection of 70 mg in a 1 mL deliverable volume.
The erenumab AI is a single-use, disposable, handheld manual injection device for fixed 
dose SC injection of either 70 mg or 140 mg in a 1 mL deliverable volume. 
Additional details are in the IPIM.
Other noninvestigational medical devices may be used in the conduct of this study as 
part of standard care. 
Noninvestigational medical devices (eg, syringes, sterile needles), that are commercially 
available are not usually provided or reimbursed by Amgen (except, for example, if 
required by local regulation).  The investigator will be responsible for obtaining supplies 
of these devices.
Refer to Section 7.1.7 for a list of prohibited medical devices.
7.1.4
Other Protocol-required Therapies
Not applicable.
7.1.5
Other Treatment Procedures
Not applicable.
7.1.6
Product Complaints
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material.
This includes any investigational product(s) or device(s) (eg, the PFS or AI) provisioned
and/or repackaged/modified by Amgen. 
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Any product complaint(s) associated with any investigational product(s) or devices(s) 
supplied by Amgen are to be reported according to the instructions provided in the IPIM. 
7.1.7
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period
Concomitant treatment with up to 2 oral migraine preventive medication is allowed 
under the following conditions: 
(1) drug regimen (ie, formulation, frequency of use, dose) is stable ≥ 2 months prior 
to baseline period start
(2) drug regimen is at generally accepted dose, frequency and route for its use in 
migraine
(3) drug regimen is not anticipated to change during baseline period or 
postrandomization (ie, during the subject’s study participation).
Examples of such medications include but are not limited to the following:
•
Antiepileptics (eg, divalproex sodium, sodium valproate, topiramate, 
carbamazepine, levetiracetam).
•
Angiotensin receptor blockers (eg, candesartan) or ACE inhibitors (eg, lisinopril).
•
Beta blockers.
•
Calcium channel blockers (verapamil, amlodipine, cinnarizine, lomerizine) or 
calcium antagonists (eg, flunarizine).
•
Tricyclic antidepressants.
•
Other antidepressants (eg, serotonin-norepinephrine reuptake inhibitors, 
selective serotonin-reuptake inhibitors).
•
Other drugs used for migraine prevention (eg, coenzyme Q10, clonidine, 
guanfacine, methysergide, cyproheptadine, pizotifen, butterbur, feverfew, 
magnesium (≥500 mg/day), riboflavin (≥100 mg/day).
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Prohibited Medications
Time Period for 
Exclusion
Concurrent use of non-investigational anti-CGRP mAbs
Prior history of treatment 
with and throughout the 
study
Use of the following acute medications for the acute treatment of 
migraine:
Barbiturates or butalbital-containing medication for > 4 days/month
Short-acting opioids or short-acting opioid-containing 
medication for >15 days/month
Long-acting opioids or long-acting opioid-containing 
medication
Cannabidiol (CBD)-containing products anticipated to have a 
systemic effect (eg, ingested or inhaled products)
> 4 days/month
2 months before the start 
of the screening period 
and throughout the study
Investigational medications 
30 days or 5 half-lives
before the start of the 
screening period and 
throughout the study
Botulinum toxin (in the head and/or neck region)
4 months before the start 
of the screening period 
and throughout the study
Prohibited Procedures or Devices
Time Period for Exclusion
For any indication
Infusion rescue therapy (ie, steroids, valproate sodium, 
dihydroergotamine) 
Note:  infusion rescue therapy may be allowed during DBTP if 
medically justified
During screening period 
or baseline period
For any indication 
Devices (such as stimulation devices), or procedures (such as 
nerve blocks, or psychotherapy). 
3 months before the start 
of the screening period 
and throughout the study
Cognitive Behavioral Therapy
Subjects on a stable, maintenance phase of a cognitive behavioral 
therapy (CBT) program for migraine are allowed. CBT is defined 
as stable, on a maintenance phase if subject has undergone 
≥ 6 weekly or biweekly sessions of CBT administered by 
adequately trained psychologists and who, for at least 3 months 
before the start of the baseline period, only follow “booster” CBT 
sessions at a monthly, bimonthly or quarterly frequency.
3 months before the start 
of the screening period
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7.2
Method of Treatment Assignment
Subjects will be randomized in a 1:1:1 allocation ratio, to erenumab 70 mg/mL SC every 
4 weeks, erenumab 140 mg/mL SC every 4 weeks, or matching placebo, respectively, in 
a double-blind manner for nonopioid-treated cohort and opioid-treated cohort separately.  
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The randomization will be performed by IRT, and the randomization number will be 
assigned by IRT and appear on the IRT randomization document.  The randomization 
number is different than the subject identification number and will not be utilized by the 
site as a subject identifier.
The randomization will be stratified by concomitant treatment with an oral preventive 
(Yes or No) in the nonopioid-treated cohort.   
The randomization date is to be documented in the subject’s medical record and on the 
enrollment CRF. 
7.3
Blinding
This study has a 24-week DBTP and a 28-week OLTP.  Treatment assignment will be 
blinded to all subjects, site personnel, and Amgen as described below.  During the 
24-week DBTP, treatment assignment will be blinded to all subjects, site 
personnel, and Amgen.  Following the DBTP, during the 28-week OLTP, study 
team members in direct contact with sites, investigators, and subjects will remain 
blinded to the initial dose level.
7.3.1
Site Personnel Access to Individual Treatment Assignments
A subject’s treatment assignment during DBTP is to only be unblinded by the 
investigator when knowledge of the treatment is essential for the further management of 
the subject on this study or may potentially impact the safety of the subject.  Unblinding 
at the study site for any other reason will be considered a protocol deviation.  It is 
encouraged that the Amgen Trial Manager be notified before the blind is broken unless 
the investigator believes that identification of the study treatment is required for a 
medical emergency.  If this is not possible, the Amgen Trial Manager must be notified 
within 24 hours after breaking the blind.  The date and reason that the blind was broken 
must be recorded in the source documentation and CRF, as applicable.
7.3.2
Access to Individual Subject Treatment Assignments by Amgen or 
Designees
Blinded individuals will not have access to unblinded information until the study is 
completed.  Unblinding and potentially unblinding information is not to be distributed to 
study team members in direct contact with sites, investigators or subjects prior to the 
final analysis. 
7.4
Dose Modification
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7.4.1
Dose-cohort Study Escalation/De-escalation and Stopping Rules
There will be no dose changes or dose stopping rules as part of this protocol.
7.4.2
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation
7.4.2.1
Amgen Investigational Product:  Erenumab or Matching Placebo
Dose adjustments are not permitted.
7.4.3
Hepatotoxicity Stopping and Rechallenge Rules
Refer to Section 12.7 for details regarding drug-induced liver injury guidelines, as 
specified in the Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation, July 2009. 
7.5
Preparation/Handling/Storage/Accountability
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product during the study are provided in the IPIM.
7.6
Treatment Compliance
Administration of investigational product will be conducted at sites or at home during 
scheduled time points.  
Noncompliance is to be documented in the medical file and will be reflected in the 
electronic CRF.  Noncompliant subjects are to be re-educated on the importance of 
adhering to the investigational product administration schedule and reminded that 
repeated cycles of noncompliance could be a reason for discontinuation of study 
treatment.
7.7
Treatment of Overdose
Overdose with this product has not been reported.  No specific antidote exists.  In the 
case of an overdose, the subject should be treated symptomatically and supportive 
measures implemented as necessary.
7.8
Prior and Concomitant Treatment
7.8.1
Prior Treatment
For prior migraine preventive medications ending 2 months prior to start of 
baseline, therapy name, indication, dose, unit, frequency, start and stop dates will 
be collected in the prior migraine preventive medication CRF.  
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For all other prior therapies that were being taken/used within 120 days prior to 
screening through the signing of the informed consent, therapy name, start and 
stop dates will be collected in the concomitant medication CRF.  
7.8.2
Concomitant Treatment
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 7.1.7. 
Concomitant therapies are to be collected from screening through the end of study. 
Concomitant medication that is taken to treat headaches or migraine symptoms 
acutely and/or may lead or contribute to MOH will be reported in the eDiary.  
All other concomitant medications will be reported on the Concomitant 
Medications electronic case report form (eCRF) including any allowable 
concomitant migraine preventive medication. 
8.
Discontinuation Criteria
Subjects have the right to withdraw from investigational product and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
and for any reason without prejudice to their future medical care by the physician or at 
the institution.
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, device, and/or other protocol-required therapies, protocol procedures, or the 
study as a whole at any time prior to study completion for the reasons listed in 
Sections 8.1, 8.2.1, and 8.2.2. 
8.1
Discontinuation of Study Treatment
Subjects can decline to continue receiving investigational product and/or other 
protocol-required therapies or procedures at any time during the study but continue 
participation in the study.  If this occurs, the investigator is to discuss with the subject the 
appropriate processes for discontinuation from investigational product or other 
protocol-required therapies and must discuss with the subject the possibilities for 
continuation of the Schedule of Activities (see Table 2-1) including different options of 
follow-up (eg, in person, by phone/mail, through family/friends, in 
correspondence/communication with other treating physicians, from the review of 
medical records) and collection of data, including endpoints, adverse events, and 
device-related events, as applicable and must document this decision in the subject’s 
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medical records.  Subjects who have discontinued investigational product and/or other 
protocol-required therapies or procedures should not be automatically removed from the 
study.  Whenever safe and feasible, it is imperative that subjects remain on-study to 
ensure safety surveillance and/or collection of outcome data.
Subjects who permanently discontinue investigational product during the DBTP are to 
continue eDiary entry and to complete the remaining study visits through the week 24/ 
ET visit for the assessment of primary and secondary endpoints. 
Subjects who permanently discontinue investigational product during the OLTP are to 
complete the study procedures for the week 52 End of Study visit. 
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following:
•
Decision by Sponsor
•
Lost to follow-up
•
Death
•
Ineligibility determined
•
Protocol deviation
•
Noncompliance 
•
Adverse event
•
Subject request
•
Pregnancy
8.2
Discontinuation From the Study
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publicly available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study, and must document the 
subject’s decision to withdraw in the subject’s medical records.  
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly (see
Section 12.6 for further details). Refer to the Schedule of Activities (Table 2-1) for data 
to be collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
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8.2.1
Reasons for Removal From Washout, Run-in or Invasive Procedures
Not applicable.  
8.2.2
Reasons for Removal From Study
Reasons for removal of a subject from the study after enrollment/randomization are:
•
Decision by sponsor
•
Withdrawal of consent from study
•
Death
•
Lost to follow-up
8.3
Lost to Follow-up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit:
•
The site must attempt to contact the subject and reschedule the missed visit as 
soon as possible and counsel the subject on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the subject wishes to and/or 
is able to continue in the study.
•
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and, if necessary, a certified letter to the subject’s last 
known mailing address or local equivalent methods).  These contact attempts are 
to be documented in the subject’s medical record.
•
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
•
For subjects who are lost to follow-up, the investigator can search publicly
available records (where permitted) to ascertain survival status.  This ensures 
that the data set(s) produced as an outcome of the study is/are as 
comprehensive as possible.
9.
Study Assessments and Procedures
Study procedures and their time points are summarized in the Schedule of Activities 
(see Table 2-1). 
As protocol waivers or exemptions are not allowed if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the subject is to continue or 
discontinue study treatment.
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Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct.
9.1
General Study Periods
9.1.1
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.
9.1.1.1
Screening Period 
The screening period is up to 7 weeks, which consists of an up to 3-week initial
screening period and a 4-week baseline period.
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
If a subject has not met all eligibility criteria during the screening period, the subject will 
be registered as a screen fail.  Screen fail subjects may be eligible for rescreening 1 time
if the condition that led to screen failure is expected to be transient.
Rescreen subjects must first be registered as screen failures in IRT and subsequently 
registered as rescreens.  Once the subject is registered as rescreened, a new up to 7-
week screening period will begin.  Subjects will retain the same subject identification 
number assigned at the original screening.  If the rescreening period begins more than 
60 days after the original signing of the informed consent form, all screening procedures, 
including informed consent, must be repeated.
9.1.1.2
Baseline Period
The 4-week baseline period starts when the subject has met all Part 1 eligibility criteria 
(refer to Section 6.1 and Section 6.2) and enters the baseline period and ends when the 
subject is randomized or does not complete baseline or does not meet all Part 2 
eligibility criteria (refer to Section 6.3 and Section 6.4) and is screen failed.  
The total duration of the baseline period must be at least 29 days and no more 
than 35 days.  Refer to Sections 9.2.2.1 and 9.2.2.3 for information on the BDI-II 
and eligibility calculation, which are to be completed at the end of the baseline 
period using the eDiary.     
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9.1.1.3
Randomization
Upon completion of the baseline period, subjects found to meet eligibility requirements 
will undergo randomization in IRT and be assigned a study treatment in a blinded 
manner. 
9.1.2
Treatment Period
Visits will occur per the Schedule of Activities (Table 2-1).  The date of the first dose of 
IP is defined as day 1.  All subsequent doses and study visits will be scheduled based 
on the day 1 date.  On-study visits may be completed ± 3 days of the scheduled visit.  
Administration of IP is to be administered once every 4 weeks during each visit that it is 
required.
9.1.3
Early Termination
Upon permanent discontinuation from the study for any reason other than study 
completion or withdrawal of consent, an ET visit will be performed approximately 
28 days after the last dose of investigational product.
Subjects who early terminate the study before week 24 should complete the week 24/ET 
assessments (Table 2-1).  
Subjects who early terminate the study after week 24 and before week 52 should 
complete the week 52/EOS assessments (Table 2-2).  
9.1.4
End of Study
Subjects who reach week 52 will end the study and complete all week 52/EOS
assessments, according to Table 2-2. 
9.2
Description of General Study Assessments and Procedures
The sections below provide a description of the individual study procedures for required 
time points.
9.2.1
General Assessments  
9.2.1.1
Informed Consent
All subjects must sign and personally date the IRB/IEC approved informed consent 
before any study-specific procedures are performed. 
9.2.1.2
Demographics
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness.  
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Additionally, demographic data will be used to study the impact on biomarker variability 
of the investigational product.  
9.2.1.3
Medical History
The Investigator or designee will collect a complete medical (including targeted 
cardiovascular), psychiatric, and surgical history that started within 120 days prior to
medical history assessment at screening. Medical history will include information on the 
subject's concurrent medical conditions. Record all findings on the medical history CRF. 
In addition to the medical history above, migraine history must date back to the original 
diagnosis. The current severity will be collected for each condition that has not resolved.
Targeted medical history is to be recorded in the neurologic medical history CRF, 
cardiovascular medical history CRF, cardiac risk factors CRF, and headache and 
migraine frequency medical history CRF.
9.2.1.4
Physical Examination  
Physical examination will be performed as per standard of care.  Physical examination 
findings should be recorded on the appropriate CRF (eg, medical history, event).
9.2.1.5
Physical Measurements
Height (in centimeters) should be measured without shoes. Weight (in kilograms) should 
be measured without shoes.   
9.2.1.6
Performance Status  
Not applicable.
9.2.2
Efficacy Assessments
9.2.2.1
Clinical Outcome Assessments and Electronic Diaries (eDiaries)
The COAs will be collected by subjects using a handheld eDiary at various frequencies. 
The eDiary will collect the following COAs daily at home starting in the baseline period 
and throughout the DBTP, and then again daily starting from week 40 visit through the 
week 52/EOS visit of the OLTP: 
•
Date and time of start of headache (ie, migraine or nonmigraine headache)
•
Date and time of end of each headache 
•
Worst pain severity per headache day
•
Pain features (eg, 1-sided, throbbing, worsens, with exercise/physical activity)
•
Other migraine symptoms (eg, aura, nausea, vomiting, photophobia, phonophobia)
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•
Use of acute medications to treat headaches or migraine symptoms (medication 
name [from pre-entered list] date and time of dosing, number of times taken of each 
date, number of units taken)  
Study center staff will assign and provide an eDiary to the subject at the week -4 visit 
(after confirming the subject’s part 1 eligibility prior to baseline period entry). The study 
center staff will train the subject on how to use the eDiary (eg, turning on/off, charging, 
navigating screens, transmitting data, contacting the help desk for technical assistance) 
and complete the questions. The subject will be instructed to interact with the eDiary 
every day and to bring the eDiary to every study visit. During the baseline period after 
at least 28 full calendar days have passed (inclusive of the day the subject was 
set-up on the eDiary device), the subject will return for their end of baseline period 
visit/ day 1 visit.  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.  During this visit, site staff will be able to activate the baseline 
period BDI-II on the subject’s eDiary device, as well as perform the eligibility 
calculation. 
For randomized subjects, all Day 1 study assessments, including eDiary 
questionnaires, should be completed prior to subject’s first dose of 
investigational product.  For subsequent study visits, the order of completing 
study assessments will be at the investigator’s discretion. 
The subject’s eDiary will also be used for the completion of the following patient-reported 
outcome measures:
•
MPFID
•
HIT-6 
•
MFIQ
•
MIDAS questionnaire
•
Sleep questionnaire
•
Allodynia symptoms checklist 12 items (ASC-12) questionnaire 
•
BDI-II
•
GAD-7 
•
PGIC
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9.2.2.2
Allodynia Symptoms Checklist 12 items (ASC-12)
The ASC-12 is a subject reported outcome measure used to assess the frequency of 
allodynia symptoms. The checklist will ask subjects to assess how often they 
experience increased pain or an unpleasant sensation on their skin during their most 
severe type of headache while engaging in each of the following: combing their hair, 
pulling their hair back (eg, ponytail), shaving their face, wearing eyeglasses, wearing 
contact lenses, wearing earrings, wearing a necklace, wearing tight clothing, taking a 
shower (when the shower water hits their face), resting their face or head on a pillow, 
exposure to heat (eg, cooking, washing their face with hot water), and exposure to cold 
(eg, using an ice pack, washing their face with cold water).
The subject answers each question using the following categories: “Does not apply to 
me”, “Never”, “Rarely”, “Less than half of the time”, “Half the time or more”. Responses 
to each question are assigned a score. A positive response to answer options 1 to 3 is 
scored as 0, a positive response to answer option 4 is scored as a 1, and a positive 
response to answer option 5 is scored a 2. The final grading is based on the sum of the 
12 items. 
Subjects will complete the ASC-12 using the eDiary.
9.2.2.3
Beck Depression Inventory (BDI-II)
The BDI-II is a 21-item questionnaire that assesses the severity of depression. Each 
item is scored from 0 to 3. The total score is categorized into 4 severity grades: minimal 
depression (0 to 13), mild depression (14 to 19), moderate depression (20 to 28), and 
severe depression (29 to 63).  The BDI-II will be collected at the initial screening, 
baseline and DBTP periods. At initial screening, BDI-II will be collected in the electronic 
case report form (eCRF) for eligibility purposes only. The baseline period and DBTP 
BDI-II will be collected by eDiary.
Sites will be able to activate the baseline period BDI-II on the eDiary at the end of 
the subject’s baseline period, after at least 28 full calendar days have passed 
(inclusive of the day the subject was set-up on the eDiary device).    
9.2.2.4
General Anxiety Disorder 7-item questionnaire (GAD-7)
The GAD-7 is a self-administered 7-item instrument that uses some of the 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 
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3 (‘nearly every day’).  Items are summed to provide a total score. Score interpretation 
is as follows: 1 to 4 minimal symptoms, 5 to 9 mild symptoms, 10 to 14 moderate 
symptoms, and 15 to 21 severe symptoms. Changes of 5 points or more are clinically 
meaningful.  
9.2.2.5
Headache Impact Test-6 (HIT-6)
The HIT-6 is a short-form self-administered questionnaire based on the internet-HIT 
question pool. The HIT-6 was developed as a global measure of adverse headache 
impact to assess headache severity in the previous month and change in a subject’s 
clinical status over a short period of time. Six questions cover severe pain, limitation of 
daily activity (household, work, school, and social), wanting to lie down when headache 
is experienced, feeling too tired to work or do daily activities because of headache, 
feeling “fed up” or irritated because of headache, and headache limiting ability to 
concentrate or work on daily activities. Each of the 6 questions is responded to using 
1 of 5 response categories: “never”, “rarely”, “sometimes”, “very often”, or “always”.
For each HIT-6 item, 6, 8, 10, 11, or 13 points, respectively, are assigned to the 
response provided. These points are summed to produce a total HIT-6 score that 
ranges from 36 to 78. The HIT-6 scores are categorized into 4 grades, representing little 
or no impact (49 or less), some impact (50 to 55), substantial impact (56 to 59), and 
severe impact (60 to 78) due to headache. No recall period is specified for the first 
3 items.  The recall period is the past 4 weeks for the last 3 items.
Subjects will complete the HIT-6 using the eDiary.
9.2.2.6
Migraine Disability Assessment Questionnaire (MIDAS)
The MIDAS Questionnaire is a 5-item self-administered questionnaire that sums the 
number of productive days lost over the past 3 months in 2 settings: the workplace and 
the home. The MIDAS also assesses disability in family, social, and leisure activities. 
The MIDAS score is the sum of missed days due to a headache from paid work, 
housework, and nonwork (family, social, leisure) activities; and days at paid work or 
housework where productivity was reduced by at least half.  The recall period is 
3 months. 
The score is categorized into 4 severity grades: grade I = 0 to 5 (defined as minimal or 
infrequent disability), grade II = 6 to 10 (mild or infrequent disability), grade III = 11 to 
20 (moderate disability), and grade IV = 21 and over (severe disability). Two other 
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questions (A and B) are not scored, but were designed to provide the physician with 
clinically relevant information on headache frequency and pain severity. 
Subjects will complete the modified MIDAS using the eDiary.
9.2.2.7
Migraine Functional Impact Questionnaire (MFIQ)
The MFIQ is a self-administered 26-item instrument measuring the impact of migraine on 
broader functioning (ie, Physical, Social, and Emotional Functioning).  It has 4 domains, 
Impact on Physical Functioning (5 items), Impact on Usual Activities (10 items), Impact 
on Social Functioning (5 items), and Impact on Emotional Functioning (5 items).  In 
addition, there is 1 stand-alone global item assessing the overall impact on usual 
activities. Subjects respond to items using a 5-point scale assigned scores from 1 to 5, 
with 5 representing the greatest burden. The scores 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.
Subjects will complete the MFIQ using the eDiary.
9.2.2.8
Migraine Physical Function Impact Diary (MPFID)
The MPFID is a self-administered 13-item instrument measuring physical functioning.  It 
has 2 domains, Impact on Everyday Activities (7 items) and Physical Impairment 
(5 items), and 1 stand-alone global question which provides an assessment of overall 
impact on everyday activities. 
Subjects respond to items using a 5-point scale, with difficulty items ranging from 
"Without any difficulty" to "Unable to do" and frequency items ranging from "None of the 
time" to "All of the time". These are assigned scores from 1 to 5, with 5 representing the 
greatest burden. For each domain, the scores will be calculated as the sum of the item 
responses and the sum will be rescaled to a 0 to 100 scale, with higher scores 
representing greater impact of migraine (ie, higher burden). There will be a score for 
each of the 2 domains and a third score for the stand-alone item. The recall period is 
the past 24 hours. Subjects will complete the MPFID daily using the eDiary.
9.2.2.9
Patient Global Impression of Change (PGIC)
The PGIC is a subject-reported outcome that evaluates general aspects of a subject’s 
health and assesses if there has been an improvement or decline in clinical status. The 
PGIC employs a 7-point Likert scale that ranges from (1) ‘Very much improved’ to (7) 
‘Very much worse’.  Subjects will complete the PGIC using the eDiary.
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9.2.2.10
Sleep Questionnaire (ARMR sleep questionnaire)
The American Registry for Migraine Research (ARMR) sleep questionnaire is a novel 
self-administered 10-item patient-reported outcome that measures parameters of sleep 
quantity, sleep quality and daytime sleepiness and their relationship with migraine 
symptomatology and treatment over a 3-month recall period. Items 1 to 3 of the 
questionnaire evaluate parameters of sleep quantity as a discrete time variable. Items 
4-6 and 8-10 evaluate several behaviors that denote poor sleep quality and excessive 
daytime sleepiness using a five-level Likert scale that ranges from ‘strongly disagree’ to 
‘strongly agree’.  For each question, ‘not applicable’ options are also provided and are 
not scored. Each item may be scored separately or in combination within the same 
domain.  Item 7 refers to lifetime sleep disorders history and will only be collected at day 
1 post randomization visit.
Subjects will complete the ARMR sleep questionnaire using the eDiary.
9.2.2.11
Health Resource Utilization Resource Questionnaire (HRU)
The questionnaire is designed to collect data on HRU. Specifically, the HRU 
questionnaire aims to capture frequency of headache-related inpatient hospitalizations 
and outpatient emergency department visits, urgent care visits, and other clinical visits.  
The recall period for the HRU questionnaire is 24 weeks.  The questionnaire with the 
24-week recall will be administered at day 1 and week 24 of the DBTP.
The HRU questionnaire assessed at the ET visit before week 24 should only include 
HRU recalled since the previous assessment to avoid collecting duplicate information.  
For example, the 24-week HRU questionnaire assessed at week 20 as the ET visit 
should only include HRU recalled since the previous assessment at day 1 (ie, 20-week 
recall).  
HRU questionnaire is a clinician-reported outcome (CRO) to be collected at clinic visits 
through subject interview. The HRU data is to be inputted in the eCRF.
9.2.3
Safety Assessments
Planned time points for all safety assessments are listed in the Schedule of Activities
see (Table 2-1). 
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9.2.3.1
Adverse Events
9.2.3.1.1
Time Period and Frequency for Collecting and Reporting Safety 
Event Information
9.2.3.1.1.1
Adverse Events
Adverse events related to any study procedures/study-activity are reported after the 
first dose of investigational product. All other adverse events are reported after the 
first dose of investigational product. 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of investigational 
product through the end of study are reported using the Event CRF.
The adverse event grading scale to be used for this study will be the Common 
Terminology Criteria for Adverse Events (CTCAE) and is described in Section 12.4. 
9.2.3.1.1.2
Serious Adverse Events
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through the end of study are reported using the Event CRF.
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee within 24 hours, as indicated in Section 12.4.  The investigator will submit any 
updated serious adverse event data to the sponsor within 24 hours of it being available. 
The criteria for grade 4 in the CTCAE grading scale differs from the regulatory criteria for 
serious adverse events.  It is left to the investigator’s judgment to report these grade 4 
abnormalities as serious adverse events.
9.2.3.1.1.3
Serious Adverse Events After the Protocol-required Reporting 
Period
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after end of study.  However, these serious 
adverse events can be reported to Amgen.  Per local requirements in some countries,
investigators are required to report serious adverse events that they become aware of 
after end of study.  If serious adverse events are reported, the investigator is to report 
them to Amgen within 24 hours following the investigator’s knowledge of the event.
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases and handled accordingly based 
on relationship to investigational product. 
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The method of recording, evaluating, and assessing causality of adverse events, and 
serious adverse events and the procedures for completing and transmitting serious 
adverse event reports are provided in Section 12.4. 
9.2.3.1.2
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and nonleading verbal questioning of the subject is the 
preferred method to inquire about adverse event occurrence.
9.2.3.1.3
Follow-up of Adverse Events and Serious Adverse Events
After the initial adverse event/serious adverse event report, the investigator is required to 
proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 8.3).  
Further information on follow-up procedures is given in Section 12.4. 
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Event CRF.
9.2.3.1.4
Regulatory Reporting Requirements for Serious Adverse Events
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen.
Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators.
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy and forwarded 
to investigators as necessary.
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An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB/IEC, if appropriate according to local requirements.
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities.  Aggregate 
analyses may also be unblinded by the Safety Assessment Team as appropriate.  
Investigators will receive notification of related serious adverse events reports sent to 
regulatory authorities in accordance with local requirements.
9.2.3.1.5
Pregnancy and Lactation
Details of all pregnancies and/or lactation in female subjects and, if indicated, female 
partners of male subjects who become pregnant, will be collected after the start of 
study treatment through 16 weeks after the last dose of study drug. 
If a pregnancy is reported, the investigator is to inform Amgen within 24 hours of learning 
of the pregnancy and/or lactation and is to follow the procedures outlined in 
Section 12.5.  Amgen Global Patient Safety will follow-up with the investigator regarding 
additional information that may be requested.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events.
Further details regarding pregnancy and lactation are provided in Section 12.5. 
9.2.3.1.6
Adverse Device Effects
In order to fulfill regulatory reporting obligations worldwide, the investigator is 
responsible for the detection and documentation of any adverse device effects that occur 
during the study with such devices. 
An adverse device effect is any adverse event related to the use of a combination 
product or medical device.  Adverse device effects include adverse events resulting from 
insufficient or inadequate instructions for use, adverse events resulting from any 
malfunction of the device, or adverse events resulting from use error or from intentional 
misuse of the device.
All adverse device effects are to be reported as adverse events following the same 
reporting periods and procedures.
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The investigator is responsible for ensuring that all adverse device effects observed by 
the investigator or reported by the subject that occur after first dose of investigational 
product through the end of the study is reported using the Event CRF. 
Product complaints are described in Section 7.1.6. 
Further details regarding adverse device effects can be found in Section 12.4.  
9.2.3.2
Vital Signs
The following measurements must be performed: systolic/diastolic blood pressure, heart 
rate, respiratory rate, and temperature. Subject must be in a supine position in a rested 
and calm state for at least 5 minutes before blood pressure assessments are conducted. 
If the subject is unable to be in the supine position, the subject should be in most 
recumbent position as possible. The position selected for a subject should be the same 
that is used throughout the study and documented on the vital sign CRF. The 
temperature location selected for a subject should be the same that is used throughout 
the study and documented on the vital signs CRF. Record all measurements on the vital 
signs CRF.
9.2.3.3
Electrocardiograms (ECGs)
Subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted.  If the subject is unable to be in the supine 
position, the subject should be in most recumbent position as possible. The ECG must 
include the following measurements: heart rate, QRS, QT, QTc, and PR intervals. The 
PI or (eg, designated site physician) will review all ECGs. Once signed, the original 
ECG tracing will be retained with the subject's source documents. At the request of the 
sponsor, a copy of the original ECG will be made available to Amgen. Findings should 
be recorded on the ECG electronic case report form (eCRF).  
9.2.3.4
Vital Status
Not applicable.
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9.2.3.5
Other Safety
Not applicable.
9.2.4
Clinical Laboratory Assessments
Refer to Section 12.2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Table 2-1) for the timing and frequency. 
The investigator is responsible for reviewing laboratory test results and recording any 
clinically relevant changes occurring during the study in the Event CRF.  The investigator 
must determine whether an abnormal value in an individual study subject represents a 
clinically significant change from the subject’s baseline values.  In general, abnormal 
laboratory findings without clinical significance (based on the investigator's judgment) 
are not to be recorded as adverse events.  However, laboratory value changes that 
require treatment or adjustment in current therapy are considered adverse events.  
Where applicable, clinical sequelae (not the laboratory abnormality) are to be recorded 
as the adverse event.
Urine drug tests (UDTs) performed at screening that return positive likely due to 
the use of an allowable over-the-counter (OTC) medication may be retested prior 
to eligibility determination.
All protocol-required laboratory assessments, as defined in Section 12.2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities
(Table 2-1).  
Laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded. 
9.2.4.1
Pregnancy Testing
A high sensitive urine pregnancy test should be completed at screening and at day 1 
pre-randomization 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 
Worksheet, see Figure 12-2).  Refer to Section 12.5 for contraceptive requirements.  
Post day 1 pregnancy testing should be completed as per the Schedule of 
Activities (Table 2-1, Table 2-2).  Additional on-treatment pregnancy testing may be 
performed at the investigator’s discretion or as required per local laws and regulations. 
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9.2.4.2
Prespecified Biomarker Assessments
Not applicable.
9.2.5
Pharmacokinetic Assessments
Not applicable.
9.2.6
Pharmacodynamic Assessments
Not applicable.
9.2.7
Pharmacogenetic Assessments
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed.  These optional pharmacogenetic analyses focus on 
inherited genetic variations to evaluate their possible correlation to the disease and/or 
responsiveness to the therapies used in this study.  The goals of the optional studies 
include the use of genetic markers to help in the investigation of migraine and other 
neurological diseases, and/or to identify subjects who may have positive or negative 
response to erenumab.  For subjects who consent to this analysis, DNA may be 
extracted.
The final disposition of samples will be described in Section 12.6. 
9.2.8
Antibody Testing Procedures
Not applicable.
9.2.9
Biomarker Development
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention. 
Biomarker development can be useful in developing markers to identify disease 
subtypes, guide therapy, and/or predict disease severity.
Amgen may attempt to develop test(s) designed to identify subjects most likely to 
respond positively or negatively to erenumab to investigate and further understand CM. 
Blood samples are to be collected for biomarker development at the time points 
specified in the Schedule of Activities (Table 2-1). 
9.2.10
Clinical Outcome Assessments
Refer to Section 9.2.2 for COA details.
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9.2.11
Health Economics OR Medical Resource Utilization and Health 
Economics
Medical resource utilization and health economics data, associated with medical 
encounters, will be collected in the CRF by the investigator and study-site personnel for 
all subjects throughout the study.  Protocol-mandated procedures, tests, and encounters 
are excluded. 
The data collected may be used to conduct exploratory economic analyses and will 
include:
•
Number and duration of medical care encounters, including surgeries, and other 
selected procedures (inpatient and outpatient)
•
Duration of hospitalization (total days or length of stay, including duration by 
wards eg, intensive care unit) 
•
Number and type of diagnostic and therapeutic tests and procedures
•
Outpatient medical encounters and treatments (including physician or emergency 
room visits, tests and procedures, and medications).
9.2.12
Optional Substudies
Up to 30 subjects will be asked to participate in an optional interview-based substudy.  
The substudy will be conducted at selected US sites and will consist of 2 qualitative 
interviews to be conducted during the first week after randomization (ie, substudy
interview 1) and no later than a week after the subject’s last visit in the DBTP
(ie, substudy interview 2). 
The objective of the substudy is to evaluate individual subjects’ experiences related to 
migraine, especially as it relates to the impact on functioning during and between 
migraine attacks and the perceived effect of study treatment. The relationship between 
headache and migraine attack and the subject-level perception of treatment effect will 
also be explored and will help illustrate the subject perspective of treatment response.
Participation in the substudy is optional and a separate consent form will be requested 
for substudy inclusion. Substudy participants who discontinue study treatment early are 
encouraged to complete substudy interview 2. 
Refer to Appendix 8 for more information on the substudy.
9.2.13
Other Assessments  
Not applicable.
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10.
Statistical Considerations
10.1
Sample Size Determination
The sample size calculation has been performed based on the primary endpoint 
(absence of MOH at month 6 [week 24]) for the nonopioid-treated cohort.
Based on a subgroup analysis of subjects who failed preventive migraine medication,
overused acute headache medication, and had at least 14 MHD at baseline in the 
erenumab CM pivotal Study 20120295, 33.1%, 50.5%, and 64.1% of subjects in 
placebo, erenumab 70 mg and erenumab 140 mg treatment group, respectively, 
achieved absence of MOH at month 3 (week 12).  Assuming similar response rates over
month 4, 5 and 6 (week 13 through 24) and a conservative scenario that includes a 
dropout rate of 20% during the 6-month DBTP, the planned sample size of 183 subjects 
per group will provide 85% power for 70 mg versus placebo and > 99% power for 
140 mg versus placebo using a 2-sample chi-squared test with a 2-sided significance 
level of 0.05. 
In addition, up to 138 opioid-treated cohort subjects will be randomized to receive 
erenumab or placebo (46 on placebo, 46 on 70 mg, and 46 on 140 mg).
10.2
Analysis Sets, Subgroups, and Covariates
10.2.1
Analysis Sets
Each analysis set will be defined separately for the nonopioid-treated cohort and the 
opioid-treated cohort.
10.2.1.1
Full Analysis Set  
The full analysis set (FAS) consists of all subjects who were randomized in the study. 
Analysis of disposition, demographic and baseline characteristics, and important 
protocol deviations will utilize this analysis set.
10.2.1.2
Efficacy Analysis Set
The efficacy analysis set (EAS) for the binary efficacy endpoint during DBTP is a subset 
of FAS consisting of subjects who receive at least 1 dose of investigational product
during DBTP.  The EAS for the continuous secondary endpoint expressed as change 
from baseline is a subset of FAS consisting of subjects who receive at least 1 dose of 
investigational product and have at least 1 change from baseline value during the DBTP.  
The respective EAS will be used to perform the analyses for the efficacy endpoints of 
interest during DBTP. Other efficacy endpoints will use this set or appropriate subsets of 
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this set depending on the endpoint.  Subjects will be analyzed according to their 
randomized treatment in DBTP, regardless of the treatment received. 
10.2.1.3
Safety Analysis Set
The safety analysis set (SAS) will consist of all randomized subjects who received at 
least 1 dose of investigational product. Subjects will be analyzed according to the 
randomized treatment unless a subject receives the incorrect dose during the entire 
DBTP.  Analysis for safety endpoints and summary of investigational product
administration will utilize this analysis set.
10.2.1.4
Open-label Treatment Period Analysis Set
The open-label treatment period analysis set will consist of all subjects who receive at 
least 1 dose of erenumab in the OLTP. This analysis set will be used to summarize data 
collected during the OLTP. 
10.2.2
Covariates
All formal analyses of efficacy endpoints in nonopioid-treated cohort will be adjusted for 
the following covariates:
• Concomitant oral migraine preventive treatment initiated before screening AND taken 
during baseline (Yes or No)
• Corresponding baseline value for the endpoint being analyzed
10.2.3
Subgroups
The primary and key secondary endpoints for the nonopioid cohort will be analyzed in 
the subgroups defined by concomitant oral migraine preventive treatment initiated before
screening and taken during baseline (Yes or No), key demographics (eg, geographic 
region), prior history of treatment with onabotulinumtoxinA (Yes or No), total number or 
prior treatment failures (1, 2, or 3 or more treatment failures), and acute headache 
medication overuse category (triptan medication overuse, simple analgesics and/or 
NSAIDs medication overuse, combination analgesics overuse, or combination 
therapies overuse).
10.2.4
Handling of Missing and Incomplete Data
Subjects may miss specific data points for a variety of reasons. In general, data could 
be missing due to a subject’s early withdrawal from the study, a missed visit, or inability 
to evaluate an endpoint at a particular point in time. For this study, efficacy endpoints 
will be collected via eDiary and subjects could miss entering several days of data in each 
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monthly interval. The general procedures outlined below describe how missing data in 
efficacy will be handled.
For the endpoints derived from daily eDiary, if at least 14 days of eDiary are collected 
in the monthly interval, then the monthly frequency measurements (eg, migraine days, 
headache days) will be prorated based on the number of days with available information.
Missing items in each COA questionnaire will be handled based on the scoring 
algorithm for each COA.
Continuous monthly measurements derived based on above approach will be analyzed
using generalized linear mixed model without imputation for missing data. For
dichotomous endpoints, non-response imputation (NRI) will be used to impute missing 
monthly measurements.
Missing data in safety data will not be imputed except for partial AE start dates.
10.2.4.1
Missing and Incomplete Dates
Missing or incomplete dates will be listed as reported, except for incomplete start date of 
an AE or concomitant medication, which will be imputed as follows:
Missing
Imputation
Exception
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
— 
10.3
Adaptive Design
Not applicable.
10.4
Statistical Analyses
Below is a summary of the timing and methods for the planned statistical analyses.  
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10.4.1
Planned Analyses
10.4.1.1
Primary Analysis
The primary hypothesis will be tested once the last subject in the nonopioid-treated
cohort has completed the week 24/ET assessments during the DBTP, and all data for 
the primary endpoint has been collected. At this time, the DBTP treatment assignment 
for this cohort will be unblinded to the sponsor. If data collection for all subjects in the 
opioid-treated cohort for the DBTP is also complete, the DBTP treatment assignment for 
this cohort will also be unblinded.  Otherwise, the unblinding of treatment 
assignment for this cohort and the analysis of the DBTP data for opioid-treated 
cohort will be done in the final analysis.  Study subjects and investigators will remain 
blinded to original DBTP treatment assignment until study completion.  All efficacy 
analyses and safety analyses will be conducted for the DBTP.  However, safety data 
collected during OLTP before the data cutoff date for the primary analysis will also be 
summarized. 
10.4.1.2
Final Analysis
The final analysis will be performed after all subjects (nonopioid-treated and 
opioid-treated) have completed the study through the week 52/EOS visit. 
10.4.2
Methods of Analyses
10.4.2.1
General Considerations
Formal statistical analyses using statistical models and hypothesis testing will be 
performed for the nonopioid-treated cohort only.
Summary statistics will be computed by treatment group and visit. For continuous 
endpoints, the following descriptive statistics will be computed: number of observations, 
means, medians, standard deviations, standard errors, first and third quartiles, 
minimums and maximums, and 2-sided 95% CIs of the means (CIs will be provided for 
efficacy endpoints only). For categorical endpoints, the summaries will contain the 
number and percentage of subjects in each category.
The dichotomous efficacy endpoints will be analyzed using the stratified 
Cochran-Mantel-Haenszel (CMH) test after the missing data is imputed as nonresponse.  
Continuous secondary endpoints will be analyzed using a linear mixed effects model 
including treatment group, baseline value, stratification factor, scheduled visit, and the 
interaction of treatment group with scheduled visit, without any imputation for missing 
data at the monthly level.   
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The 2 erenumab dose groups will be compared with placebo for the primary and 
secondary efficacy endpoints in the nonopioid-treated cohort using a simple fixed 
sequence procedure with study-wise type I error rate α = 0.05.  The order of the 
endpoints to be tested is prespecified below. If any test is not significant at the α = 0.05 
level, then no further testing will be performed.  
Primary and secondary endpoints in erenumab 140 mg versus placebo:
1. Absence of MOH at month 6 (week 24) of DBTP (140 mg)
2. Change from baseline in mean monthly AHMD over months 4, 5, and 6 (week 13 
through 24) of the DBTP (140 mg)
3. Sustained MOH remission during DBTP (140 mg) 
Primary and secondary endpoints in erenumab 70 mg versus placebo:
4. Absence of MOH at month 6 (week 24) of the DBTP (70 mg)
5. Change from baseline in mean monthly AHMD over months 4, 5, and 6 (week 13 
through 24) of the DBTP (70 mg)
6. Sustained MOH remission during DBTP (70 mg)  
Patient reported outcome-related secondary endpoints for the non-EU region
7. Change from the baseline in mean monthly average physical impairment domain 
scores as measured by the MPFID over months 4, 5, and 6 (week 13 through 24) of 
the DBTP (140 mg)
8. Change from the baseline in mean monthly average impact on everyday activities 
domain scores as measured by the MPFID over months 4, 5, and 6 (week 13 
through 24) of the DBTP (140 mg)
9. Change from the baseline in mean monthly average physical impairment domain 
scores as measured by the MPFID over months 4, 5, and 6 (week 13 through 24) of 
the DBTP (70 mg)
10. Change from the baseline in mean monthly average impact on everyday activities 
domain scores as measured by the MPFID over months 4, 5, and 6 (week 13 
through 24) of the DBTP (70 mg)
OR
Patient reported outcome-related secondary endpoints for the EU region
7. Change from baseline in mean HIT-6 score over months 4, 5, and 6 (week 13 
through 24) of the DBTP (140 mg)
8. Change from baseline in mean HIT-6 score over months 4, 5, and 6 (week 13 
through 24) of the DBTP (70 mg)
10.4.2.2
Efficacy Analyses
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Endpoint
Statistical Analysis Methods
Primary
The primary comparison of absence of MOH at month 6 (week 24)
between each erenumab dosing group and placebo will be analyzed using 
a stratified CMH test after the missing data are imputed as nonresponse.  
The proportion of subjects with absence of MOH will be reported for each 
treatment group.  The odds ratio between each erenumab group and 
placebo, the corresponding 95% Cl and p-value will be reported.  
Secondary
The continuous secondary endpoints will be analyzed using a linear mixed 
effects repeated measure model including treatment group, baseline 
value, stratification factor, scheduled visit, and the interaction of treatment 
group with scheduled visit, without any imputation for missing data.  The 
LSM change from baseline with the 95% CI for each treatment group, the 
treatment difference (each erenumab group – placebo) with the 95% CI, 
and p-value will be reported.
The dichotomized secondary endpoint will be analyzed using the same 
methodology as for the primary endpoint.
Exploratory
The continuous exploratory efficacy endpoints at each assessment time 
will be analyzed using the repeated measures linear mixed effects model 
that includes treatment group, baseline values, stratification factor, 
scheduled visit, and the interaction of treatment and scheduled visit 
without any imputation for missing data.  Dichotomized endpoints will be 
analyzed using a stratified CMH test with missing data imputed as 
nonresponse.  The difference in LSM (or odds ratios) of treatment groups 
and placebo with associated 95% CIs and p-values will be reported.
10.4.2.3
Safety Analyses
10.4.2.3.1
Analyses of Primary Safety Endpoint(s)
All safety analyses will be performed for the DBTP and the OLTP separately.  For safety 
endpoints in the DBTP, all randomized subjects who received at least 1 dose of 
investigational product (ie, SAS) will be analyzed according to the randomized treatment 
unless a subject has received the incorrect dose during the entire DBTP. 
10.4.2.3.2
Adverse Events 
Subject incidence or exposure-adjusted subject incidence rates 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 device 
effects, adverse events leading to withdrawal from investigational product, 
treatment-related adverse events and significant treatment emergent adverse events will 
also be provided.
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10.4.2.3.3
Laboratory Test Results
Not applicable, laboratory measurements are only to be performed at screening.
10.4.2.3.4
Vital Signs
The analyses of vital signs will include summary statistics over time by treatment group.   
10.4.2.3.5
Physical Measurements
Not applicable, physical measurements are only to be performed at baseline and day 1. 
10.4.2.3.6
Electrocardiogram
Not applicable; ECG is only to be measured at baseline.
10.4.2.3.7
Antibody Formation
Not applicable. 
10.4.2.3.8
Exposure to Investigational Product
Descriptive statistics will be produced to describe the exposure to IP by treatment group 
and treatment period. 
10.4.2.3.9
Exposure to Other Protocol-required Therapy
Not applicable.  
10.4.2.3.10
Exposure to Concomitant Medication
Number and proportion of subjects receiving headache-related medication will be 
summarized by acute medication category for each treatment group.
10.4.2.4
Other Analyses
Not applicable.  
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11.
References
Bellamy JL, Cady RK, Durham PL. Salivary levels of CGRP and VIP in rhinosinusitis and 
migraine patients. Headache. 2006;46:24-33.
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medications and evolution from episodic to chronic migraine: a longitudinal population 
based study. Headache. 2008;48:1157-1168.
Chiang CC, Schwedt TJ, Wang SJ, Dodick DW. Treatment of medication-overuse 
headache: A systematic review. Cephalalgia. 2016;36(4):371-86.
Chiapparini L, Grazzi L, Ferraro S, et al. Functional-MRI evaluation of pain processing in 
chronic migraine with medication overuse. Neurol Sci. 2009;30(Suppl 1):S71-4.
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Diener HC, Holle D, Solbach K, Gaul C. Medication-overuse headache: risk factors, 
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Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral
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Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiol Rev.
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Goadsby PJ, Edvinsson L, Ekman R. Release of vasoactive peptides in the
extracerebral circulation of humans and the cat during activation of the trigeminovascular
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Goadsby PG, Lipton RB, Ferrari MD. Migraine—current understanding and treatment. N 
Engl J Med. 2002;364(4):257-270.
Grazzi L, Chiapparini L, Ferraro S, et al. Chronic migraine with medication overuse pre-
post withdrawal of symptomatic medication: clinical results and FMRI correlations. 
Headache. 2010;50(6):998-1004. 
Ho TW, Ferrari MD, Dodick DW, et al. Efficacy and tolerability of MK 0974 (telcagepant), 
a new oral antagonist of calcitonin gene related peptide receptor, compared with 
zolmitriptan for acute migraine:  a randomised, placebo controlled, parallel treatment 
trial. Lancet. 2008a;372:2115-2123.
Ho TW, Mannix LK, Fan X, et al; MK 0974 Protocol 004 study group. Randomized 
controlled trial of an oral CGRP receptor antagonist, MK 0974, in acute treatment of 
migraine. Neurology. 2008b;70:1304-1312. 
Ho TW, Connor KM, Zhang Y, et al. Randomized controlled trial of the CGRP receptor 
antagonist telcagepant for migraine prevention. Neurology. 2014;83:958-966.
Juhasz G, Zsombok T, Jakab B, Nemeth J, Szolcsanyi J, Bagdy G. Sumatriptan causes
parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and
migraine headache during nitroglycerin induced migraine attack. Cephalalgia. 
2005;25(3):179-183.
Kristoffersen ES, Lundqvist C. Medication overuse headache: a review J Pain Research
2014;7:367-378. 
Lai TH, Chou KH, Fuh JL, et al.  Gray matter changes related to medication overuse in 
patients with chronic migraine.  Cephalalgia.  2016;36(14):1324-1333.
Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J. CGRP may
play a causative role in migraine. Cephalalgia. 2002;22:54-61.
Linde M, Gustavsson A, Stovner LJ, et al.  The cost of headache disorders in Europe:  
the Eurolight project.  Eur J Neurol.  2012;19(5):703-711.
May A, Schulte LH. Chronic migraine: risk factors, mechanisms and treatment. Nat Rev 
Neurol. 2016;12(8):455-464. 
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Meng ID, Dodick D, Ossipov MH, Porreca F. Pathophysiology of Medication Overuse 
headache: insights and hypotheses from preclinical studies. Cephalalgia.
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Petersen KA, Lassen LH, Birk S, Lesko L, Olesen J. BIBN4096BS antagonizes human
alpha-calcitonin gene related peptide-induced headache and extracerebral artery
dilatation. Clin Pharmacol Ther. 2005;77:202-213.
Raggi A, Schiavolin S, Leonardi M, et al. Chronic migraine with medication overuse: 
Association between disability and quality of life measures, and impact of disease on 
patients' lives. J of Neuro Sci. 2015;348(1-2):60-66.
Riederer F, Gantenbein AR, Marti M, Luechinger R, Kollias S, Sándor PS. Decrease of 
Gray Matter Volume in the Midbrain is Associated with Treatment Response in 
Medication-Overuse Headache: Possible Influence of Orbitofrontal Cortex J of Neuro 
Sci. 2013;33(39):15343-15349. 
Riederer F, Marti M, Luechinger R, et al.  Grey matter changes associated with 
medication-overuse headache:  correlations with disease related disability and anxiety.  
World J Biol Psychiatry.  2012;13(7):517-525.
Sarchielli P, Pini LA, Zanchin G, et al. Clinical-biochemical correlates of migraine attacks 
in rizatriptan responders and non-responders. Cephalalgia. 2006;3:257-265.
Schwedt TJ, Chong CD.  Medication overuse headache:  pathophysiological insights 
from structural and functional brain MRI research.  Headache.  2017;57(7):1173-1178.
Sun H, Dodick DW, Silberstein S, et al. Safety and efficacy of AMG 334 for prevention of 
episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 
Neurol. 2016;15(4):382-390.
Tajti J, Uddman R, Möller S, Sundler F, Edvinsson L. Messenger molecules and
receptor mRNA in the human trigeminal ganglion. J Auton Nerv Syst. 1999;76:176-183.
Tepper SJ, Diener HC, Ashima M, et al. Efficacy of erenumab for the treatment of 
patients with chronic migraine in presence of medication overuse. Poster 18th 
International Headache Society Meeting – Vancouver, 7-10 September 2017
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12.
Appendices
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12.1
Appendix 1.  List of Abbreviations and Definitions of Terms
Abbreviation or Term
Definition/Explanation
AAN
American Academy of Neurology
ACE
angiotensin-converting enzyme
Acute headache 
medication
Acute headache medications include: 
• 
Triptan-based migraine medications
• 
Ergotamine-based migraine medications
• 
Non-opioid acute headache medications
• 
Non-opioid butalbital containing medications
• 
Opioid-containing acute headache medications
• 
Opioid-containing butalbital containing medications
Acute headache 
medication day
Any calendar day in which an acute headache medication intake is 
reported. 
Acute migraine-specific 
medication
Acute medication that is considered specific for the treatment of 
migraine (ie, ergotamine derivatives or triptans)
AHMD
Acute headache medication day
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ASC
Allodynia symptom checklist
AST
Aspartate aminotransferase
BDI-II
Beck Depression Inventory - II
BIL
Bilirubin
CBD
Cannabidiol
CBT
Cognitive behavioral therapy
CFR
US Code of Federal Regulations
CGRP
Calcitonin gene-related peptide
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Abbreviation or Term
Definition/Explanation
CM
(per ICHD-3)
Chronic migraine
defined as headache occurring on 15 or more days/month for 
more than 3 months, which, on at least 8 days/month, has the 
features of migraine headache.
A.
Headache (migraine-like or tension-type-like) on 
≥ 15 days/month for >3 months, and fulfilling criteria B 
and C
B.
Occurring in a patient who has had at least five attacks 
fulfilling criteria B-D for Migraine without aura and/or 
criteria B and C for Migraine with aura
C.
On ≥8 days/month for >3 months, fulfilling any of the 
following:
1.criteria C and D for Migraine without aura
2.criteria B and C for Migraine with aura
3.believed by the patient to be migraine at onset and 
relieved by a triptan or ergot derivative
D.
Not better accounted for by another ICHD-3 diagnosis
CM-MOH
Chronic migraine subjects who met thresholds for medication overuse
headache
CMH
Cochran-Mantel-Haenszel
COA
Clinical outcomes assessment
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
DBTP
Double-blind treatment period
DILI
drug induced liver injury
EAS
Efficacy analysis set
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
eDiary  
Electronic diary
EM
Episodic Migraine (ie, < 15 headache days/month)
End of Follow-up
defined as when the last subject completes the last protocol-specified 
assessment in the study  
End of Study for 
Individual Subject
defined as the last day that protocol-specified procedures are 
conducted for an individual subject
End of Study (end of 
trial)
defined as the date when the last subject across all sites is assessed 
or receives an intervention for evaluation in the study (ie, last subject 
last visit), following any additional parts in the study (eg, long-term 
follow-up), as applicable
End of Treatment
(EOT)
defined as the last assessment for the protocol-specified treatment 
period of the study for an individual subject
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Abbreviation or Term
Definition/Explanation
Enrollment
When the investigator decides that the subject has met Part 1 and 
Part 2 eligibility criteria and follow procedures for subject 
randomization
ET
Early termination
EU
European Union
FAS
Full analysis set
FSH
follicle stimulating hormone
GAD-7 
Generalized Anxiety Disorder 7-item scale
GCP
Good Clinical Practice
Headache day
A headache day is defined as any calendar day in which the subject 
experiences a qualified headache (initial onset, continuation, or 
recurrence of the headache).  A qualified headache is defined as:
•
A qualified migraine headache or
•
A qualified nonmigraine headache, which is a headache that 
lasts ≥4 hours and is not a qualified migraine headache or
•
A headache of any duration for which acute headache 
treatment is administered
Headache day 
(moderate to severe)
A qualified headache day that subjects indicate its peak severity as 
being of at least moderate severity
Headache episode
A headache event that is defined by the date and hour of reported 
headache onset and headache cessation. A headache day may 
contain multiple short headache episodes and a single headache 
episode may last more than a day
HepBcAb 
Hepatitis B core antibody 
HepBsAg 
Hepatitis B surface antigen
HIT-6  
Headache Impact Test-6 
HIV
Human immunodeficiency virus
HRT
Hormonal replacement therapy
HRU
Health resource utilization
ICH
International Council for Harmonisation
ICHD-3 
International Classification of Headache Disorders, 3rd Edition
IgG
Immunoglobulin G
IHS
International headache society
INR
International normalized ratio
IPIM
Investigational product instruction manual
IRB/IEC
Institutional Review Board/Independent ethics committee
IRT
interactive response technology that is linked to a central
computer in real time as an interface to collect and process
information
IUD
intrauterine device  
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Abbreviation or Term
Definition/Explanation
IUS
Intrauterine hormonal-releasing system
LSM
Least squares mean
Medication overuse 
(per ICHD-3)
> 3 consecutive months of regular medication overuse above the 
following thresholds:
•
Triptans, ergotamine, opioids/opioid-containing medication, 
combination therapies: ≥10 days per month 
•
Simple analgesics and NSAIDS only: ≥15 days per month of 
simple analgesics and NSAIDs
Medication overuse 
(per protocol)
Mean monthly acute headache medication days above the following 
thresholds 
•
Triptans, ergotamine, opioids/opioid-containing medication, 
combination therapies: ≥10 days per study month 
•
Simple analgesics and NSAIDS only: ≥15 days per study 
month of simple analgesics and NSAIDs
MFIQ
Migraine Functional Impact Questionnaire
MHD
Monthly headache days
MIDAS
Migraine Disability Assessment 
Migraine day
A migraine day is defined as any calendar day in which the subject 
experiences a qualified migraine headache (onset, continuation or 
recurrence of the migraine headache).  A qualified migraine headache 
is defined as a migraine with or without aura lasting for ≥4 hours, and 
meeting at least 1 of the following criteria (a and/or b):
a.
≥2 of the following pain features:
•
Unilateral
•
Throbbing
•
Moderate to severe
•
Exacerbated with exercise/physical activity
b.
≥1 of the following associated symptoms:
•
Nausea 
•
vomiting
•
Phonophobia and photophobia
If the subject took a migraine-specific medication (ie, triptan, or 
ergotamine) during aura or to treat headache on a calendar day, then 
it will be counted as a migraine day regardless of the duration and pain 
features/associated symptoms.
Migraine-free day
A migraine-free day is defined as any calendar day in which the 
subject does not experience any headache pain or any symptoms 
including aura, nausea, vomiting, phonophobia, and photophobia, and 
does not take any acute headache medication.
MMD
Monthly migraine days
MO
Medication overuse
MOH
Medication overuse headache
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Abbreviation or Term
Definition/Explanation
MOH (ICHD-3 
definition)
Headache occurring on 15 or more days per month in a subject with a 
pre-existing primary headache and developing as a consequence of 
regular overuse of acute or symptomatic headache medication (on 
10 or more or 15 or more days/month, depending on the medication) 
for more than 3 months.  It usually, but not invariably, resolves after 
the overuse is stopped.
Diagnostic criteria (per ICHD-3):
a.
Headache occurring on ≥15 days per month in a subject with 
a pre-existing headache disorder
b.
Regular overuse for > 3 months of 1 or more drugs that can be 
taken for acute and/or symptomatic treatment of headache
c.
Not better accounted for by another ICHD-3 diagnosis
MOH (protocol defined)
Mean monthly acute headache medication days over 3 consecutive 
study months at or above ICHD-3 defined thresholds AND mean 
monthly qualified headache days of any severity ≥14 days over the 
same consecutive study months
MPFID
Migraine Physical Function Impact Diary
MRI
Magnetic resonance imaging
NCT
National Clinical Trials 
NSAID
Nonsteroidal anti-inflammatory drug
OLTP
Open-label treatment period
Opioid medication day
Any day in which an opioid/opioid containing medication was 
administered
PFS
Prefilled syringe
PGIC
Patient’s Global Impression of Change
QM
every 4 weeks (ie, 28 days ±4)
Randomization
A subject is randomized to a treatment assignment 
SAS
Safety analysis set
SC
Subcutaneous
Source Data
Information from an original record or certified copy of the original 
record containing subject information for use in clinical research.  The 
information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained in 
source documents (original records or certified copies).  (ICH 
Guideline [E6]).  Examples of source data include Subject 
identification, Randomization identification, and Stratification Value.
Study Day 1
Defined as the first day that protocol-specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject
Study month
generally 4 weeks
TBL
total bilirubin  
ULN
upper limit of normal
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Abbreviation or Term
Definition/Explanation
US
United States
12.2
Appendix 2.  Clinical Laboratory Tests
The tests detailed in Table 12-1 will be performed by the central laboratory, except urine 
pregnancy testing. During the Baseline period and through the DBTP, hematology 
and chemistry testing will be at the discretion of the investigator, as well as
chemistry testing during the OLTP. 
Local laboratory results are only required in the event that the central laboratory results 
are not available in time for either study treatment administration and/or response 
evaluation.  If a local sample is required, it is important that the sample for central 
analysis is obtained at the same time.  Additionally, if the local laboratory results are 
used to make either a study treatment decision or response evaluation, the results must 
be entered into the case report form (CRF). 
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Sections 6.1 to 6.4 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.
Table 12-1.  Analyte Listing
Central Laboratory:  
Chemistrya
Central Laboratory:  Hematologyb
Other Labsc
Sodium
Potassium
Chloride
Bicarbonate 
Total protein
Calcium
Adjusted calcium
Magnesium
Phosphorus
Glucose
BUN or Urea
Creatinine
Uric acid
LDH
Cholesterold
HDLd
LDLd
Triglycerides  
Total bilirubin
RBC
Hemoglobin
Hematocrit
MCV 
MCH
MCHC
RDW
Reticulocytes
Platelets
WBC
Differential
• Neutrophils
• Eosinophils
• Basophils
• Lymphocytes
• Monocytes 
Central Laboratory: 
Urine drug screening
Pharmacogenetic 
studies (optional)  
Biomarker development
Hep B surface antigen
Total Hep B core 
antibody
Hep C antibody
HIV
Local Laboratory: 
Pregnancy testing-urine
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Central Laboratory:  
Chemistrya
Central Laboratory:  Hematologyb
Other Labsc
Direct bilirubin
ALP
AST (SGOT)
ALT (SGPT)
Albumin
Footnotes defined on next page
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; HDL = high density lipoprotein; Hep = hepatitis; HIV = human immunodeficiency 
virus; LDH = lactate dehydrogenase; LDL = low density lipoprotein; MCH = mean corpuscular hemoglobin; 
MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; RBC = red blood 
cell count; RDW = Red cell distribution width; SGOT = serum glutamic-oxaloacetic transaminase; 
SGPT = serum glutamic-pyruvic transaminase; WBC = white blood cell count
a During the Baseline Period, DBTP, and OLTP, chemistry testing will be at the discretion of the 
investigator and performed at central laboratories. 
b During the Baseline Period and DBTP, hematology testing will be at the discretion of the investigator and 
performed at central laboratories
c Performed at either central or local laboratories, as noted.
d To be tested at screening only. 
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12.3
Appendix 3.  Study Governance Considerations
Independent Review Committee
Not applicable.
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 RB/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 US 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 patient population.
The investigator or his/her delegated representative will explain to the subject the aims, 
methods, anticipated benefits, and potential hazards of the study before any 
protocol-specific screening procedures or any investigational product(s) is/are 
administered, and answer all questions regarding the study.  
Subjects must be informed that their participation is voluntary.  Subjects will then be 
required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act requirements, where applicable, and the IRB/IEC or study site.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
informed consent form.
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study unless it is a local requirement.  The 
investigator shall then inform the primary care physician.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record.
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The acquisition of informed consent is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject and by the person who conducted the informed consent discussion.  Subject 
withdrawal of consent or discontinuation from study treatment and/or procedures must 
also be documented in the subject’s medical records; refer to Section 8. 
Subjects must be re-consented to the most current version of the informed consent 
form(s) during their participation in the study. 
The original signed informed consent form is to be retained in accordance with 
institutional policy, and a copy of the informed consent form(s) must be provided to the 
subject. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.  (Refer to ICH GCP guideline, Section 4.8.9.)
A subject who is rescreened is not required to sign another informed consent form if the 
rescreening occurs within 60 days from the previous informed consent form signature 
date.
The informed consent form will contain a separate section that addresses the use of 
remaining mandatory samples for optional future research.  The investigator or 
authorized designee will explain to each subject the objectives of the future research.  
Subjects will be told that they are free to refuse to participate and may withdraw their 
specimens at any time and for any reason during the storage period.  A separate 
signature will be required to document a subject’s agreement to allow any remaining 
specimens to be used for future research.  Subjects who decline to participate will not 
provide this separate signature.
Data Protection/Subject Confidentiality
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen.
Subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred. 
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On the Case Report Form (CRF) demographics page, in addition to the unique subject 
identification number, include the age at time of enrollment.
For serious adverse events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with local 
laws and regulations), and age (in accordance with local laws and regulations).
Documents that are not submitted to Amgen (eg, signed informed consent forms) are to 
be kept in confidence by the investigator, except as described below.
In compliance with governmental regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.  
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information.
Publication Policy
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication.
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
International Committee of Medical Journal Editors Recommendations for the Conduct of 
Reporting, Editing, and Publications of Scholarly Work in Medical Journals, which states:  
Authorship credit is to be based on:  (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the article 
or revising it critically for important intellectual content; (3) final approval of the version to 
be published; and (4) agreement to be accountable for all aspects of the work in 
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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 
submitted to Amgen for review.  The Clinical Trial Agreement among the institution, 
investigator, and Amgen will detail the procedures for, and timing of, Amgen’s review of 
publications.
Investigator Signatory Obligations
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator.
The coordinating investigator, identified by Amgen, will be any or all of the following:
•
A recognized expert in the therapeutic area
•
An Investigator who provided significant contributions to either the design or 
interpretation of the study
•
An Investigator contributing a high number of eligible subjects
Data Quality Assurance
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, centrally or 
adjudicated data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
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Clinical monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and 
that the study is being conducted in accordance with the currently approved protocol and 
any other study agreements, ICH GCP, and all applicable regulatory requirements per 
the sponsor’s monitoring plan. 
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved.
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected.
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research and Development 
Compliance and Audit function (or designees).  Inspection of site facilities (eg, 
pharmacy, protocol-required therapy storage areas, laboratories) and review of 
study-related records will occur to evaluate the study conduct and compliance with the 
protocol, ICH GCP, and applicable regulatory requirements.
Retention of study documents will be governed by the Clinical Trial Agreement.
Case report forms must be completed in English.  TRADENAMES® (if used) for 
concomitant medications may be entered in the local language.  Consult the 
country-specific language requirements.
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.
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Source Documents
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form.
Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site.
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence.  Source documents may also include data captured in the IRT
system (if used, such as subject ID and randomization number) and CRF entries if the 
CRF is the site of the original recording (ie, there is no other written or electronic record 
of data, such as paper questionnaires for a clinical outcome assessment).
Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available.
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.
Elements to include:
•
Subject files containing completed CRFs, informed consent forms, and subject 
identification list
•
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the 
IRB/IEC and Amgen
•
Investigational product-related correspondence including [Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational 
Product for Destruction Form(s), Final Investigational Product Reconciliation 
Statement, as applicable
•
Noninvestigational product(s), and/or medical device(s) or combination 
product(s) documentation, as applicable
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Retention of study documents will be governed by the Clinical Trial Agreement.
Study and Site Closure
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP. 
Both Amgen and the Investigator reserve the right to terminate the Investigator’s 
participation in the study according to the Clinical Trial Agreement.  The investigator is to
notify the IRB/IEC in writing of the study’s completion or early termination and send a 
copy of the notification to Amgen.
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially.
Compensation
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document.
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12.4
Appendix 4.  Safety Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting
Definition of Adverse Event
Adverse Event Definition
•
An adverse event is any untoward medical occurrence in a clinical study 
subject irrespective of a causal relationship with the study treatment.  
•
Note:  An adverse event can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease (new 
or exacerbated) temporally associated with the use of a treatment, 
combination product, medical device or procedure.
Events Meeting the Adverse Event Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (eg, electrocardiogram, radiological 
scans, vital signs measurements), including those that worsen from 
baseline, that are considered clinically significant in the medical and 
scientific judgment of the investigator (ie, not related to progression of 
underlying disease).
•
Exacerbation of a chronic or intermittent pre-existing condition including 
either an increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study treatment administration 
even though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug 
interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of 
either study treatment or a concomitant medication.  Overdose per se will 
not be reported as an adverse event/serious adverse event unless it is an 
intentional overdose taken with possible suicidal/self-harming intent.  Such 
overdoses are to be reported regardless of sequelae.
•
“Lack of efficacy” or “failure of expected pharmacological action” per se will 
not be reported as an adverse event or serious adverse event.  Such 
instances will be captured in the efficacy assessments.  However, the 
signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will 
be reported as adverse event or serious adverse event if they fulfill the 
definition of an adverse event or serious adverse event. 
Events NOT Meeting the Adverse Event Definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy):  the 
condition that leads to the procedure is the adverse event.
•
Situations in which an untoward medical occurrence did not occur (social 
and/or convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
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Definition of Serious Adverse Event
A Serious Adverse Event is defined as any untoward medical occurrence 
that, meets at least 1 of the following serious criteria: 
Results in death (fatal)
Immediately life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
Requires in-patient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting.  Complications that occur during 
hospitalization are an adverse event.  If a complication prolongs hospitalization or 
fulfills any other serious criteria, the event is serious.  When in doubt as to whether 
“hospitalization” occurred or was necessary, the adverse event is to be considered 
serious.  Hospitalization for elective treatment of a pre-existing condition that did 
not worsen from baseline is not considered an adverse event.
Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle) which 
may interfere with or prevent everyday life functions but do not constitute a 
substantial disruption.
Is a congenital anomaly/birth defect
Other medically important serious event
Medical or scientific judgment is to be exercised in deciding whether serious 
adverse event reporting is appropriate in other situations such as important 
medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require medical or surgical 
intervention to prevent 1 of the other outcomes listed in the above definition.  
These events are typically to be considered serious.
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
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Definition of Adverse Device Effect
The detection and documentation procedures for adverse device effects described in 
this protocol apply to all Amgen medical devices provided for use in the study (see 
Section 7.1.3 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 adverse events resulting 
from insufficient or inadequate instructions for use, adverse events resulting from any 
malfunction of the device, or adverse events resulting from use error or from 
intentional misuse of the device.
Recording Adverse Events and Serious Adverse Events
Adverse Event and Serious Adverse Event Recording
•
When an adverse event or serious adverse event occurs, it is the 
responsibility of the investigator to review all documentation (eg, hospital 
progress notes, laboratory, and diagnostics reports) related to the event.
•
The investigator will then record all relevant adverse event/ serious 
adverse event information in the Event case report form (CRF). 
•
The investigator must assign the following adverse event attributes:
•
Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms);
•
Dates of onset and resolution (if resolved);
•
Severity (or toxicity defined below);
•
Assessment of relatedness to investigational product (erenumab or 
placebo) or Amgen medical devices (prefilled syringes); and
•
Action taken.
•
If the severity of an adverse event changes from the date of onset to the 
date of resolution, record as a single event with the worst severity on the 
Event CRF.
•
It is not acceptable for the investigator to send photocopies of the subject’s 
medical records to sponsor in lieu of completion of the Event CRF page.
•
If specifically requested, the investigator may need to provide additional 
follow-up information, such as discharge summaries, medical records, or 
extracts from the medical records.  In this case, all subject identifiers, with 
the exception of the subject number, will be blinded on the copies of the 
medical records before submission to Amgen. 
•
The investigator will attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information.  In such cases, the 
diagnosis (not the individual signs/symptoms) will be documented as the 
adverse event/serious adverse event.
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Evaluating Adverse Events and Serious Adverse Events
Assessment of Severity
The investigator will make an assessment of severity for each adverse event and 
serious adverse event reported during the study.  The assessment of severity will be 
based on:  
The Common Terminology Criteria for Adverse Events, version 4.03 which is 
available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Assessment of Causality
•
The investigator is obligated to assess the relationship between 
investigational product and device and each occurrence of each adverse 
event/serious adverse event.
•
Relatedness means that there are facts or reasons to support a 
relationship between investigational product and the event. 
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, 
and other risk factors, as well as the temporal relationship of the event to 
study treatment administration will be considered and investigated.
•
The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment.
•
For each adverse event/serious adverse event, the investigator must 
document in the medical notes that he/she has reviewed the adverse 
event/serious adverse event and has provided an assessment of causality.
•
There may be situations in which a serious adverse event has occurred 
and the investigator has minimal information to include in the initial report.  
However, it is very important that the investigator always make an 
assessment of causality for every event before the initial transmission of 
the serious adverse event data.
•
The investigator may change his/her opinion of causality in light of 
follow-up information and send a serious adverse event follow-up report 
with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining 
regulatory reporting requirements.
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Follow-up of Adverse Event and Serious Adverse Event
•
The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or 
as requested by Amgen to elucidate the nature and/or causality of the 
adverse event or serious adverse event as fully as possible.  This may 
include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.
•
If a subject is permanently withdrawn from protocol-required therapies 
because of a serious adverse event, this information must be submitted to 
Amgen.
•
If a subject dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Amgen with a copy of any 
postmortem findings including histopathology.   
•
New or updated information will be recorded in the originally completed 
Event CRF.
•
The investigator will submit any updated serious adverse event data to 
Amgen within 24 hours of receipt of the information.
Reporting of Serious Adverse Event
Serious Adverse Event Reporting via Electronic Data Collection Tool
•
The primary mechanism for reporting serious adverse event will be the 
electronic data capture (EDC) system via the Safety Report Form. 
•
If the EDC system is unavailable for more than 24 hours, then the site will 
report the information to Amgen using an electronic Serious Adverse 
Contingency Report Form (see Figure 12-1) within 24 hours of the 
investigator’s knowledge of the event. 
•
The site will enter the serious adverse event data into the electronic system 
as soon as it becomes available.
•
After the study is completed at a given site, the EDC system will be taken 
off-line to prevent the entry of new data or changes to existing data.
•
If a site receives a report of a new serious adverse event from a study 
subject or receives updated data on a previously reported serious adverse 
event after the EDC has been taken off-line, then the site can report this 
information on a paper Serious Adverse Event Report Form
(see Figure 12-1).
Adverse Device Effects:  Recording, Evaluating and Reporting
•
Any adverse event resulting from an adverse device effect that occur during the 
study will be documented in the subject’s medical records, in accordance with the 
investigator’s normal clinical practice, and on the Event CRF page.
•
It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by Amgen) at the time of the initial 
report and describes any corrective or remedial actions taken to prevent 
recurrence of the incident.
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Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Report Form
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12.5
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 6.2. 
Female subjects of childbearing potential must receive pregnancy prevention counseling 
and be advised of the risk to the fetus if they become pregnant during treatment and for 
16 weeks after the last dose of protocol-required therapies.
Definition of Females of Childbearing Potential
A female is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy.
Females in the following categories are not considered female of childbearing potential: 
•
Premenopausal female with 1 of the following:
•
Documented hysterectomy; 
•
Documented bilateral salpingectomy; or
•
Documented bilateral oophorectomy. 
Note:  Site personnel documentation from the following sources is acceptable:  1) review 
of subject’s medical records; 2) subject’s medical examination; or 3) subject’s medical 
history interview. 
•
Premenarchal female
•
Postmenopausal female
•
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.
•
Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the nonhormonal highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment
Contraception Methods for Female Subjects
Acceptable Methods of Effective Contraception
•
Combined (estrogen and progestogen containing) or progestogen-only hormonal 
methods given via oral, intravaginal, transdermal, injectable, or implantable 
route)
•
Intrauterine device (IUD)
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•
Intrauterine hormonal-releasing system (IUS)
•
Bilateral tubal ligation/occlusion
•
Vasectomized partner (provided that partner is the sole sexual partner of the 
female subject of childbearing potential and that the vasectomized partner has 
received medical assessment of the surgical success)
•
Sexual abstinence (defined as refraining from heterosexual intercourse during 
the entire period of risk associated with the study treatments; the reliability of 
sexual abstinence must be evaluated in relation to the duration of the trial and 
the preferred and usual lifestyle of the subject) 
•
Male or female condom with or without spermicide
• 
Cap, diaphragm or sponge with spermicide
•
Double barrier method:  the male uses a condom and the female may choose 
either a cap, diaphragm, or sponge with spermicide (a female condom is not an 
option due to the risk of tearing when both partners use a condom) 
Unacceptable Methods of Birth Control for Female Subjects
Birth control methods that are considered unacceptable in clinical trials include:
•
Periodic abstinence (calendar, symptothermal, 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 study drug. 
•
Information will be recorded on the Pregnancy Notification Worksheet (see 
Figure 12-2).  The worksheet must be submitted to Amgen Global Patient Safety 
within 24 hours of learning of a subject’s pregnancy.  (Note: Sites are not 
required to provide any information on the Pregnancy Notification Worksheet 
that violates the country or regions local privacy laws). 
•
After obtaining the female subject’s signed authorization for release of 
pregnancy and infant health information, the investigator will collect pregnancy 
and infant health information and complete the pregnancy questionnaire for any 
female subject who becomes pregnant while taking protocol-required therapies 
through 16 weeks 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).
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•
Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
•
While pregnancy itself is not considered to be an adverse event or serious 
adverse event, any pregnancy complication or report of a congenital anomaly or 
developmental delay, fetal death, or suspected adverse reactions in the neonate 
will be reported as an adverse event or serious adverse event.  Note that an 
elective termination with no information on a fetal congenital malformation or 
maternal complication is generally not considered an adverse event, but still 
must be reported to Amgen as a pregnancy exposure case. 
•
If the outcome of the pregnancy meets a criterion for immediate classification as 
a serious adverse event (eg, female subject experiences a spontaneous 
abortion, stillbirth, or neonatal death or there is a fetal or neonatal congenital 
anomaly) the investigator will report the event as a serious adverse event.
•
Any serious adverse event occurring as a result of a poststudy pregnancy which 
is considered reasonably related to the study treatment by the investigator, will 
be reported to Amgen Global Patient Safety as described in Section 12.4.  While 
the investigator is not obligated to actively seek this information in former study 
subjects, he or she may learn of a serious adverse event through spontaneous 
reporting. 
•
Any female subject who becomes pregnant while participating will discontinue 
study treatment (see Section 8.1 for details).
Male Subjects With Partners Who Become Pregnant
•
In the event a male subject fathers a child during treatment, and for an additional
16 weeks after the last dose of study drug, the information will be recorded on 
the Pregnancy Notification Worksheet.  The worksheet (see Figure 12-2) must be 
submitted to Amgen Global Patient Safety within 24 hours of the site’s 
awareness of the pregnancy.  (Note:  Sites are not required to provide any 
information on the Pregnancy Notification Worksheet that violates the country or 
regions local privacy laws).
•
The investigator will attempt to obtain a signed authorization for release of
pregnancy and infant health information directly from the pregnant female partner 
to obtain additional pregnancy information.
•
After obtaining the female partner’s signed authorization for release of pregnancy
and infant health information, the investigator will collect pregnancy outcome and
infant health information on the pregnant partner and her baby and complete the
pregnancy questionnaires.  This information will be forwarded to Amgen Global
Patient Safety.
•
Generally, infant follow-up will be conducted up to 12 months after the birth of the
child (if applicable).
•
Any termination of the pregnancy will be reported to Amgen Global Patient Safety
regardless of fetal status (presence or absence of anomalies) or indication for
procedure.
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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 Worksheet (see below) 
and submitted to Amgen Global Patient Safety within 24 hours of the 
investigator’s knowledge of event.
•
Study treatment will be discontinued if female subject breastfeeds during the 
study as described in exclusion criterion 235. 
•
With the female subjects signed authorization for release of mother and infant 
health information, the investigator will collect mother and infant health 
information and complete the lactation questionnaire on any female subject who 
breastfeeds while taking protocol-required therapies through the last dose of 
study drug after discontinuing protocol-required therapies.
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Figure 12-2.  Pregnancy and Lactation Notification Worksheet
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12.6
Appendix 6.  Sample Storage and Destruction
Any blood sample collected according to the Schedule of Activities (Table 2-1) can be 
analyzed for any of the tests outlined in the protocol and for any tests necessary to 
minimize risks to study subjects.  This includes testing to ensure analytical methods
produce reliable and valid data throughout the course of the study.  This can also 
include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability. 
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality. 
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand 
migraine, the dose response and/or prediction of response to erenumab, characterize 
antibody response, and characterize aspects of the molecule (eg, mechanism of 
action/target, metabolites).  Results from this analysis are to be documented and 
maintained, but are not necessarily reported as part of this study.  Samples can be 
retained for up to 20 years.  
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of pharmacogenetic, biomarker development, or other 
exploratory studies are not placed in the subject’s medical record and are not to be 
made available to the subject, members of the family, the personal physician, or other 
third parties, except as specified in the informed consent.
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood and any other components from the cells can be located and destroyed.  Samples 
will be destroyed once all protocol-defined procedures are completed.  However, 
information collected from samples prior to the request for destruction, will be retained 
by Amgen.
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
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appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  See 
Section 12.3 for subject confidentiality. 
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12.7
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and 
Follow-up Assessments and Study Treatment Rechallenge 
Guidelines
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis (as 
described below) may meet the criteria for withholding or permanent discontinuation of 
Amgen investigational product or other protocol-required therapies, as specified in the 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation,
July 2009. 
Criteria for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver biomarkers (TBL, INR and transaminases) has not been 
identified. 
Important alternative causes for elevated AST/ALT and/or TBL values include, but are 
not limited to:
•
Hepatobiliary tract disease
•
Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, 
herpes simplex virus, varicella, toxoplasmosis, and parvovirus)
•
Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia
•
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants and mushrooms
•
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit BIL glucuronidation (eg, indinavir, 
atazanavir)
•
Alpha-1 antitrypsin deficiency
•
Alcoholic hepatitis
•
Autoimmune hepatitis
•
Wilson’s disease and hemochromatosis
•
Nonalcoholic fatty liver disease including steatohepatitis
•
Nonhepatic causes (eg, rhabdomyolysis, hemolysis)
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If investigational product(s) is/are withheld, the subject is to be followed for possible drug 
induced liver injury (DILI) according to recommendations in the last section of this 
appendix. 
Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL, is discovered and the laboratory abnormalities resolve 
to normal or baseline (see next section in this appendix).
Table 12-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity
Analyte
Temporary Withholding
Permanent Discontinuation
TBL
> 2x ULN 
at any time
> 3x ULN
OR
INR
--
> 1.5x (for subjects not on 
anticoagulation therapy)
OR
AND
AST/ALT
> 8x ULN at any time
> 5x ULN but < 8x ULN for ≥2 weeks
> 5x ULN but < 8x ULN and unable to 
adhere to enhanced monitoring schedule
> 3x ULN with clinical signs or symptoms 
that are consistent with hepatitis (such as 
right upper quadrant pain/tenderness, 
fever, nausea, vomiting, and jaundice)
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values
> 3x ULN (when baseline was < ULN)
OR
ALP
> 8x ULN at any time
--
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin; ULN = upper limit of normal
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity
The decision to rechallenge the subject is to be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen.
If signs or symptoms recur with rechallenge, then Amgen investigational product is to be 
permanently discontinued.  Subjects who clearly meet the criteria for permanent 
discontinuation (as described in Table 12-2) are never to be rechallenged.
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Drug-induced Liver Injury Reporting and Additional Assessments
Reporting
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation, according to the criteria specified in the above, require 
the following:
•
The event is to be reported to Amgen as a serious adverse event within 24 hours 
of discovery or notification of the event (ie, before additional etiologic 
investigations have been concluded)
•
The appropriate Case Report Form (CRF) (eg, Event CRF) that captures 
information necessary to facilitate the evaluation of treatment-emergent liver 
abnormalities is to be completed and sent to Amgen  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 12.4.
Additional Clinical Assessments and Observation
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Table 12-2 or who experience AST or ALT elevations > 3 x upper limit of normal (ULN) 
or 2-fold increases above baseline values for subjects with elevated values before drug 
are to undergo a period of “close observation” until abnormalities return to normal or to 
the subject’s baseline levels.  
Assessments that are to be performed during this period include: 
•
Repeat AST, ALT, ALP, BIL (total and direct), and INR within 24 hours 
•
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and
direct), and INR is to be performed every 24 hours until laboratory abnormalities 
improve
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic.
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Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL.  
The following are to be considered depending on the clinical situation:
•
Complete blood count with differential to assess for eosinophilia
•
Serum total immunoglobulin G (IgG), anti-nuclear antibody anti-smooth muscle 
antibody, and liver kidney microsomal antibody-1 to assess for autoimmune 
hepatitis
•
Serum acetaminophen (paracetamol) levels
•
A more detailed history of: 
•
Prior and/or concurrent diseases or illness
•
Exposure to environmental and/or industrial chemical agents 
•
Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting, and fever
•
Prior and/or concurrent use of alcohol, recreational drugs and special diets
•
Concomitant use of medications (including nonprescription medicines and herbal 
and dietary supplements), plants, and mushrooms
•
Viral serologies
•
Creatine phosphokinase, haptoglobin, lactate dehydrogenase and peripheral 
blood smear
•
Appropriate liver imaging if clinically indicated
•
Appropriate blood sampling for pharmacokinetic analysis if this has not already 
been collected
•
Hepatology consult (liver biopsy may be considered in consultation with a 
hepatologist)
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  The 
“close observation period” is to continue for a minimum of 4 weeks after discontinuation 
of all investigational product(s) and protocol-required therapies.
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in the corresponding CRFs.  
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12.8
Appendix 8.  Substudy:  Qualitative Interview Substudy to ‘A 
Phase 4, Randomized, Double-blind, Placebo-controlled, Parallel 
group Study to Evaluate the Efficacy and Safety of Erenumab in 
Adults With Chronic Migraine and Medication Overuse Headache.’ 
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. These 
interviews enable the capture of data from study subjects to complement the finding from 
clinical trials. For example, treatment satisfaction can be assessed to understand which 
aspects of the treatment are valued by patients such as symptom benefit, delivery 
method, adverse event (AE) tolerability and used to help generate value messages for 
the product. Interviewing clinical trial participants at the start and end of the double-blind 
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 clinical 
outcome assessment (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 events, 
viability of proposed dosing regimen, and informal cost/benefit trade-offs.
Research Question and Objective(s) of the Qualitative Interview Substudy
The objective of this substudy is to assess the experience of treatment benefit 
experienced by subjects in Study 20170703, especially in terms of change in functioning 
during and in between migraine attacks, resulting from a preventive treatment for 
migraine.
Substudy Design 
Qualitative interviews will be conducted with subjects who opt in to this optional 
substudy. Interviews will be conducted via entry interviews, conducted within 7 days of 
the first IP dose, and exit interviews, conducted within 7 days of the week 24 visit or 
within approximately 14 days of the early termination (ET) visit.  If possible, within 
7 days from early termination notification will be targeted.  
Substudy Study Population or Data Resource 
The population for this substudy will be comprised of adult subjects with migraine 
participating in the Amgen clinical trial of erenumab (Study Number 20170703) who opt 
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in to this optional substudy at selected sites.  Subjects will be recruited throughout the 
study accrual period at approximately five (5) US-based sites participating in the main or 
parent clinical trial.  An additional site participating in the parent clinical trial may be 
added to the substudy in order to ensure recruitment feasibility. Data sources will include 
the transcripts of audio-recordings of the telephone interviews. Clinical trial data and 
data to characterize the sample collected in the clinical trial (Study Number 20170703) 
will be accessed for the subjects interviewed as part of the current substudy, to 
characterize the sample.
Summary of Substudy Subject Eligibility Criteria  
Study subjects must meet the following criteria to be considered for enrollment into the 
substudy:
1) Be randomized in Study 20170703 and have successfully received a first dose of 
investigational product (IP); 
2) Have provided supplementary informed consent to participate in the substudy;
3) Be willing and able to participate in two (2) telephone interviews lasting 
approximately one hour in duration each;
4) Able to read, understand, and speak English sufficiently to participate in the 
interviews;
5) Be willing and able to be audio-recorded during the interview sessions.
Meeting any of the following criterion will exclude a subject from enrollment into the 
substudy:
1) Unable to complete entry interview within seven (7) days from first IP dose;
2) Unable to complete exit interview within seven (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 subject’s ability participate in 
an interview-based discussion.
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Substudy Duration and Substudy Procedures
Subjects are required to participate in two telephone interviews, lasting approximately 
one-hour each. Entry interviews will be conducted within seven (7) days from first IP 
dose; exit interviews will be conducted in close proximity with the week 24 or early 
termination visits (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).
Subjects enrolled in the clinical trial 20170703 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 randomization and successful 
dosing with IP, depending on site preference. Clinical site staff will explain the 
substudy objectives and procedures to the subject and obtain a supplementary written 
informed consent. The subject will sign two copies of the consent form. Sites will send a 
wet-ink version of the informed consent to Evidera 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.
The subject must personally sign and date the IRB/IEC approved substudy informed 
consent before commencement of substudy specific procedures.  A subject is 
considered enrolled in the substudy when the investigator decides that the subject has 
met the substudy eligibility criteria and subject has signed and dated the substudy 
informed consent.
Evidera staff who are trained and experienced in qualitative data collection will conduct 
telephone interviews using a semi-structured interview guide. Subjects will be 
interviewed about their pre-treatment status and any perceived changes during the trial. 
Subjects will be interviewed about changes experienced and probed about the 
meaningfulness of the changes experienced. During the interviews, interviewers will 
probe subjects for specific examples to qualitatively illustrate the subjects’ experience.
Patients will take part in a telephone-based entry interview at the start of treatment (no 
later than 7 days from first IP dose), lasting approximately one-hour. Subjects will be 
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specifically asked about their experiences with functioning during and in between 
migraine attacks before receiving the initial study dose.
During the exit interview portion of the substudy, the subjects will take part in a final 
telephone interview, approximately one-hour in duration (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). Subjects will be 
specifically asked to compare their experience from the end of the DBTP or early 
termination visit around changes in functioning during and in between migraine attacks 
after receiving the preventive treatment for migraine. After open ended questions, if 
subjects do not mention the impacts they noted at entry interview, the interviewer will 
probe on those impacts. The interviews will also explore what aspects of improvement or 
worsening of their migraine (eg, frequency, severity, duration) drove the changes, as 
well as the ‘meaningfulness’ of change/no change reported by the patient.
All interviews, both entry and exit, will be conducted using a standardized interview 
guide to drive the conversation and elicit concepts of interest important to the current 
study, such as migraine impact, effectiveness of treatment, and day-to-day functioning of 
the subject.
Variables
Substudy Outcome Variable(s) 
Subjects’ prospective and qualitative data of changes resulting from treatment received 
in the double-blind period will be collected via telephone interview. Concepts that 
emerge from the qualitative interviews in relation to migraine impact, treatment efficacy, 
and migraine experience will be the outcome. Data will be analyzed by subjects’ 
perception of change, subjects’ perception of treatment benefit, and subjects’ description 
of migraine experience using qualitative data analysis software (ie, Atlas.ti). Upon 
unblinding as outlined in the parent protocol, the clinical trial data may be further used to 
explore response perceptions.
Exposure Variable(s) 
Subjects will be randomized to placebo, erenumab 70 mg subcutaneously (SC) 
injections every 4 weeks, or erenumab 140 mg SC injections every 4 weeks in the DBTP 
of study protocol 20170703. Interviewers and subjects will be blinded to the treatment 
that subjects are/were administered during the DBTP of the parent clinical trial.
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Substudy Sample Size 
The substudy is based on a convenience sample, aiming to enroll clinical trial subjects 
willing to opt in to this optional study at study sites where the substudy will be conducted. 
The substudy sample size was selected to allow a probability of conducting interviews 
with subjects enrolled on all three treatment arms.
The substudy sample will be a subset of up to 30 subjects who will be recruited from 
Amgen-identified clinical sites participating in the clinical trial 20170703 across the 
United States. Best efforts will be made to ensure that the sample includes subjects with 
diverse demographic characteristics from the pool of trial subjects.
The substudy sample is limited by the clinical trial sample during the timeline for this 
study.
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 and 
quantitative 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 treatment arm, once the 
data has been unblinded, other exploratory sub groups 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 discussion guide to allow the 
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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 (LQR) analyses (Calman 
et al, 2013; Saldana, 2003), which is distinguished from a traditional qualitative approach 
by the fact that the key focus of analysis is on how and why patient 
experiences/perceptions change over time. This innovative approach will be used to 
characterize changes in patients’ perceptions and experiences over time, particularly in 
concepts the patients 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 two-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 on the study 
population over time.
All analysis will be conducted by Evidera staff with experience in qualitative research.
Patient characteristics collected in the clinical trial will be summarized for describing the 
sample. Descriptive statistics (eg, n, mean, standard deviation, and/or frequency) will be 
used to characterize the sample in terms of questionnaire data, sociodemographic, and 
clinical characteristics.
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 20170703. 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.
Definition of Safety Events 
Refer to Section 9.2.3.1 of the parent protocol for definition of safety events.
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Safety Reporting Requirements
The clinic site Investigator is responsible for ensuring that safety events (adverse events, 
product complaints and other safety findings) are reported in accordance to Amgen’s 
clinical trial 20170703 protocol. Evidera will report any AEs to the clinic site and Amgen 
within 1 business day of awareness.
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 clinical trial 20170703 
protocol.
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References
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. 
Food and Drug Administration (FDA). Plan for Issuance of Patient-Focused Drug 
Development Guidance. 2017. Available at: 
https://www.fda.gov/downloads/forindustry/userfees/.../ucm563618.pdf. 
Friese S, Ringmayr T. ATLAS.ti 7 User Guide and Reference. Berlin: ATLAS.ti Scientific 
Software Development GmBH; 2013.
Saldana J. Longitudinal Qualitative Research: Analyzing Change Through Time. 
AltaMira Press, US; 2003.
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Amgen Proprietary - Confidential 
Amendment 2 
Protocol Title:  A Phase 4, Randomized, Double-blind, Placebo-controlled, Parallel-group 
Study to Evaluate the Efficacy and Safety of Erenumab in Adults With Chronic Migraine 
and Medication Overuse Headache 
 
Amgen Protocol Number (Erenumab) 20170703 
EudraCT number 2018-003342-16 
NCT number NCT03971071 
 
Amendment Date: 
27 May 2020 
 
Rationale: 
This protocol is being amended to: 
• 
Update duration of study to approximately 59 weeks 
• 
Schedule of Activities 
o Clarify the baseline period as 4 weeks before day 1 
o Clarify the information collected and process will be done by interactive response 
technology (IRT) 
o Clarify the clinical outcome assessment or patient reported outcomes for HIT-6, 
MFIQ, and ASC 12 will be done post-randomization on day 1 in the clinic 
o Clarify the substudy informed consent can also be obtained at the same time as the 
main study informed consent during screening instead of after randomization 
o Clarify the entry interview will be conducted within 7 days from first dose of 
investigational product and the exit interview will be conducted within 7 days prior to 
week 24 visit or within approximately 14 days post early termination visit 
• 
Clarify key exclusion criteria 
o Update changes in drug regimen (ie, changes in dose or frequency of use) of an 
allowed migraine preventive medication within 2 months from screening  
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Amgen Proprietary - Confidential 
o Removed criterion for subjects with body mass index > 40 kg/m2 assessed at 
screening  
o Clarify if subject has known hypersensitivity to any of the components to be 
administered during dosing will be excluded from the study 
o Update the subjects taking short-acting opioid or opioid-containing analgesic for any 
indication as exclusion criteria 
• 
Clarify that the blinding will be continued in both double-blind and open-label treatment 
period 
• 
Update the exploratory objectives and endpoints of both double-blind and open-label 
treatment periods 
Other Changes: 
• 
Updated primary completion and end of study definitions 
• 
Updated the lifestyle restrictions to be followed to participate in the study 
• 
Medical history and the prior therapies were deleted from the list of minimal set of screen 
failure information collected 
• 
Updated Excluded Treatments, Medical Devices, and/or Procedures During Study Period 
• 
Updated method of collection of information for prior treatment and concomitant treatment 
• 
Updated time period and frequency for collecting and reporting safety event information 
• 
Updated reasons for removal from study 
• 
Updated list of abbreviations and definitions of terms 
• 
Included cardiac risk factor case report form (CRF) to collect the medical history information 
• 
Updated time points to activate the baseline period BDI-II on the eDiary 
• 
Updated time points of additional pregnancy testing and collection of information regarding 
pregnancies and lactation during the study 
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Product: Erenumab 
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Amgen Proprietary - Confidential 
Description of Changes 
Section:  Global 
Change:  Editorial changes (including typographical, grammatical, and formatting) have been 
made throughout the document. 
Section:  Global 
Change:  Updated protocol date from 19 April 2019 to 27 May 2020. 
Section:  Global 
Change:  Revised “months” to “study months” when referring to the timing of the study. 
Section:  Title page 
Replace: 
NCT Number: 
Unavailable for first version 
With: 
NCT Number: 
NCT03971071 
Section:  Title page 
Add: 
Protocol Date: 
Document Version 
Date 
Original 
20 September 2018 
Amendment 1 (v2.0) 
19 April 2019 
Amendment 2 (v3.0) 
27 May 2020 
Section:  1, Protocol Synopsis, Objective(s)/Endpoint(s), Primary  
Replace: 
Objectives 
Endpoints 
Primary 
• 
To evaluate the effect of 
erenumab compared with placebo 
on achieving MOH remission 
during the double-blind treatment 
period (DBTP) 
• 
Absence of MOH at month 6 as 
defined by mean monthly 
treatment acute headache 
medication days 
(AHMD) < 10 days over 
months 4, 5, and 6 OR mean 
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Objectives 
Endpoints 
monthly headache days (MHD) 
< 14 days over months 4, 5, and 
6 of the DBTP where AHMD 
include any eDiary day in which 
an acute headache medication 
intake is reported 
With: 
Objectives 
Endpoints 
Primary 
• 
To evaluate the effect of 
erenumab compared with placebo 
on achieving MOH remission 
during the double-blind treatment 
period (DBTP) 
• 
Absence of MOH at month 6 as 
defined by mean monthly acute 
headache medication days 
(AHMD) < 10 days over 
months 4, 5, and 6 (week 13 
through 24) OR mean monthly 
headache days (MHD) < 14 days 
over months 4, 5, and 6 (week 13 
through 24) of the DBTP where 
AHMD include any eDiary day in 
which an acute headache 
medication intake is reported 
Section:  1, Protocol Synopsis, Objective(s)/Endpoint(s), Primary Estimand and Secondary 
Add: 
Objectives 
Endpoints 
Primary Estimand 
The estimand for the primary efficacy endpoint consists of: 
• 
The target population, which includes subjects diagnosed with CM and MOH who 
have a history of at least 1 preventive treatment failure and do not use opioid 
medication for more than 4 days per month 
• 
The endpoint, which is the absence of MOH at month 6 as defined by mean 
monthly AHMD < 10 days over months 4, 5, and 6 (week 13 through 24) OR 
mean MHD < 14 days over months 4, 5, and 6 (week 13 through 24) of the DBTP 
• 
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of investigational product (IP), regardless of adherence to 
treatment. 
• 
The summary measure, which is the odds ratio of absence of MOH between each 
erenumab dose group (ie, 70 mg or 140 mg) and the placebo group 
Secondary 
• 
To evaluate the effect of 
erenumab compared with placebo 
in reducing acute headache 
• 
Change from baseline in mean 
monthly AHMD over months 4, 5, 
and 6 (week 13 through 24) of 
the DBTP 
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Objectives 
Endpoints 
medication days (AHMD) during 
the DBTP 
The estimand for the secondary objective on AHMD consists of: 
• 
The target population, which includes subjects diagnosed with CM and MOH who 
have a history of at least 1 preventive treatment failure and do not use opioid 
medication for more than 4 days per month. 
• 
The endpoint, which is the change from baseline in mean monthly AHMD over 
months 4, 5, and 6 (week 13 through 24) of the DBTP  
• 
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of investigational product (IP) and have at least 1 change 
from baseline in MHD, regardless of adherence to treatment. 
• 
The summary measure, which is the difference in mean of the endpoint between 
each erenumab dose group (ie, 70 mg and 140 mg) and the placebo group 
• 
To evaluate the effect of 
erenumab compared with placebo 
on sustaining MOH remission 
during the DBTP 
• 
Sustained MOH remission during 
DBTP, as defined by absence of 
MOH at months 3 (week 12) and 
6 (week 24) of the DBTP, and 
“absence of MOH” is achieved 
when mean monthly 
AHMD < 10 days OR mean 
MHD < 14 days over the 
respective 3-month period  
The estimand for the secondary objective on sustained absence of MOH consists of: 
• 
The target population, which includes subjects diagnosed with CM and MOH who 
have a history of at least 1 preventive treatment failure and do not use opioid 
medication for more than 4 days per month 
• 
The endpoint, which is the sustained MOH remission during DBTP, as defined by 
absence of MOH over months 1, 2, and 3 (week 1 through 12) AND over months 
4, 5, and 6 (week 13 through 24) of the DBTP.  Absence of MOH is achieved 
when mean monthly AHMD < 10 days OR mean MHD < 14 days over the 
respective 3-month period 
• 
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of investigational product (IP), regardless of adherence to 
treatment. 
• 
The summary measure, which is the odds ratio of sustained MOH remission 
between each erenumab dose group (ie, 70 mg and 140 mg) and the placebo 
group 
• 
To evaluate the effect of 
erenumab compared with placebo 
on reducing the impact of 
migraines on physical impairment 
and everyday activities as 
measured by the Migraine 
Physical Function Impact Diary 
(MPFID) during the DBTPa 
• 
Change from baseline in mean 
monthly average physical 
impairment domain scores as 
measured by the MPFID over 
months 4, 5, and 6 (week 13 
through 24) of the DBTP 
• 
Change from baseline in mean 
monthly average impact on 
everyday activities domain scores 
as measured by the MPFID over 
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Objectives 
Endpoints 
months 4, 5, and 6 (week 13 
through 24) of the DBTP 
The estimand for the secondary objective on MPFID consists of: 
• 
The target population, which includes subjects diagnosed with CM and MOH who 
have a history of at least 1 preventive treatment failure and do not use opioid 
medication for more than 4 days per month 
• 
The endpoints, which include (1) the change from baseline in mean monthly 
average physical impairment domain scores and (2) the change from baseline in 
mean monthly average impact on everyday activities domain scores as measured 
by the MPFID over months 4, 5, and 6 (week 13 through 24) of the DBTP  
• 
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of investigational product (IP) and have at least 1 change 
from baseline in the respective domain score, regardless of adherence to 
treatment. 
• 
The summary measure, which is the difference in mean of the endpoint between 
each erenumab dose group (ie, 70 mg and 140 mg) and the placebo group 
• 
To evaluate the effect of 
erenumab compared to placebo 
on change from baseline in 
headache impact scores as 
measured by the Headache 
Impact Test (HIT-6)a  
• 
Change from baseline in mean 
HIT-6 score over months 4, 5, 
and 6 (week 13 through 24) of 
the DBTP 
The estimand for the secondary objective on HIT-6 consists of: 
• 
The target population, which includes subjects diagnosed with CM and MOH who 
have a history of at least 1 preventive treatment failure and do not use opioid 
medication for more than 4 days per month  
• 
The endpoint, which is the change from baseline in mean HIT-6 total score over 
months 4, 5, and 6 (week 13 through 24) of the DBTP  
• 
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of investigational product (IP) and have at least 1 change 
from baseline in HIT-6 total score, regardless of adherence to treatment. 
• 
The summary measure, which is the difference in mean of the endpoint between 
each erenumab dose group (ie, 70 mg and 140 mg) and the placebo group 
Section:  1, Protocol Synopsis, Objective(s)/Endpoint(s), Safety  
Replace: 
Objectives 
Endpoints 
Safety 
• 
To evaluate the safety and 
tolerability of erenumab in 
subjects with CM-MOH 
• 
Adverse events 
• 
Clinical laboratory values and vital 
signs 
With: 
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Objectives 
Endpoints 
Safety 
• 
To evaluate the safety and 
tolerability of erenumab in 
subjects with CM-MOH 
• 
Adverse events 
• 
Vital signs 
Section:  1, Protocol Synopsis, Hypothesis 
Add: 
The primary clinical hypothesis of Study 20170703 is that preventive treatment with monthly 
injections of erenumab is superior to placebo in achieving MOH remission for subjects with 
CM-MOH in the nonopioid-treated cohort who have a history of at least 1 preventive treatment 
failure as measured by the absence of the MOH status based on the mean over months 4, 5, 
and 6 (week 13 through 24) of the DBTP.  
Section:  1, Protocol Synopsis, Procedures, paragraph 1 
Delete: 
After signing informed consent, subjects will enter an up to 7-week screening period, which is 
composed of an initial screening period up to 3 weeks (21 days) followed by a 4-week (28-day) 
baseline period.  Subjects will be randomized/enrolled into the 24-week DBTP and will begin to 
receive double-blind investigational product SC every 4 weeks.  Subjects who successfully 
complete the DBTP will have the opportunity to enter a 28-week OLTP.  Subjects will use an 
electronic diary (eDiary) everyday throughout the baseline period, DBTP, and during the last 
quarter of the OLTP (defined as starting at the week 40 visit through week 52/End of Study 
[EOS]) to report information about their migraine and nonmigraine headaches, other 
migraine-related symptoms, and acute headache medication use.  Subjects will have scheduled 
in-clinic study visits throughout the study. 
Section:  1, Protocol Synopsis, Statistical Considerations, paragraph 5,6, 7,8 
Replace: 
The primary analysis will be performed when the last subject in the nonopioid-treated cohort 
completes the week 24 assessments or discontinues the DBTP.  The final analysis for the study 
will be performed after all subjects (nonopioid-treated and opioid-treated cohorts) complete the 
study through the OLTP last visit or discontinue from the study. 
Formal statistical analyses using statistical models and hypothesis testing will be performed for 
the nonopioid-treated cohort only. 
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For the primary and other dichotomous efficacy endpoints, a stratified 
Cochran-Mantel-Haenszel test will be used after the missing data is imputed as nonresponse.  
Continuous secondary endpoints will be analyzed using a linear mixed effects model including 
treatment group, baseline value, stratification factor, scheduled visit, and the interaction of 
treatment group with scheduled visit, without any imputation for missing data.  The mean 
change from baseline for each treatment group, the treatment difference, 95% CI, and p-value 
will be reported.  
The 2 erenumab dose groups will be compared with placebo for the primary and secondary 
efficacy endpoints in the nonopioid-treated cohort using a simple fixed sequence procedure with 
a study-wise type I error rate α = 0.05.  The order of the endpoints to be tested is prespecified 
below. If any test is not significant at the α = 0.05 level, no further testing will be performed.  
Primary and secondary endpoints in erenumab 140 mg versus placebo: 
6. 
Absence of MOH at month 6 of the DBTP (140 mg) 
7. 
Change from baseline in mean monthly AHMD over months 4, 5, and 6 of the DBTP 
(140 mg) 
8. 
Sustained MOH remission during DBTP (140 mg) 
Primary and secondary endpoints in erenumab 70 mg versus placebo: 
9. 
Absence of MOH at month 6 of the DBTP (70 mg) 
10. Change from baseline in mean monthly AHMD over months 4, 5, and 6 of the DBTP 
(70 mg) 
Sustained MOH remission during DBTP (70 mg)Patient-reported outcome-related secondary 
endpoints for the non-European Union (EU) region: 
11. Change from the baseline in mean monthly average physical impairment domain scores 
as measured by the MPFID over months 4, 5, and 6 of the DBTP (140 mg) 
12. Change from the baseline in mean monthly average impact on everyday activities domain 
scores as measured by the MPFID over months 4, 5, and 6 of the DBTP (140 mg) 
13. Change from the baseline in mean monthly average physical impairment domain scores 
as measured by the MPFID over months 4, 5, and 6 of the DBTP (70 mg) 
14. Change from the baseline in mean monthly average impact on everyday activities domain 
scores as measured by the MPFID over months 4, 5, and 6 of the DBTP (70 mg) 
OR 
Patient-reported outcome-related secondary endpoints for the EU region: 
7. Change from baseline in mean HIT-6 score over months 4, 5, and 6 of the DBTP (140 mg) 
8. Change from baseline in mean HIT-6 score over months 4, 5, and 6 of the DBTP (70 mg) 
For a full description of statistical analysis methods, please refer to Section 10. 
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With: 
Primary and secondary endpoints in erenumab 140 mg versus placebo: 
15. 
Absence of MOH at month 6 (week 24) of the DBTP (140 mg) 
16. 
Change from baseline in mean monthly AHMD over months 4, 5, and 6 (week 13 
through 24) of the DBTP (140 mg) 
17. 
Sustained MOH remission during DBTP (140 mg) 
Primary and secondary endpoints in erenumab 70 mg versus placebo: 
18. Absence of MOH at month 6 (week 24) of the DBTP (70 mg) 
19. Change from baseline in mean monthly AHMD over months 4, 5, and 6 (week 13 through 
24) of the DBTP (70 mg) 
20. Sustained MOH remission during DBTP (70 mg) 
Patient-reported outcome-related secondary endpoints for the non-European Union (EU) region: 
21. Change from the baseline in mean monthly average physical impairment domain scores 
as measured by the MPFID over months 4, 5, and 6 (week 13 through 24) of the DBTP 
(140 mg) 
22. Change from the baseline in mean monthly average impact on everyday activities domain 
scores as measured by the MPFID over months 4, 5, and 6 (week 13 through 24) of the 
DBTP (140 mg) 
23. Change from the baseline in mean monthly average physical impairment domain scores 
as measured by the MPFID over months 4, 5, and 6 (week 13 through 24) of the DBTP 
(70 mg) 
24. Change from the baseline in mean monthly average impact on everyday activities domain 
scores as measured by the MPFID over months 4, 5, and 6 (week 13 through 24) of the 
DBTP (70 mg) 
OR 
Patient-reported outcome-related secondary endpoints for the EU region: 
9. Change from baseline in mean HIT-6 score over months 4, 5, and 6 (week 13 through 24) 
of the DBTP (140 mg) 
10. Change from baseline in mean HIT-6 score over months 4, 5, and 6 (week 13 through 24) 
of the DBTP (70 mg) 
For a full description of statistical analysis methods, please refer to Section 10. 
Approved 
 
 


Product: Erenumab 
Protocol Number:  20170703 
Date:  27 May 2020 
Page 10 of 61 
Amgen Proprietary - Confidential 
Section:  2.2, Schedule of Activities, Table 2-1.  Schedule of Activities - Study Visits Through Double-blind Treatment Period, header 
rows 
Delete: 
 
Screening Period 
Treatment Period 
 
 
Initial Screening 
Period 
Baseline 
Period 
Double-blind Treatment Period (24 Weeks) 
 
PROCEDURE 
(up to 3 weeks 
before Baseline) 
(up to 4 weeks 
before Day 1) 
Day 1 
Wk 4 Wk 8 Wk 12 Wk 16 Wk 20 
Wk 24/ 
ETa 
Notes 
Section:  2.2, Schedule of Activities, Table 2-1.  Schedule of Activities - Study Visits Through Double-blind Treatment Period, table 
rows 
Replace: 
IVRS/IWRS call 
X 
 
X 
X X 
X 
X 
X 
X 
 
CLINICAL OUTCOME ASSESSMENTS/PATIENT-REPORTED OUTCOMES 
HIT-6 
 
 
X 
X X 
X 
X 
X 
X 
eDiary in clinic 
MFIQ 
 
 
X 
X X 
X 
X 
X 
X 
eDiary in clinic 
ASC-12 
 
 
X 
  
X 
 
 
X 
eDiary in clinic 
With: 
IRT call 
X 
 
X 
X X 
X 
X 
X 
X 
 
CLINICAL OUTCOME ASSESSMENTS/PATIENT-REPORTED OUTCOMES 
HIT-6 
 
 
X 
X X 
X 
X 
X 
X 
Post-randomization on Day 1; 
eDiary in clinic 
MFIQ 
 
 
X 
X X 
X 
X 
X 
X 
Post-randomization on Day 1; 
eDiary in clinic 
ASC-12 
 
 
X 
 
 
X 
 
 
X 
Post-randomization on Day 1; 
eDiary in clinic 
 
 
Approved 
 
 


Product: Erenumab 
Protocol Number:  20170703 
Date:  27 May 2020 
Page 11 of 61 
Amgen Proprietary - Confidential 
Section:  2.2, Schedule of Activities, Table 2-1.  Schedule of Activities - Study Visits Through Double-blind Treatment Period, table 
rows 
Replace: 
 
Screening Period 
Treatment Period 
 
 
Initial Screening 
Period 
Baseline 
Period 
Double-blind Treatment Period (24 Weeks) 
 
PROCEDURE 
(up to 3 weeks 
before Baseline) 
(up to 4 weeks 
before Day 1) 
Day 1 
Wk 4 Wk 8 Wk 12 Wk 16 Wk 20 
Wk 24/ 
ETa 
 
Notes 
MIDAS 
 
 
X 
 
 
X 
 
 
X 
Post-randomization on Day 1; in 
clinic 
BDI-IIf 
X 
X 
 
 
 
X 
 
 
X 
eDiary; in clinic 
GAD-7 
 
 
X 
 
 
X 
 
 
X 
Post-randomization on Day 1; in 
clinic 
Sleep Questionnaire  
 
 
X 
 
 
X 
 
 
X 
Post-randomization on Day 1; in 
clinic 
PGIC 
 
 
 
 
 
 
 
 
X 
In clinic 
With: 
 
Screening Period 
Treatment Period 
 
 
Initial Screening 
Period 
Baseline 
Perioda 
Double-blind Treatment Period (24 Weeks) 
 
PROCEDURE 
(up to 3 weeks 
before Baseline) 
(4 weeks 
before Day 1) 
Day 1b 
Wk 4 Wk 8 Wk 12 Wk 16 Wk 20 
Wk 24/ 
ETc 
 
Notes 
MIDAS 
 
 
X 
 
 
X 
 
 
X 
Post-randomization on Day 1; eDiary 
in clinic 
BDI-IIh 
X 
Xi 
 
 
 
X 
 
 
X 
eDiary; in clinic 
GAD-7 
 
 
X 
 
 
X 
 
 
X 
Post-randomization on Day 1; eDiary 
in clinic 
Sleep Questionnaire  
 
 
X 
 
 
X 
 
 
X 
Post-randomization on Day 1; eDiary 
in clinic 
PGIC 
 
 
 
 
 
 
 
 
X 
eDiary in clinic 
 
Approved 
 
 


Product: Erenumab 
Protocol Number:  20170703 
Date:  27 May 2020 
Page 12 of 61 
Amgen Proprietary - Confidential 
Section:  2.2, Schedule of Activities, Table 2-1.  Schedule of Activities - Study Visits Through 
Double-blind Treatment Period, Table abbreviations footnote “c” 
Replace: 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ASC-
12 = Allodynia Symptoms Checklist-12; BDI-II = Beck Depression Inventory-II; BP = blood pressure; 
DBTP = double-blind treatment period; eDiary = electronic diary; ET = early termination; GAD-7 = Generalized 
Anxiety Disorder 7-item Scale; HIT-6 = Headache Impact Test-6; HIV = human immunodeficiency virus; HR = heart 
rate; HRU = Health Resource Utilization;  IVRS/IWRS = Interactive Voice Response System/Interactive Web 
Response System; MFIQ = Migraine Functional Impact Questionnaire; MIDAS = Migraine Disability Assessment; 
MPFID = Migraine Physical Function Impact Diary; OLTP = open-label treatment period; PGIC = Patient Global 
Impression of Change; RR = respiratory rate  
a A subject who discontinues the study during the DBTP will complete the assessments of the week 24/ ET visit 
approximately 28 (+3) days after the last dose of investigational product.  
b Including pre-filled syringe in DBTP and autoinjector during OLTP. 
c All clinical laboratory testing at screening (except pregnancy testing) will be performed at a central laboratory.  
Thereafter, only ALP, AST, and ALT will be performed routinely at a central laboratory. 
d Additional on-treatment local laboratory 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.  
e For subjects who provided informed consent for the pharmacogenetic studies, DNA will be obtained from residual 
cells from the biomarker blood sample.  Therefore, additional sampling is not required. 
f The BDI-II will be collected via paper CRF during screening and eDiary thereafter. 
g The baseline HRU questionnaire will have a 24-week recall of prior utilization.  The HRU questionnaire assessed at 
the ET visit before week 24 should only include HRU recalled since the previous assessment to avoid collecting 
duplicate information.  For example, the 24-week HRU questionnaire assessed at week 20 as the ET visit should 
only include HRU recalled since the previous assessment at day 1 (ie, 20-week recall). 
With: 
ASC-12 = Allodynia Symptoms Checklist-12; BDI-II = Beck Depression Inventory-II; BP = blood pressure; 
DBTP = double-blind treatment period; eDiary = electronic diary; ET = early termination; GAD-7 = Generalized 
Anxiety Disorder 7-item Scale; HIT-6 = Headache Impact Test-6; HIV = human immunodeficiency virus; HR = heart 
rate; HRU = Health Resource Utilization; IRT = Interactive Response Technology; MFIQ = Migraine Functional 
Impact Questionnaire; MIDAS = Migraine Disability Assessment; MPFID = Migraine Physical Function Impact Diary; 
OLTP = open-label treatment period; PGIC = Patient Global Impression of Change; RR = respiratory rate  
a The baseline period ends when either a subject is screen failed or randomized into the study.  
Randomization occurs at the Day 1 visit which must occur between 29 to 35 days after baseline entry 
(inclusive of the first day that eDiary device is assigned to subject).  
b On Day 1, all study assessments should be completed prior to subject’s first dose of investigational 
product. 
c A subject who discontinues the study during the DBTP will complete the assessments of the week 24/ ET visit 
approximately 28 (+3) days after the last dose of investigational product.  
d Including pre-filled syringe in DBTP and autoinjector during OLTP. 
e All clinical laboratory testing at screening (except pregnancy testing) will be performed at a central laboratory. 
f Additional on-treatment local laboratory 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.  
g For subjects who provided informed consent for the pharmacogenetic studies, DNA will be obtained from residual 
cells from the biomarker blood sample.  Therefore, additional sampling is not required. 
h The BDI-II will be collected via paper CRF during screening and eDiary thereafter. 
i The Baseline Period BDI-II will be completed at the end of the Baseline Period using the eDiary, after at least 
28 days of data has been entered in the eDiary. 
j The baseline HRU questionnaire will have a 24-week recall of prior utilization.  The HRU questionnaire assessed at 
the ET visit before week 24 should only include HRU recalled since the previous assessment to avoid collecting 
duplicate information.  For example, the 24-week HRU questionnaire assessed at week 20 as the ET visit should 
only include HRU recalled since the previous assessment at day 1 (ie, 20-week recall). 
Section:  2.2, Schedule of Activities, Table 2-2.  Schedule of Activities - Study Visits Through 
Open-label Treatment Period, General and Safety Assessments, table rows 
Approved 
 
 


Product: Erenumab 
Protocol Number:  20170703 
Date:  27 May 2020 
Page 13 of 61 
Amgen Proprietary - Confidential 
Replace: 
IVRS/IWRS callb 
X 
X 
 
 
X 
 
 
X 
 
With: 
IRT callb 
X 
X 
 
 
X 
 
 
X 
 
Section:  2.2, Schedule of Activities, Table 2-2.  Schedule of Activities - Study Visits Through 
Open-label Treatment Period 
Replace: 
 
Treatment Period 
 
 
Open-label Treatment Period (28 Weeks) 
 
PROCEDURE 
Wk 24 
(OLTP 
Entry 
Visit) 
Wk 28 Wk 32 Wk 36 
Wk 40 Wk 44 Wk 48 
Wk 52/ 
EOSa 
Notes 
LABORATORY ASSESSMENTS 
Urine pregnancy test 
(females of childbearing 
potential only)d 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urine drug test 
X (to be performed at the discretion of the investigator) 
 
 
With: 
 
Treatment Period 
 
 
Open-label Treatment Period (28 Weeks) 
 
PROCEDURE 
Wk 24 
(OLTP 
Entry 
Visit) 
Wk 28 Wk 32 Wk 36 
Wk 40 Wk 44 Wk 48 
Wk 52/ 
EOSa 
Notes 
LABORATORY ASSESSMENTS 
Urine pregnancy test 
(females of childbearing 
potential only)d 
X 
X 
X 
X 
 
Urine drug test 
X (to be performed at the discretion of the investigator) 
 
Approved 
 
 


Product: Erenumab 
Protocol Number:  20170703 
Date:  27 May 2020 
Page 14 of 61 
Amgen Proprietary - Confidential 
Section:  2.2, Schedule of Activities, Table 2-2.  Schedule of Activities - Study Visits Through Open-label Treatment Period,rows 
Replace: 
CLINICAL OUTCOME ASSESSMENTS/PATIENT-REPORTED OUTCOMES 
Site re-assigns eDiary to subject 
 
 
 
 
X 
 
 
 
 
eDiary 
 
 
 
 
X (Daily) 
Daily during 
assessment 
months 
Subject brings eDiary to center for 
use during visit or to return 
 
 
 
 
 
 
 
X 
Sites should 
retain eDiary at 
EOS visit 
MPFID  
 
 
 
 
X (Daily) 
Daily during 
assessment 
months 
With: 
CLINICAL OUTCOME ASSESSMENTS/PATIENT-REPORTED OUTCOMES 
Site re-assigns eDiary to subject 
 
 
 
 
X 
 
 
 
 
eDiary 
 
 
 
 
X (Daily) 
Daily during 
assessment 
study months 
Subject brings eDiary to center for 
use during visit or to return 
 
 
 
 
 
 
 
X 
Sites should 
retain eDiary at 
EOS visit 
MPFID  
 
 
 
 
X (Daily) 
Daily during 
assessment 
study months 
Section:  2.2, Schedule of Activities, Table 2-2.  Schedule of Activities - Study Visits Through Open-label Treatment Period 
Replace: 
 
Approved 
 
 


Product: Erenumab 
Protocol Number:  20170703 
Date:  27 May 2020 
Page 15 of 61 
Amgen Proprietary - Confidential 
 
Treatment Period 
 
 
Open-label Treatment Period (28 Weeks) 
 
PROCEDURE 
Wk 24 
(OLTP 
Entry 
Visit) 
Wk 28 Wk 32 Wk 36 
Wk 40 Wk 44 Wk 48 
Wk 52/ 
EOSa 
Notes 
HIT-6 
 
 
 
 
 
 
 
X 
In clinic 
MFIQ 
 
 
 
 
 
 
 
X 
In clinic 
MIDAS 
 
 
 
 
 
 
 
X 
In clinic 
With: 
 
Treatment Period 
 
 
Open-label Treatment Period (28 Weeks) 
 
PROCEDURE 
Wk 24 
(OLTP 
Entry 
Visit) 
Wk 28 Wk 32 Wk 36 
Wk 40 Wk 44 Wk 48 
Wk 52/ 
EOSa 
Notes 
HIT-6 
 
 
 
 
 
 
 
X 
eDiary in 
clinic 
MFIQ 
 
 
 
 
 
 
 
X 
eDiary in 
clinic 
MIDAS 
 
 
 
 
 
 
 
X 
eDiary in 
clinic 
Section:  2.2, Schedule of Activities, Table 2-2.  Schedule of Activities - Study Visits Through 
Open-label Treatment Period 
Replace: 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BP = blood 
pressure;  DBTP = double-blind treatment period; eDiary = electronic diary; EOS = end of study; ET = early 
termination; HIT-6 = Headache Impact Test-6; HR = heart rate; IVRS/IWRS = Interactive Voice Response 
System/Interactive Web Response System; MFIQ = Migraine Functional Impact Questionnaire; MIDAS = Migraine 
Disability Assessment; MPFID = Migraine Physical Function Impact Diary; OLTP = open-label treatment period; 
RR = respiratory rate  
a A subject who discontinues investigational product during the OLTP or who completes the study will perform the 
week 52/EOS visit assessments.  Subjects who early terminate will complete the assessments approximately 
28 (+3) days after the last dose of investigational product. 
b All subjects will be enrolled via IVRS/IWRS in the OLTP to maintain the initial treatment blinding in DBTP.  Subjects 
who received active treatment during the DBTP will remain on the same dose.  Subjects who received placebo will 
receive either 70 mg or 140 mg in a 1:1 ratio.  
c Including pre-filled syringe in DBTP and autoinjector during OLTP. 
d Additional on-treatment local laboratory 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. 
e Study drug supply ceases at week 48.   
With: 
Approved 
 
 


Product: Erenumab 
Protocol Number:  20170703 
Date:  27 May 2020 
Page 16 of 61 
Amgen Proprietary - Confidential 
BP = blood pressure;  DBTP = double-blind treatment period; eDiary = electronic diary; EOS = end of study; ET = 
early termination; HIT-6 = Headache Impact Test-6; HR = heart rate; IRT = Interactive Response Technology; 
MFIQ = Migraine Functional Impact Questionnaire; MIDAS = Migraine Disability Assessment; MPFID = Migraine 
Physical Function Impact Diary; OLTP = open-label treatment period; RR = respiratory rate  
a A subject who discontinues investigational product during the OLTP or who completes the study will perform the 
week 52/EOS visit assessments.  Subjects who early terminate will complete the assessments approximately 
28 (+3) days after the last dose of investigational product. 
b All subjects will be enrolled via IRT in the OLTP to maintain the initial treatment blinding in DBTP.  Subjects who 
received active treatment during the DBTP will remain on the same dose.  Subjects who received placebo will 
receive either 70 mg or 140 mg in a 1:1 ratio.  
c Including pre-filled syringe in DBTP and autoinjector during OLTP. 
d Additional on-treatment local laboratory 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. 
e Study drug supply ceases at week 48.   
Section:  2.2, Schedule of Activities, Table 2-3.  Schedule of Activities – Optional Interview-
based Substudy (Selected US Sites Only), header rows 
Delete: 
 
 
Treatment Period 
 
 
Screening 
Period 
Baseline 
Period 
Double-blind Treatment Period (24 Weeks) 
 
PROCEDURE 
(up to 
3 weeks 
before 
Baseline) 
(up to 
4 weeks 
before 
Day 1) 
Day 1 
(pre 
rand) 
Day 1 
(post-rand) Wk 4 Wk 8 Wk 12 Wk 16 Wk 20 
Wk 24/ 
ET 
Notes 
Section:  2.2, Schedule of Activities, Table 2-3.  Schedule of Activities – Optional Interview-
based Substudy (Selected US Sites Only) 
Replace: 
INTERVIEW-BASED SUBSTUDY 
Interviewa 
 
 
Xc 
 
 
 
 
 
Xd 
 
With: 
INTERVIEW-BASED SUBSTUDY 
Interviewb 
 
 
Xc 
 
 
 
 
Xd 
 
Section:  2.2, Schedule of Activities, Table 2-3.  Schedule of Activities – Optional Interview-
based Substudy (Selected US Sites Only), footnotes 
Replace: 
a The first interview (Interview 1) will be conducted within the first week after randomization, the second interview 
(Interview 2) will be conducted within 1 week after the subject’s last visit during the DBTP. 
Approved 
 
 


Product: Erenumab 
Protocol Number:  20170703 
Date:  27 May 2020 
Page 17 of 61 
Amgen Proprietary - Confidential 
With: 
a The Substudy subject informed consent can also be obtained at the same time as the main study informed 
consent during Screening instead of after randomization. 
b The first interview (Interview 1) will be conducted within the first week after randomization, the second interview 
(Interview 2) will be conducted within 1 week after the subject’s last visit during the DBTP. 
c The entry interview will be conducted within 7 days from first investigational product dose. 
d The exit interview will be conducted in close proximity with the week 24 or early termination visits (within 7 
days prior to week 24 visit or within approximately 14 days post early termination visit.  If possible within 7 
days post early termination will be targeted). 
Section:  3.1 Study Rationale, Paragraph 2 
Add: 
In Study 20120295, erenumab 70 mg and 140 mg subcutaneously (SC) every 4 weeks were 
superior to placebo in reducing monthly migraine days (MMD) from baseline to the last study 
month of the double-blind treatment period (DBTP) in subjects with chronic migraine (CM) with 
or without medication overuse status at baseline.  In a prespecified subgroup analysis including 
subjects with CM with medication overuse (CM-MO subjects), both doses of erenumab 
achieved numerical and nominal superiority to placebo in reducing MMD (least-squares mean 
[LSM]: -3.1 days for both 70 mg and 140 mg versus placebo, p < 0.001), achieving ≥ 50% 
reduction in MMD at month 3 (odds ratio: 2.67 and 2.51 for 70 mg and 140 mg, respectively; 
p = -0.004 and 0.007, respectively) and acute headache medication days (AHMD) (LSM: -3.3 
and -2.8 for 70 mg and 140 mg, respectively; p < 0.001) (Tepper et al, 2017).  A subsequent 
post hoc subgroup analysis including CM-MO subjects who had failed 1 or more migraine 
preventive treatment further confirmed this observation with numerically superior reductions for 
both erenumab doses as compared with placebo in MMD (LSM:  2.54 and 4.44 for 70 mg and 
140 mg, respectively), moderate to severe headache days (LSM:  1.81 and 3.82 for 70 mg and 
140 mg, respectively) and AHMD (LSM:  2.61 and 4.26 for 70 mg and 140 mg, respectively).  In 
addition, more subjects treated with erenumab (47% and 52% in 70 mg and 140 mg, 
respectively) met medication overuse-free status at the end of DBTP as compared with placebo 
(29%).    
 
Section:  3.3, Benefit/Risk Assessment  
Replace: 
The overall benefit-risk evaluation for erenumab is favorable for the treatment of patients with 
CM-MOH. 
Approved 
 
 


Product: Erenumab 
Protocol Number:  20170703 
Date:  27 May 2020 
Page 18 of 61 
Amgen Proprietary - Confidential 
The following benefit risk assessment supports the conduct of this clinical trial.  Reference 
should be made to the Investigator’s Brochure and Prescribing Information, where Aimovig is 
approved, for further data on erenumab. 
3.3.1 Therapeutic Context  
Based on the American Academy of Neurology (AAN) “Classification of Evidence Matrix for 
Therapeutic Questions”, none of the existing therapeutic options is currently classified as a 
class I intervention (ie, “highly likely to be effective”) for reducing monthly headache days 
(MHD), moderate to severe headache days, MMD, or migraine-related disability in patients with 
MOH.  
A summary of current standard of care options and their evidentiary basis is presented in Table 
3-1 (Chiang et al, 2016). 
Table 3-1.  Conclusions and Recommendations for the Treatment of 
Medication Overuse Headache 
Therapeutic Option 
Recommendation 
AAN Classification of 
Evidence Matrix for 
Therapeutic Questions 
Early discontinuation 
(ie, washout) without 
preventive medication 
Possibly effective in reducing headache 
frequency and acute medication 
consumption 
Class III studies 
 
Possibly effective in reducing headache 
frequency and acute medication 
consumption, improving MIDAS score, 
quality of life, anxiety and depression up 
to at least 1 year after discontinuation 
Class III studies 
Preventive medication 
without mandatory early 
discontinuation 
Likely that onabotulinumtoxinA is effective 
in reducing headache days, migraine 
days, moderate/severe headache days, 
cumulative hours on headache days, 
headache episodes, migraine episodes, 
migraine-related disability (HIT-6), and 
triptan intake in subjects with CM-MOH 
Class II studies 
 
Likely that topiramate is effective in 
reducing mean number of monthly 
migraine days and possible that 
topiramate is effective in reducing acute 
medication consumption in CM-MOH 
Class II and III studies, 
respectively 
 
Likely that nabilone is effective in reducing 
acute medication consumption, headache 
severity and improving quality of life 
Single Class II study 
 
Possible that acupuncture is effective in 
reducing acute medication consumption 
and headache-related disability 
Single Class II study 
Approved 
 
 


Product: Erenumab 
Protocol Number:  20170703 
Date:  27 May 2020 
Page 19 of 61 
Amgen Proprietary - Confidential 
 
Insufficient evidence to support or refute 
effectiveness of valproic acid, pregabalin, 
occipital nerve stimulation, occipital nerve 
block in any measurement of efficacy in 
MOH 
Class III, IV studies 
AAN = American Academy of Neurology; CM = chronic migraine; HIT-6 = Headache Impact Test-6; 
MIDAS = migraine disability assessment; MOH = medication overuse headache. 
3.3.2 Key Benefits  
Erenumab 70 mg and 140 mg SC QM are approved in Europe, US, and other regions worldwide 
for the prevention of migraine in adults.  
Based on subgroup analyses performed in subjects with CM-MO who participated in Study 
20120295, erenumab 70 mg and 140 mg were numerically and nominally superior to placebo in 
reducing MMD, moderate to severe headache days, AHMD, and reverting medication overuse 
status at week 12. 
3.3.3 Key Risks  
The most common adverse reactions in the migraine studies were injection site reactions and 
constipation.  Table 3-2 summarizes all adverse reactions that occurred in Aimovig-treated 
subjects during the 12-week placebo-controlled period of the pooled trials.  Most adverse 
reactions were mild or moderate in severity. 
Table 3-2.  Adverse Reactions With Aimovig 
System Organ 
Class 
Adverse 
Reaction 
Preferred 
Term 
Frequency 
Category 
Overall 
subject 
incidence at 
70 mg 
(N = 893)  
n (%) 
Overall 
subject 
incidence at 
140 mg 
(N = 507)  
n (%) 
Nature/ 
Severity/ 
Seriousness 
General 
disorders and 
administration 
site conditions 
Injection site 
reactionsa 
Common 
50 (5.6) a 
23 (4.5)a 
 
Gastrointestinal 
disorders 
Constipation 
Common 
12 (1.3) 
16 (3.2) 
 
Musculoskeletal 
and connective 
tissue disorders 
Muscle 
spasm 
Common 
1 (0.1) 
10 (2.0) 
One grade 3 
(0.2%) event 
was reported; 
all others 
were grade 
1 or 2b 
Approved 
 
 


Product: Erenumab 
Protocol Number:  20170703 
Date:  27 May 2020 
Page 20 of 61 
Amgen Proprietary - Confidential 
Skin and 
subcutaneous 
tissue disorders 
Pruritusc 
Common 
6 (0.7) c 
9 (1.8)c 
 
Note:  Frequency is provided by the Council for International Organizations of Medical Sciences category (eg, Very 
Common [≥ 10%], Common [≥ 1% and < 10%], uncommon [≥ 0.1% and < 1%], rare [≥ 0.01% and < 0.1%], very rare 
[< 0.01%]). 
a Injection Site Reactions includes multiple preferred terms, such as injection site pain and injection site erythema. 
b Severity grades are based on the Common Terminology Criteria for Adverse Events (CTCAE):  grade 1,  mild; 
grade 2, moderate; grade 3, severe or medically significant; grade 4, life-threatening consequences; grade 5, death. 
c Pruritus includes preferred terms of generalized pruritus, pruritus, and pruritic rash. 
In placebo-controlled clinical studies, 1.3% of subjects treated with erenumab discontinued 
double-blind treatment because of adverse events.  The most frequent injection site reactions 
were injection site pain, injection site erythema, and injection site pruritus. 
Key risks of treatment in MOH are expected to be similar to those of treatment in migraine. 
3.3.3.1 Risks Not Established in Special Populations  
The safety of erenumab has not been established in migraine subjects with major 
cardiovascular disease (myocardial infarction, stroke, transient ischemic attack, unstable 
angina, coronary artery bypass surgery, or other revascularization procedures within 12 months 
prior to screening), in the long-term use of erenumab, in elderly subjects > 65 years of age, in a 
pediatric population < 18 years of age, or during pregnancy and breastfeeding. 
With: 
The identified risks for AMG 334 are documented in Appendix A of the currently 
approved IB (Edition  11:  February 2020).  A limited number of adverse drug reactions 
(injection site reactions, constipation, muscle spasm, and pruritis) have been identified 
at low frequencies (< 5%) in clinical trials.  In post-marketing settings, hypersensitivity 
reactions (including rash, angioedema and anaphylactoid reactions) and constipation 
with serious complications have been reported.  Available safety data for the clinical 
trials with AMG 334 are summarized in Section 6.3 of the AMG 334 Investigator’s 
Brochure, Annex 2.    
Section:  4.1, Objectives and Endpoint 
Delete: 
Objectives 
Endpoints 
Primary 
• 
To evaluate the effect of erenumab 
compared with placebo on achieving 
• 
Absence of MOH at month 6 as 
defined by mean monthly treatment 
acute headache medication days 
Approved 
 
 


Product: Erenumab 
Protocol Number:  20170703 
Date:  27 May 2020 
Page 21 of 61 
Amgen Proprietary - Confidential 
Objectives 
Endpoints 
MOH remission during the 
double-blind treatment period (DBTP) 
(AHMD) < 10 days over months 4, 5, 
and 6 OR mean monthly headache 
days (MHD) < 14 days over months 4, 
5, and 6 of the DBTP where AHMD 
include any eDiary day in which an 
acute headache medication intake is 
reported 
Section:  4.1, Objectives and Endpoint, Primary Estimand and Secondary 
Add: 
Objectives 
Endpoints 
Primary 
• 
To evaluate the effect of 
erenumab compared with placebo 
on achieving MOH remission 
during the double-blind treatment 
period (DBTP) 
• 
Absence of MOH at month 6 as 
defined by mean monthly acute 
headache medication days 
(AHMD) < 10 days over 
months 4, 5, and 6 (week 12 
through 24) OR mean monthly 
headache days (MHD) < 14 days 
over months 4, 5, and 6 (week 12 
through 24) of the DBTP where 
AHMD include any eDiary day in 
which an acute headache 
medication intake is reported 
Primary Estimand 
The estimand for the primary efficacy endpoint consists of: 
• 
The target population, which includes subjects diagnosed with CM and MOH who 
have a history of at least 1 preventive treatment failure and do not use opioid 
medication for more than 4 days per month 
• 
The endpoint, which is the absence of MOH at month 6 as defined by mean 
monthly AHMD < 10 days over months 4, 5, and 6 (week 13 through 24) OR 
mean MHD < 14 days over months 4, 5, and 6 (week 13 through 24)of the DBTP 
• 
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of investigational product (IP), regardless of adherence to 
treatment. 
• 
The summary measure, which is the odds ratio of absence of MOH between each 
erenumab dose group (ie, 70 mg or 140 mg) and the placebo group 
Approved 
 
 


Product: Erenumab 
Protocol Number:  20170703 
Date:  27 May 2020 
Page 22 of 61 
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Objectives 
Endpoints 
Secondary 
• 
To evaluate the effect of 
erenumab compared with placebo 
in reducing acute headache 
medication days (AHMD) during 
the DBTP 
• 
Change from baseline in mean 
monthly AHMD over months 4, 5, 
and 6 (week 13 through 24) of 
the DBTP 
The estimand for the secondary objective on AHMD consists of: 
• 
The target population, which includes subjects diagnosed with CM and MOH who 
have a history of at least 1 preventive treatment failure and do not use opioid 
medication for more than 4 days per month. 
• 
The endpoint, which is the change from baseline in mean monthly AHMD over 
months 4, 5, and 6 (week 13 through 24) of the DBTP  
• 
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of investigational product (IP) and have at least 1 change 
from baseline in MHD, regardless of adherence to treatment. 
• 
The summary measure, which is the difference in mean of the endpoint between 
each erenumab dose group (ie, 70 mg and 140 mg) and the placebo group 
• 
To evaluate the effect of 
erenumab compared with placebo 
on sustaining MOH remission 
during the DBTP 
• 
Sustained MOH remission during 
DBTP, as defined by absence of 
MOH at months 3 (week 12) and 
6 (week 24) of the DBTP, and 
“absence of MOH” is achieved 
when mean monthly 
AHMD < 10 days OR mean 
MHD < 14 days over the 
respective 3-month period  
The estimand for the secondary objective on sustained absence of MOH consists of: 
• 
The target population, which includes subjects diagnosed with CM and MOH who 
have a history of at least 1 preventive treatment failure and do not use opioid 
medication for more than 4 days per month 
• 
The endpoint, which is the sustained MOH remission during DBTP, as defined by 
absence of MOH over months 1, 2, and 3 (week 1 through week 12) AND over 
months 4, 5, and 6 (week 13 through 24) of the DBTP.  Absence of MOH is 
achieved when mean monthly AHMD < 10 days OR mean MHD < 14 days over 
the respective 3-month period 
• 
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of investigational product (IP), regardless of adherence to 
treatment. 
• 
The summary measure, which is the odds ratio of sustained MOH remission 
between each erenumab dose group (ie, 70 mg and 140 mg) and the placebo 
group 
• 
To evaluate the effect of 
erenumab compared with placebo 
on reducing the impact of 
migraines on physical impairment 
and everyday activities as 
• 
Change from baseline in mean 
monthly average physical 
impairment domain scores as 
measured by the MPFID over 
Approved 
 
 


Product: Erenumab 
Protocol Number:  20170703 
Date:  27 May 2020 
Page 23 of 61 
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Objectives 
Endpoints 
measured by the Migraine 
Physical Function Impact Diary 
(MPFID) during the DBTPa 
months 4, 5, and 6 (week 13 
through 24) of the DBTP 
• 
Change from baseline in mean 
monthly average impact on 
everyday activities domain scores 
as measured by the MPFID over 
months 4, 5, and 6 (week 13 
through 24) of the DBTP 
The estimand for the secondary objective on MPFID consists of: 
• 
The target population, which includes subjects diagnosed with CM and MOH who 
have a history of at least 1 preventive treatment failure and do not use opioid 
medication for more than 4 days per month 
• 
The endpoints, which include (1) the change from baseline in mean monthly 
average physical impairment domain scores and (2) the change from baseline in 
mean monthly average impact on everyday activities domain scores as measured 
by the MPFID over months 4, 5, and 6 (week 13 through 24) of the DBTP  
• 
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of investigational product (IP) and have at least 1 change 
from baseline in the respective domain score, regardless of adherence to 
treatment. 
• 
The summary measure, which is the difference in mean of the endpoint between 
each erenumab dose group (ie, 70 mg and 140 mg) and the placebo group 
• 
To evaluate the effect of 
erenumab compared to placebo 
on change from baseline in 
headache impact scores as 
measured by the Headache 
Impact Test (HIT-6)a  
• 
Change from baseline in mean 
HIT-6 score over months 4, 5, 
and 6 (week 13 through 24) of 
the DBTP 
The estimand for the secondary objective on HIT-6 consists of: 
• 
The target population, which includes subjects diagnosed with CM and MOH who 
have a history of at least 1 preventive treatment failure and do not use opioid 
medication for more than 4 days per month  
• 
The endpoint, which is the change from baseline in mean HIT-6 total score over 
months 4, 5, and 6 (week 13 through 24) of the DBTP  
• 
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of investigational product (IP) and have at least 1 change 
from baseline in HIT-6 total score, regardless of adherence to treatment. 
• 
The summary measure, which is the difference in mean of the endpoint between 
each erenumab dose group (ie, 70 mg and 140 mg) and the placebo group 
Safety 
• 
To evaluate the safety and 
tolerability of erenumab in 
subjects with CM-MOH 
• 
Adverse events 
• 
Vital signs 
a In the EU region only, HIT-6 will replace MPFID as a secondary endpoint and MPFID will be evaluated as an 
exploratory endpoint.  In non-EU regions, MPFID will remain as a secondary endpoint while HIT-6 will be evaluated 
as an exploratory endpoint. 
 
Approved 
 
 


Product: Erenumab 
Protocol Number:  20170703 
Date:  27 May 2020 
Page 24 of 61 
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Objectives 
Endpoints 
Exploratory (Double-blind treatment period) 
• 
To explore the effect of erenumab 
compared with placebo in 
promoting conversion to EM 
• 
Achievement of conversion to 
episodic migraine (EM) at 
month 3 defined as mean MHD 
< 14 days over months 1, 2, and 
3 (week 1 through 12) of the 
DBTP 
• 
Achievement of conversion to EM 
at month 6, defined as mean 
MHD < 14 days over months 4, 5, 
and 6 (week 13 through 24) of 
the DBTP 
• 
Achievement of conversion to EM 
over 6 months, defined as mean 
MHD < 14 days over months 1 
through 6 (week 1 through 24) of 
the DBTP 
• 
To explore the effect of erenumab 
compared with placebo on the 
change of at least moderate pain 
intensity MHD from baseline to 
the DBTP  
• 
Change from baseline in  MHD of 
at least moderate pain intensity 
at monthly assessment time 
points  
• 
Change from baseline in mean at 
least moderate pain intensity 
MHD over months 4, 5, and 6 
(week 13 through 24) of the 
DBTP 
• 
Achievement of at least 30%, 
50%, and 75% reductions from 
baseline in at least moderate 
pain intensity MHD at monthly 
assessment time points 
• 
Achievement of at least 30%, 
50%, and 75% reduction from 
baseline in mean at least 
moderate pain intensity MHD 
over months 4, 5, and 6 (week 13 
through 24) of the DBTP  
• 
To explore the effect of erenumab 
compared with placebo on the 
change from baseline in monthly 
migraine days (MMD) during the 
DBTP 
• 
Change from baseline in MMD at 
monthly assessment time points  
• 
Change from baseline in mean 
MMD over months 4, 5, and 6 
(week 13 through 24) of the 
DBTP 
• 
Achievement of at least a 30%, 
50%, and 75% reductions from 
baseline in MMD at monthly 
assessment time points  
• 
Achievement of at least 30%, 
50%, and 75% reductions from 
baseline in MMD mean over 
Approved 
 
 


Product: Erenumab 
Protocol Number:  20170703 
Date:  27 May 2020 
Page 25 of 61 
Amgen Proprietary - Confidential 
Objectives 
Endpoints 
months 4, 5, and 6 (week 13 
through 24) of the DBTP 
• 
To explore the effect of erenumab 
compared with placebo on the 
change from baseline in average 
headache pain severity during the 
DBTP 
• 
Change from baseline in the 
monthly average pain severity 
score of qualified headache days 
at monthly assessment time 
points 
• 
Change from baseline in the 
mean monthly average pain 
severity score of qualified 
headache days over months 4, 5, 
and 6 (week 13 through 24) of 
the DBTP 
• 
To explore the effect of erenumab 
compared with placebo on the 
change from baseline in migraine-
free days during the DBTP 
• 
Change from baseline in monthly 
migraine-free days at monthly 
assessment time points of the 
DBTP 
• 
Change from baseline in mean 
monthly migraine-free days over 
months 4, 5, and 6 (week 13 
through 24) of the DBTP 
• 
To explore migraine-related 
disability metrics as measured by 
the migraine functional impact 
questionnaire (MFIQ) 
• 
Change from baseline in MFIQ 
domain scores and overall impact 
on usual activities global item 
score at assessment time points 
• 
To explore migraine-related 
disability and productivity as 
measured by the Migraine 
Disability Assessment (MIDAS) 
Questionnaire 
• 
Change from baseline in  
MIDAS total score, absenteeism 
score and presenteeism score at 
assessment time points during 
DBTP  
• 
Cumulative (sum of) changes 
from baseline in MIDAS total 
score, absenteeism score and 
presenteeism score over 
6 months during DBTP 
• 
To explore the effect of erenumab 
compared with placebo on the 
change from baseline in health 
resource utilization (HRU) 
• 
Occurrence of at 
least 1 headache-related 
hospitalization or outpatient HRU 
during the DBTP 
• 
Occurrence of at 
least 1 headache-related 
hospitalization during the DBTP 
• 
Occurrence of at 
least 1 headache-related 
outpatient HRU during the DBTP 
• 
Occurrence of at least 
1 headache-related outpatient 
emergency room visit during the 
DBTP 
Approved 
 
 


Product: Erenumab 
Protocol Number:  20170703 
Date:  27 May 2020 
Page 26 of 61 
Amgen Proprietary - Confidential 
Objectives 
Endpoints 
• 
Occurrence of at least 
1 headache-related outpatient 
urgent care visit during the DBTP 
• 
Occurrence of at least 
1 headache-related outpatient 
clinic visit during the DBTP 
• 
To explore the effect of erenumab 
compared with placebo on the 
change from baseline in 
depression and anxiety 
symptoms 
 
 
• 
Change from baseline in 
Generalized Anxiety Disorder 
7-item scale (GAD-7) score at 
assessment time points 
• 
Change from baseline in Beck 
Depression Inventory-II (BDI-II) 
score at assessment time points 
• 
To explore the effect of erenumab 
compared with placebo on the 
change from baseline in 
measures of sleep quality 
• 
Change from baseline in each of 
the sleep questionnaire domain 
scores at assessment time points 
• 
To explore the effect of erenumab 
compared with placebo on the 
subject’s assessment of the 
change in clinical status since the 
start of treatment 
• 
Change in clinical status as 
measured by the Patient’s Global 
Impression of Change (PGIC) as 
assessed by the subject at 
month 6 of the DBTP 
• 
To explore the effect of erenumab 
compared to placebo on the 
change from baseline in allodynia 
symptoms 
• 
Change from baseline in 
Allodynia Symptoms Checklist-12 
(ASC-12) score at assessment 
time points 
Exploratory (Open-label treatment period) 
• 
To explore the rate of MOH 
relapse in the end of open-label 
treatment period (OLTP) 
• 
MOH relapse at year 1, defined 
as both mean monthly 
AHMD ≥ 10 days over months 11, 
12, and 13 (week 41 through 52) 
AND mean MHD ≥ 14 days over 
months 11, 12, and 13 (week 41 
through 52) in subjects who 
achieved MOH remission at 
month 6 of the DBTP 
Note:  This endpoint will be 
analyzed among subjects who 
were treated with erenumab 
throughout the entire study 
• 
To explore absence of MOH at 
end of OLTP 
• 
Absence of MOH at end of study 
as defined by mean monthly 
AHMD < 10 days over months 11, 
12, and 13 (week 41 through 52) 
OR mean MHD < 14 days over 
months 11, 12, and 13 (week 41 
through 52)  
• 
To explore sustainability of MOH 
remission during OLTP 
• 
Sustained absence of MOH over 
1 year as defined by absence of 
MOH over the DBTP (months 1, 
Approved 
 
 


Product: Erenumab 
Protocol Number:  20170703 
Date:  27 May 2020 
Page 27 of 61 
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Objectives 
Endpoints 
2, and 3 [week 1 through 12], 
OR months 4, 5, and 6 [week 13 
through 24]) AND OLTP (months 
11, 12, and 13 [week 41 through 
52]). 
Note:  “Absence of MOH” is achieved 
when mean monthly AHMD < 10 days 
OR mean MHD < 14 days over the 
respective 3-month period 
This endpoint will be analyzed 
among subjects who were treated 
with erenumab throughout the 
entire study 
• 
To explore change in AHMD, 
MMD, and MHD of at least 
moderate pain intensity 
• 
Change from baseline in mean 
AHMD, MMD and MHD of at 
least moderate pain intensity at 
assessment time points  
• 
Change from week 24 (OLTP 
baseline) in mean AHMD, MMD, 
and MHD of at least moderate 
pain intensity at assessment 
time points during OLTP 
• 
To explore everyday activities as 
measured by the MPFID 
 
• 
Change from baseline in monthly 
average impact on everyday 
activities score as measured by 
the MPFID at assessment time 
points 
• 
Change from week 24 (OLTP 
baseline) in monthly average 
impact on everyday activities 
score as measured by the MPFID 
at assessment time points during 
OLTP 
• 
To explore physical impairment 
as measured by the MPFID 
• 
Change from baseline in monthly 
average physical impairment 
score as measured by the MPFID 
at assessment time points 
• 
Change from week 24 (OLTP 
baseline) in monthly average 
physical impairment score as 
measured by the MPFID at 
assessment time points during 
OLTP 
• 
To explore the daily activity 
impact of headache as measured 
by the HIT-6 
• 
Change from baseline in HIT-6 
total score at week 52 
• 
Change from week 24 (OLTP 
baseline) in HIT-6 total score at 
week 52 
Approved 
 
 


Product: Erenumab 
Protocol Number:  20170703 
Date:  27 May 2020 
Page 28 of 61 
Amgen Proprietary - Confidential 
Objectives 
Endpoints 
• 
To explore migraine-related 
disability metrics as measured by 
MFIQ 
• 
Change from baseline in MFIQ 
domain scores and overall impact 
on usual activities global item 
score at week 52 
• 
Change from week 24 (OLTP 
baseline) in MFIQ domain scores 
and overall impact on usual 
activities global item score at 
week 52 
• 
To explore migraine-related 
disability and productivity as 
measured by the MIDAS 
Questionnaire 
• 
Change from baseline in MIDAS 
total score, absenteeism score 
and presenteeism score at 
week 52 
• 
Change from week 24 (OLTP 
baseline) in MIDAS total score, 
absenteeism score, and 
presenteeism score at week 52 
Exploratory (Opioid-treated Cohort Only)a  
• 
To explore the effect of erenumab 
compared with placebo in 
reducing consumption of opioids 
in subjects stratified to the 
opioid-treated cohort during 
DBTP 
• 
Change from baseline in monthly 
opioid/opioid-containing 
medication days at assessment 
time points during DBTP 
• 
Change from baseline in mean 
monthly 
opioid/opioid-containing 
medication days over months 
4, 5, and 6 (week 13 through 24) 
of the DBTP 
• 
To explore the effect of erenumab 
compared with placebo in 
reducing consumption of opioids 
in subjects stratified to the 
opioid-treated cohort during 
OLTP  
• 
Change from baseline in monthly 
opioid/opioid-containing 
medication days at assessment 
time points during OLTP 
a In addition to these objectives/endpoints, all primary, secondary, and exploratory objectives and endpoints will be 
evaluated for the opioid-treated cohort. 
Section:  4.2 Hypotheses 
Add: 
The primary clinical hypothesis of Study 20170703 is that preventive treatment with monthly 
injections of erenumab is superior to placebo in achieving MOH remission for subjects with 
CM-MOH in the nonopioid-treated cohort who have a history of at least 1 preventive treatment 
failure as measured by the absence of the MOH status based on the mean over months 4, 5, 
and 6 (week 13 through 24) of the DBTP.  
Approved 
 
 


Product: Erenumab 
Protocol Number:  20170703 
Date:  27 May 2020 
Page 29 of 61 
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The secondary clinical hypotheses of Study 20170703 are that preventive treatment with 
monthly injections of erenumab is superior to placebo in reducing AHMDs over months 4 to 6 
(week 13 through 24) of the DBTP; sustaining MOH remission during the entire DBTP; 
reducing migraine-related impact on physical functioning and everyday activities as measured 
by Migraine Physical Function Impact Diary (MPFID) physical function and everyday activities 
domains (non-EU) or migraine-related impact on physical functioning as measured by the 
Headache Impact Test 6 (HIT-6) (EU only). 
For subjects with CM-MOH allocated to the opioid-treated cohort, an additional exploratory 
clinical hypothesis of Study 20170703 is that preventive treatment with monthly injections of 
erenumab could help reduce opioid use as measured by the mean change in monthly opioid 
medication days from baseline over months 4, 5, and 6 (week 13 through 24) of the DBTP.  
Formal statistical testing does not apply to this exploratory clinical hypothesis. 
Section:  5.2.2,Number of Sites 
Add: 
Approximately 80 investigative sites in 12 countries are expected to participate in 
Study 20170703.  Additional sites and/or countries within North America, Europe, or Asia Pacific 
may be added as deemed necessary by the study management team.  
Sites that do not enroll subjects within 3 study months of site initiation may be closed. 
Section:  5.3.1, End of Study Definition, Primary Completion, paragraph 2 (new) 
Add: 
For this study, the primary completion date is the date when the last subject in the 
nonopioid-treated cohort has completed the assessments for week 24 (month 6) or 
discontinues study. 
Section:  5.3.2, Study Duration for Subjects, paragraph 1 
Replace: 
The total study duration for subjects who successfully complete the study will be up to 
59 weeks.  Total study duration includes:  
With: 
The total study duration for subjects who successfully complete the study will be approximately 
59 weeks.  Total study duration includes:  
Approved 
 
 


Product: Erenumab 
Protocol Number:  20170703 
Date:  27 May 2020 
Page 30 of 61 
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Section:  6.2, Exclusion Criteria Part 1 
Replace: 
207. 
Changes in drug regimen (ie, changes in dose or frequency of use) of an allowed 
migraine preventive medication within 2 months from screening OR change in drug 
regimen of a medication with potential for migraine prevention within 2 months from 
screening (refer to Section 7.1.7 for the list of these medications) 
209 
Documented history of treatment with an anti-CGRP product 
213 
Excluded medical conditions include: 
• 
Currently diagnosed with fibromyalgia and/or chronic pelvic pain;  
• 
Currently diagnosed with a clinically significant cervical or intracranial disease (eg, 
chronic cervical radiculopathy, space-occupying lesions, intracranial aneurysms) 
that, in the opinion of the investigator, might confound or mimic migraine 
symptomatology;  
• 
History of major psychiatric disorder (such as schizophrenia or other psychotic 
disorders, bipolar disorder, obsessive-compulsive disorder, post-traumatic stress 
disorder), or current evidence of depression based on a BDI-II total score > 24 at 
screening.  
• 
History of malignancy within the past 5 years, with the following exception[s]:  
− 
Malignancy treated with curative intent and with no known active disease present 
for ≥ 5 years before enrollment and felt to be at low risk for recurrence by the 
treating physician 
− 
Adequately treated nonmelanoma skin cancer or lentigo maligna without 
evidence of disease 
− 
Prostatic intraepithelial neoplasia without evidence of prostate cancer 
− 
Adequately treated urothelial papillary noninvasive carcinoma or carcinoma 
in situ 
• 
Known human immunodeficiency virus (HIV) infection 
• 
Known hepatic disease with potential for hepatic function impairment or evidence of 
acute or chronic hepatitis B or hepatitis C (hepatitis status will be evaluated by 
testing for hepatitis B surface antigen [HepBsAg], total hepatitis B core antibody 
[HepBcAb] and hepatitis C antibody at screening) 
• 
Total bilirubin ≥ 2.0x upper limit of normal (ULN) or alanine aminotransferase (ALT) 
or aspartate aminotransferase (AST) ≥ 3.0 x ULN, as assessed by the central 
laboratory at screening 
219 
Exceeded 15 days per month of a short-acting opioid/opioid-containing medication 
during any of the 3 months prior to screening 
220 
Had a concomitant use of a short-acting opioid/opioid-containing medication in a 
frequency that exceeds 4 days per month with any of the following prescribed 
psychoactive substances: 
Approved 
 
 


Product: Erenumab 
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• Regular use of barbiturates as defined as any use that exceeds 4 days per month 
during any of the 3 months prior to screening 
• Regular use of central nervous system sedative-hypnotic drugs or drugs that may 
increase opioid risk such as benzodiazepines, z-drugs, gabapentinoids, tricyclic 
antidepressants, butyrophenones, phenothiazines, anticonvulsants, and muscle 
relaxants as defined as any use that exceeds 15 days per month during any of the 3 
months prior to screening. 
221 
Currently receiving treatment in another investigational device or drug study, or 
< 30 days or 5 half-lives since ending treatment on another investigational device or drug 
study(ies).  Other investigational procedures while participating in this study are 
excluded. 
222 
Subject has known sensitivity to any of the components to be administered during 
dosing. 
 
With: 
235 
Changes in drug regimen (ie, changes in dose or frequency of use) of an allowed 
migraine preventive medication within 2 months prior to start of baseline (refer to 
Section 7.1.7 for the list of these medications) 
236 
Documented history of treatment with an anti-CGRP preventive treatment 
237 
Excluded medical conditions include: 
• 
Currently diagnosed with fibromyalgia and/or chronic pelvic pain;  
• 
Currently diagnosed with a clinically significant cervical or intracranial disease (eg, 
chronic cervical radiculopathy, space-occupying lesions, intracranial aneurysms) 
that, in the opinion of the investigator, might confound or mimic migraine 
symptomatology;  
• 
History of major psychiatric disorder (such as schizophrenia or other psychotic 
disorders, bipolar disorder, obsessive-compulsive disorder, post-traumatic stress 
disorder), or current evidence of depression based on a BDI-II total score > 24 at 
screening.  
• 
History of malignancy within the past 5 years, with the following exception[s]:  
− 
Malignancy treated with curative intent and with no known active disease present 
for ≥ 5 years before screening and felt to be at low risk for recurrence by the 
treating physician 
− 
Adequately treated nonmelanoma skin cancer or lentigo maligna without 
evidence of disease 
− 
Prostatic intraepithelial neoplasia without evidence of prostate cancer 
− 
Adequately treated urothelial papillary noninvasive carcinoma or carcinoma 
in situ 
• 
Known human immunodeficiency virus (HIV) infection 
• 
Known hepatic disease with potential for hepatic function impairment or evidence of 
acute or chronic hepatitis B or hepatitis C (hepatitis status will be evaluated by 
Approved 
 
 


Product: Erenumab 
Protocol Number:  20170703 
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testing for hepatitis B surface antigen [HepBsAg], total hepatitis B core antibody 
[HepBcAb] and hepatitis C antibody at screening) 
• 
Total bilirubin ≥ 2.0x upper limit of normal (ULN) or alanine aminotransferase (ALT) 
or aspartate aminotransferase (AST) ≥ 3.0 x ULN, as assessed by the central 
laboratory at screening 
238 
Exceeded 15 days per month of a short-acting opioid/opioid-containing medication 
during any of the 2 months prior to screening 
239 
Had a concomitant use of a short-acting opioid/opioid-containing medication in a 
frequency that exceeds 4 days per month with any of the following prescribed 
psychoactive substances: 
• Regular use of barbiturates as defined as any use that exceeds 4 days per month 
during any of the 2 months prior to screening 
• Regular use of central nervous system sedative-hypnotic drugs or drugs that may 
increase opioid risk such as benzodiazepines, z-drugs, gabapentinoids, tricyclic 
antidepressants, butyrophenones, phenothiazines, anticonvulsants, and muscle 
relaxants as defined as any use that exceeds 15 days per month during any of the 
3 months prior to screening. 
240 
Currently receiving treatment in another investigational device or drug study, or 
< 30 days or 5 half-lives (whichever is longer) since ending treatment on another 
investigational device or drug study(ies).  Other investigational procedures while 
participating in this study are excluded. 
241 
Subject has known hypersensitivity to any of the components to be administered during 
dosing. 
Section:  6.2, Exclusion Criteria Part 1 
Delete: 
217 
Body mass index (BMI) > 40 kg/m2 as assessed at screening 
Section:  6.4, Exclusion Criteria Part 2 
Replace: 
225. 
Taken an opioid or opioid-containing analgesic for any indication on > 15 days during 
baseline period 
226. 
Opioid use during baseline period that in the opinion of the investigator or Amgen's 
physician, if consulted, constitutes any of the following: 
− 
misuse (use that is contrary to the prescriber's directions, eg, unsolicited dose 
escalation)  
− 
abuse (use for nonmedical intention, eg, euphoria or altered consciousness)  
− 
dependence (use that is compulsive or potentially harmful) 
− 
diversion (transfer of a legally prescribed controlled substance from the individual for 
whom it was prescribed to another person for any illicit use) 
Approved 
 
 


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230 
At risk of self-harm or harm to others as evidenced by scoring ≥ 1 point in BDI-II item 9 
and concomitant demonstration of strong suicidal ideation (ie, presence of suicidal 
planning) 
With: 
242 
Taken a short-acting opioid or opioid-containing analgesic for any indication on 
> 15 days during baseline period 
243 
Short-acting opioid use during baseline period that in the opinion of the investigator or 
Amgen's physician, if consulted, constitutes any of the following: 
− 
misuse (use that is contrary to the prescriber's directions, eg, unsolicited dose 
escalation)  
− 
abuse (use for nonmedical intention, eg, euphoria or altered consciousness)  
− 
dependence (use that is compulsive or potentially harmful) 
− 
diversion (transfer of a legally prescribed controlled substance from the individual for 
whom it was prescribed to another person for any illicit use) 
244 
At risk of self-harm or harm to others as evidenced by scoring ≥ 1 point in BDI-II item 9 
(Suicidal Thoughts or Wishes) and concomitant demonstration of strong suicidal 
ideation (ie, presence of suicidal planning) 
Section:  6.5. Lifestyle Restrictions 
Delete: 
6.5 
Lifestyle Restrictions 
6.5.1 Caffeine, Alcohol, and Tobacco 
Subjects should not consume caffeine-containing beverages or tobacco within 30 minutes 
before each study visit where vital signs will be taken.  Subjects should not participate in this 
study if there is evidence of a consistent pattern of alcohol abuse that may indicate an alcohol 
use disorder (see exclusion criterion 231).  
6.5.2 Activity 
Subjects should abstain from strenuous exercise for 24 hours before each blood collection for 
clinical laboratory tests. 
Approved 
 
 


Product: Erenumab 
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Section:  6.5, Subject Enrollment 
Replace: 
The subject identification number will be assigned via IVRS/IWRS.   
With: 
The subject identification number will be assigned via interactive response technology (IRT).   
Section:  6.6, Screen Failures, paragraph 1 
Delete: 
Screen failures are defined as subjects who consent to participate in the clinical study but are 
not subsequently enrolled/randomized in the study.  A minimal set of screen failure information 
will be collected that includes demography, screen failure details, eligibility criteria, medical 
history, prior therapies, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once if the condition that led to screen failure is expected to be transient.  Refer to 
Section 9.1.1. 
Section:  6.6, Screen Failures, paragraph 3 
Replace: 
A subject who is determined to be ineligible must be registered as a screen fail in the 
IVRS/IWRS. 
With: 
A subject who is determined to be ineligible must be registered as a screen fail in the IRT. 
 
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Section:  7.1.1, Table 7-1.  Study Treatments 
Replace: 
Unit Dose Strength(s)/ 
Dosage Level(s) and 
Dosage Frequency 
• 
Erenumab 70 mg and 140 mg will be 
administered every 4 weeks during 
DBTP and OLTP.  
• 
To preserve blinding integrity during 
the DBTP, the 70 mg dose level will be 
composed of one 1 mL injection of 
erenumab 70 mg and one 1 mL 
injection of matching placebo, and the 
140 mg dose level will be composed of 
two 1 mL injections of erenumab 
70 mg.   
• 
During OLTP, subjects will be 
maintained on their original dose 
assignment and receive IP as an 
autoinjector device. 
• 
Placebo will be administered 
every 4 weeks during the 
24-week DBTP (ie, at day 1 and 
visit weeks 4, 8, 12, 16, and 20).   
• 
To preserve blinding integrity 
during the DBTP, there will be 
two 1 mL injections of matching 
placebo for placebo assigned 
subjects 
• 
Upon completion of DBTP, 
placebo-treated subjects will be 
allocated to an active dose arm 
by IVRS/IWRS to receive either 
70 mg or 140 mg of erenumab 
every 4 weeks. 
With: 
Unit Dose Strength(s)/ 
Dosage Level(s) and 
Dosage Frequency 
• 
Erenumab 70 mg and 140 mg will be 
administered every 4 weeks during 
DBTP and OLTP.  
• 
To preserve blinding integrity during 
the DBTP, the 70 mg dose level will be 
composed of one 1 mL injection of 
erenumab 70 mg and one 1 mL 
injection of matching placebo, and the 
140 mg dose level will be composed of 
two 1 mL injections of erenumab 
70 mg.   
• 
During OLTP, subjects will be 
maintained on their original dose 
assignment and receive IP as an 
autoinjector device. 
• 
Placebo will be administered 
every 4 weeks during the 
24-week DBTP (ie, at day 1 and 
visit weeks 4, 8, 12, 16, and 20).   
• 
To preserve blinding integrity 
during the DBTP, there will be 
two 1 mL injections of matching 
placebo for placebo assigned 
subjects. 
• 
Upon completion of DBTP, 
placebo-treated subjects will be 
allocated to an active dose arm 
by IRT to receive either 70 mg or 
140 mg of erenumab every 
4 weeks. 
Approved 
 
 


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Section:  7.1.1, Table 7-1.  Study Treatments, table abbreviations 
Replace: 
CRF = case report form; DBTP = double-blind treatment period; IPIM = investigational product instruction 
manual; IVRS/IWRS = Interactive Voice Response System/Interactive Web Response System; OLTP = open-
label treatment period  
With: 
CRF = case report form; DBTP = double-blind treatment period; IPIM = investigational product instruction 
manual; IRT = Interactive Response Technology; OLTP = open-label treatment period  
Section:  7.1.7, Excluded Treatments, Medical Devices, and/or Procedures During Study 
Period, paragraph 1 
Replace: 
Concomitant treatment with 1 oral migraine preventive medication is allowed under the 
following conditions:  
With: 
Concomitant treatment with up to 2 oral migraine preventive medication is allowed under 
the following conditions:  
Section:  7.1.7, Excluded Treatments, Medical Devices, and/or Procedures During Study 
Period, bullet 7 
Add: 
• 
Other drugs used for migraine prevention (eg, coenzyme Q10, clonidine, 
guanfacine, methysergide, cyproheptadine, pizotifen, butterbur, feverfew, 
magnesium (≥ 500 mg/day), riboflavin (≥ 100 mg/day). 
Section:  7.1.7, Excluded Treatments, Medical Devices, and/or Procedures During Study 
Period, Prohibited Medications 
Replace: 
Prohibited Medications 
Time Period for Exclusion 
Concurrent use of non-investigational anti-CGRP mAbs 
Prior history of treatment 
with and throughout the 
study 
Cannabinoids 
Within 2 months prior to 
screening and throughout 
the study 
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Prohibited Medications 
Time Period for Exclusion 
Use of the following acute medications for the acute treatment of 
migraine 
Barbiturates or butalbital-containing medication for > 4 days/month 
Opioids or opioid-containing medication for >15 days/month 
3 months before the start 
of the screening period 
and throughout the study 
Investigational medications  
30 days or 5 half-lives 
before the start of the 
screening period and 
throughout the study 
Botulinum toxin (in the head and/or neck region) 
4 months before the start 
of the screening period 
and throughout the study 
Prohibited Procedures or Devices 
 
Time Period for Exclusion 
For any indication 
Infusion therapy (ie, steroids, valproate sodium, dihydroergotamine) 
Note:  infusion therapy may be allowed during DBTP if medically 
justified 
 
During screening period or 
baseline period 
For any indication  
Devices (such as stimulation devices), or procedures (such as nerve 
blocks, acupuncture, biofeedback, relaxation techniques, or 
psychotherapy).  
 
3 months before the start 
of the screening period 
and throughout the study 
Cognitive Behavioral Therapy 
Subjects on a stable, maintenance phase of a cognitive behavioral 
therapy (CBT) program for migraine are allowed.  CBT is defined as 
stable, on a maintenance phase if subject has undergone ≥ 6 weekly 
or biweekly sessions of CBT administered by adequately trained 
psychologists and who, for at least 3 months before the start of the 
baseline period, only follow “booster” CBT sessions at a monthly, 
bimonthly or quarterly frequency. 
 
3 months before the start 
of the screening period 
With:  
Prohibited Medications 
Time Period for Exclusion 
Concurrent use of non-investigational anti-CGRP mAbs 
Prior history of treatment 
with and throughout the 
study 
Use of the following acute medications for the acute treatment of 
migraine: 
Barbiturates or butalbital-containing medication for > 4 days/month 
Short-acting opioids or short-acting opioid-containing medication 
for >15 days/month 
Long-acting opioids or long-acting opioid-containing medication 
2 months before the start 
of the screening period 
and throughout the study 
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Prohibited Medications 
Time Period for Exclusion 
Cannabidiol (CBD)-containing products anticipated to have a 
systemic effect (eg, ingested or inhaled products) 
> 4 days/month 
Investigational medications  
30 days or 5 half-lives 
before the start of the 
screening period and 
throughout the study 
Botulinum toxin (in the head and/or neck region) 
4 months before the start 
of the screening period 
and throughout the study 
Prohibited Procedures or Devices 
 
Time Period for Exclusion 
For any indication 
Infusion rescue therapy (ie, steroids, valproate sodium, 
dihydroergotamine) 
Note:  infusion rescue therapy may be allowed during DBTP if 
medically justified 
 
During screening period or 
baseline period 
For any indication  
Devices (such as stimulation devices), or procedures (such as nerve 
blocks, or psychotherapy).  
 
3 months before the start 
of the screening period 
and throughout the study 
Cognitive Behavioral Therapy 
Subjects on a stable, maintenance phase of a cognitive behavioral 
therapy (CBT) program for migraine are allowed.  CBT is defined as 
stable, on a maintenance phase if subject has undergone ≥ 6 weekly 
or biweekly sessions of CBT administered by adequately trained 
psychologists and who, for at least 3 months before the start of the 
baseline period, only follow “booster” CBT sessions at a monthly, 
bimonthly or quarterly frequency. 
 
3 months before the start 
of the screening period 
Section:  7.2, Method of Treatment Assignment, paragraph 2 
Replace: 
The randomization will be performed by IVRS/IWRS, and the randomization number will be 
assigned by IVRS/IWRS and appear on the IVRS/IWRS randomization document.  The 
randomization number is different than the subject identification number and will not be 
utilized by the site as a subject identifier. 
With: 
The randomization will be performed by IRT, and the randomization number will be assigned 
by IRT and appear on the IRT randomization document.  The randomization number is 
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different than the subject identification number and will not be utilized by the site as a 
subject identifier. 
Section:  7.3, Blinding 
Replace: 
This is a double-blind study.  Treatment assignment will be blinded to all subjects, site 
personnel, and Amgen as described below. 
With: 
This study has a 24-week DBTP and a 28-week OLTP.  Treatment assignment will be 
blinded to all subjects, site personnel, and Amgen as described below.  During the 24-week 
DBTP, treatment assignment will be blinded to all subjects, site personnel, and 
Amgen.  Following the DBTP, during the 28-week OLTP, study team members in 
direct contact with sites, investigators and subjects will remain blinded to the initial 
dose level. 
Section:  7.8.1, Prior Treatment 
Replace: 
Prior therapies that were being taken/used from 120 days before screening through the 
signing of the informed consent will be collected. 
With: 
For prior migraine preventive medications, which are required to have ended 
2 months prior to baseline, therapy name, indication, dose, unit, frequency, start and 
stop dates will be collected in the prior migraine preventive medication CRF.   
For all other prior therapies that were being taken/used within 120 days prior to 
screening through the signing of the informed consent, therapy name, start and stop 
dates will be collected in the concomitant medication CRF. 
Section:  7.8.2, Concomitant Treatment, paragraph 3 and 4 (new) 
Add: 
Concomitant medication that is taken to treat headaches or migraine symptoms 
acutely and/or may lead or contribute to MOH will be reported in the eDiary.   
Approved 
 
 


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All other concomitant medications will be reported on the Concomitant Medications 
electronic case report form (eCRF) including any allowable concomitant migraine 
preventive medication.  
Section:  8.2.2, Reasons for Removal From Study, bullet 5 and 6 
Delete: 
• 
Protocol-specified criteria (after subject is enrolled/randomized on study)  
• 
New pregnancy, decision to breastfeed, or decision of unwillingness to maintain an 
acceptable contraception method during the baseline period 
Section:  9.1.1, Screening, Enrollment and/or Randomization 
Replace: 
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 
IVRS/IWRS and screen the subject in order to assess eligibility for participation. 
With: 
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. 
Section:  9.1.1.1, Screening Period 
Replace: 
The up to 3-week initial screening period starts when the subject signs and dates the 
informed consent form and ends when the subject is deemed eligible to enter the 4-week 
baseline period or discontinues before baseline entry and/or does not meet all Part 1 
eligibility criteria (refer to Sections 6.1 and 6.2). 
With: 
The screening period is up to 7 weeks, which consists of an up to 3-week initial 
screening period and a 4-week baseline period. 
Section:  9.1.1.2, Baseline Period 
Replace: 
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The 4-week baseline period starts when the subject has met all Part 1 eligibility criteria (refer 
to Section 6.1 and Section 6.2) and enters the baseline period and ends when the subject 
does not complete baseline or does not meet all Part 2 eligibility criteria (refer to Section 6.3 
and Section 6.4), or is enrolled/randomized.   
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all Part 2 eligibility criteria prior to enrollment/ randomization.  If a subject has not met 
all Part 2 eligibility criteria during the baseline period, the subject will be registered as a 
screen fail.  Screen fail subjects may be eligible for rescreening 1 time.  Refer to 
Section 9.1.1.1 for additional details regarding screen failures and rescreening. 
With: 
The 4-week baseline period starts when the subject has met all Part 1 eligibility criteria (refer 
to Section 6.1 and Section 6.2) and enters the baseline period and ends when the subject is 
randomized or does not complete baseline or does not meet all Part 2 eligibility criteria 
(refer to Section 6.3 and Section 6.4) and is screen failed.   
The total duration of the baseline period must be at least 29 days and no more than 
35 days.  Refer to Sections 9.2.2.1 and 9.2.2.3 for information on the BDI-II and 
eligibility calculation, which are to be completed at the end of the baseline period 
using the eDiary.    
Section:  9.1.1.3, Randomization 
Replace: 
Upon completion of the baseline period, subjects found to meet eligibility requirements will 
undergo randomization in IVRS/IWRS and be assigned a study treatment in a blinded 
manner. 
The subject is considered enrolled when the investigator decides that the subject has met 
Part 1 and Part 2 eligibility criteria and follow procedures for subject randomization. 
With: 
Upon completion of the baseline period, subjects found to meet eligibility requirements will 
undergo randomization in IRT and be assigned a study treatment in a blinded manner. 
Section:  9.1.2.1, Double-blind Treatment Period 
Delete: 
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9.1.2.1  
Double-blind Treatment Period 
During the DBTP, 2 SC injections will be administered per day at day 1, weeks 4, 8, 12, 16, 
and 20 (12 injections in total).  Both SC injections are to be administered within 30 minutes 
during each visit that it is required.  Subjects randomized to: 
Erenumab 70 mg every 4 weeks will receive a total of 12 injections (1 injection of erenumab 
70 mg/mL PFS and 1 injection of matching placebo) at day 1, weeks 4, 8, 12, 16, and 20. 
Erenumab 140 mg every 4 weeks will receive a total of 12 injections (2 injections of 
erenumab 70 mg/mL PFS) at day 1, weeks 4, 8, 12, 16, and 20. 
Placebo will receive a total of 12 injections (2 injections of placebo) at day 1, weeks 4, 8, 12, 
16, and 20. 
Section:  9.1.2.2, Open-label Treatment Period 
Delete: 
9.1.2.2  
Open-label Treatment Period 
Subjects who successfully complete the DBTP of the study will be given the option to 
continue in an OLTP of 28 weeks.  Entry in OLTP must occur no earlier than week 24 OLTP 
visit and no later than week 28 visit.  All subjects originally assigned to placebo will be 
allocated in a 1:1 ratio to erenumab 70 mg or erenumab 140 mg in order to protect original 
treatment blinding.  Subjects who received active treatment during the DBTP will remain on 
the same dose.  After receiving training at the week 24 visit, subjects will self-administer 
erenumab at home or during clinic visits using an auto injector.  All subjects will be 
encouraged to do self-administration, but those who either refuse or who are determined by 
the staff to not be proficient will be required to return to the clinic every 4 weeks for injections 
with the auto-injector performed by a qualified staff member.   
Section:  9.2.1.3, Medical History 
Add: 
The Investigator or designee will collect a complete medical (including targeted 
cardiovascular), psychiatric, and surgical history that started within 120 days prior to medical 
history assessment at screening.  Medical history will include information on the subject's 
concurrent medical conditions.  Record all findings on the medical history CRF.  In addition 
Approved 
 
 


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to the medical history above, migraine history must date back to the original diagnosis.  The 
current severity will be collected for each condition that has not resolved. 
Targeted medical history is to be recorded in the neurologic medical history CRF, 
cardiovascular medical history CRF, cardiac risk factors CRF, and headache and migraine 
frequency medical history CRF. 
Section:  9.2.1.5, Physical Measurements 
Delete: 
Body Mass Index should be calculated using the following formula: BMI (kg/m2) = weight 
(kg)/[height (cm)/100]2 
Section:  9.2.2.1, Clinical Outcome Assessments and Electronic Diaries (eDiaries), 
paragraph 1 
Add: 
The COAs will be collected by subjects using a handheld eDiary at various frequencies.  The 
eDiary will collect the following COAs daily at home starting in the baseline period and 
throughout the DBTP, and then again daily starting from week 40 visit through the 
week 52/EOS visit of the OLTP: 
Section:  9.2.2.1, Clinical Outcome Assessments and Electronic Diaries (eDiaries), bullet 6 
Add: 
• 
Use of acute medications to treat headaches or migraine symptoms (medication 
name [from pre-entered list] date and time of dosing, number of times taken of each 
date, number of units taken)  
Section:  9.2.2.1, Clinical Outcome Assessments and Electronic Diaries (eDiaries), 
paragraph 2 
Add: 
Study center staff will assign and provide an eDiary to the subject at the week -4 visit (after 
confirming the subject’s part 1 eligibility prior to baseline period entry).  The study center 
staff will train the subject on how to use the eDiary (eg, turning on/off, charging, navigating 
screens, transmitting data, contacting the help desk for technical assistance) and complete 
the questions.  The subject will be instructed to interact with the eDiary every day and to 
bring the eDiary to every study visit.  During the baseline period after at least 28 full 
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calendar days have passed (inclusive of the day the patient was set-up on the eDiary 
device), the subject will return for their end of baseline period visit/ day 1 visit.  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.  During this visit, 
site staff will be able to activate the baseline period BDI-II on the subject’s eDiary 
device, as well as perform the eligibility calculation.  
Section:  9.2.2.1, Clinical Outcome Assessments and Electronic Diaries (eDiaries), 
paragraph 3 (new) 
Add: 
For randomized subjects, all Day 1 study assessments, including eDiary 
questionnaires, should be completed prior to subject’s first dose of investigational 
product.  For subsequent study visits, the order of completing study assessments 
will be at the investigator’s discretion.  
Section:  9.2.2.3, Beck Depression Inventory (BDI-II), paragraph 2 (new) 
Add: 
Sites will be able to activate the baseline period BDI-II on the eDiary at the end of the 
subject’s baseline period, after at least 28 full calendar days have passed (inclusive of 
the day the subject was set-up on the eDiary device).  
Section:  9.2.2.11, Health Resource Utilization Resource Questionnaire (HRU), header 
Add:  
9.2.2.11 
Health Resource Utilization Resource Questionnaire (HRU) 
Section:  9.2.2.11, Health Resource Utilization Resource Questionnaire (HRU), paragraph 1 
Replace: 
The questionnaire is designed to collect data on HRU.  Specifically, the HRU questionnaire 
aims to capture frequency of migraine-related inpatient hospitalizations and outpatient 
emergency department visits, urgent care visits, and other clinical visits.  The recall period 
for the HRU questionnaire is 24 weeks.  The questionnaire with the 24-week recall will be 
administered at day 1 and week 24 of the DBTP. 
With: 
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The questionnaire is designed to collect data on HRU.  Specifically, the HRU questionnaire 
aims to capture frequency of headache-related inpatient hospitalizations and outpatient 
emergency department visits, urgent care visits, and other clinical visits.  The recall period 
for the HRU questionnaire is 24 weeks.  The questionnaire with the 24-week recall will be 
administered at day 1 and week 24 of the DBTP. 
Section:  9.2.3.1.1.1, Adverse Events, paragraph 1 
Replace: 
Adverse events related to any study procedures/study-activity are reported from signing of 
the informed consent form.  All other adverse events are reported after the first dose of 
investigational product.  The adverse event grading scale to be used for this study will be the 
Common Terminology Criteria for Adverse Events (CTCAE) and is described in 
Section 12.4. 
With: 
Adverse events related to any study procedures/study-activity are reported after the first 
dose of investigational product.  All other adverse events are reported after the first dose 
of investigational product.   
Section:  9.2.3.1.1.2, Serious Adverse Events, paragraph 1 
Replace: 
The investigator is responsible for ensuring that all serious adverse events observed by the 
investigator or reported by the subject that occur after randomization through the end of 
study are reported using the Event CRF. 
With: 
The investigator is responsible for ensuring that all serious adverse events observed by the 
investigator or reported by the subject that occur after signing of the informed consent 
through the end of study are reported using the Event CRF. 
Section:  9.2.3.1.5, Pregnancy and Lactation, paragraph 1 
Replace: 
Details of all pregnancies and/or lactation in female subjects and, if indicated, female 
partners of male subjects will be collected after the start of study treatment and until the end 
of treatment. 
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With: 
Details of all pregnancies and/or lactation in female subjects and, if indicated, female 
partners of male subjects who become pregnant, will be collected after the start of study 
treatment through 16 weeks after the last dose of study drug. 
Section:  9.2.4, Clinical Laboratory Assessments, paragraph 3 (new) 
Add: 
Urine drug tests (UDTs) performed at screening that return positive likely due to the 
use of an allowable over-the-counter (OTC) medication may be retested prior to 
eligibility determination. 
Section:  9.2.4.1, Pregnancy Testing, paragraph 3 
Replace: 
Additional pregnancy testing should be performed at monthly intervals during treatment with 
protocol-required therapies and up to week 52/EOS visit.  
With: 
Post day 1 pregnancy testing should be completed as per the Schedule of Activities 
(Table 2-1, Table 2-2).    
Section: 10.1 Sample Size Determination 
Add: 
The sample size calculation has been performed based on the primary endpoint (absence of 
MOH at month 6 [week 24]) for the nonopioid-treated cohort. 
Based on a subgroup analysis of subjects who failed preventive migraine medication, 
overused acute headache medication, and had at least 14 MHD at baseline in the erenumab 
CM pivotal Study 20120295, 33.1%, 50.5%, and 64.1% of subjects in placebo, erenumab 
70 mg and erenumab 140 mg treatment group, respectively, achieved absence of MOH at 
month 3 (week 12).  Assuming similar response rates over month 4, 5 and 6 (week 13 
through 24) and a conservative scenario that includes a dropout rate of 20% during the 
6-month DBTP, the planned sample size of 183 subjects per group will provide 85% power 
for 70 mg versus placebo and > 99% power for 140 mg versus placebo using a 2-sample 
chi-squared test with a 2-sided significance level of 0.05. 
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In addition, up to 138 opioid-treated cohort subjects will be randomized to receive erenumab 
or placebo (46 on placebo, 46 on 70 mg, and 46 on 140 mg). 
 
Section:  10.2.3, Subgroups 
Replace: 
The primary and key secondary endpoints for the nonopioid cohort will be analyzed in the 
subgroups defined by concomitant oral migraine preventive treatment initiated before 
screening and taken during baseline (Yes or No), key demographics (eg, geographic 
region), prior history of treatment with onabotulinumtoxinA (Yes or No), total number or prior 
treatment failures (1, 2. or 3 or more treatment failures), and acute headache medication 
overuse category (triptan or ergotamine derivative medication overuse, simple analgesics 
and/or NSAIDs medication overuse, or combination medication overuse). 
With: 
The primary and key secondary endpoints for the nonopioid cohort will be analyzed in the 
subgroups defined by concomitant oral migraine preventive treatment initiated before 
screening and taken during baseline (Yes or No), key demographics (eg, geographic 
region), prior history of treatment with onabotulinumtoxinA (Yes or No), total number or prior 
treatment failures (1, 2, or 3 or more treatment failures), and acute headache medication 
overuse category (triptan or ergotamine derivative medication overuse, simple analgesics 
and/or NSAIDs medication overuse, combination analgesics overuse, or combination 
medication therapies overuse). 
Section:  10.2.4, Handling of Missing and Incomplete Data, paragraph 1 
Add: 
Subjects may miss specific data points for a variety of reasons.  In general, data could be 
missing due to a subject’s early withdrawal from the study, a missed visit, or inability to 
evaluate an endpoint at a particular point in time.  For this study, efficacy endpoints will be 
collected via eDiary and subjects could miss entering several days of data in each monthly 
interval.  The general procedures outlined below describe how missing data in efficacy will 
be handled. 
Section:  10.2.4, Handling of Missing and Incomplete Data, paragraph 2 
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Replace: 
For the eDiary, if at least 14 days of eDiary are collected in the monthly interval, then the 
monthly frequency measurements (eg, migraine days, headache days) will be prorated 
based on the number of days with available information using the following formula: 
With: 
For the endpoints derived from daily eDiary, if at least 14 days of eDiary are collected in 
the monthly interval, then the monthly frequency measurements (eg, migraine days, 
headache days) will be prorated based on the number of days with available information. 
Section:  10.2.4, Handling of Missing and Incomplete Data, paragraph 2 
Delete: 
Number of observed migraine days *28/Number of information days in interval, where an 
information day is a diary day or headache day. 
Section:  10.2.4, Handling of Missing and Incomplete Data, paragraph 3 (new) 
Add: 
Missing items in each COA questionnaire will be handled based on the scoring 
algorithm for each COA. 
Section:  10.2.4, Handling of Missing and Incomplete Data, paragraph 5 (new) 
Add: 
Missing data in safety data will not be imputed except for partial AE start dates. 
Section:  10.4.1.1, Primary Analysis 
Replace: 
The primary hypothesis will be tested once the last subject in the nonopioid-treated cohort 
has completed the week 24 assessments or the ET visit, and all data for the primary 
endpoint has been collected.  At this time, the DBTP treatment assignment for this cohort 
will be unblinded to the sponsor. If data collection for all subjects in the opioid-treated cohort 
for the DBTP is also complete, the DBTP treatment assignment for this cohort will also be 
unblinded.  Study subjects and investigators will remain blinded to original DBTP treatment 
assignment until study completion.  All efficacy analyses and safety analyses will be 
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conducted for the DBTP.  However, safety data collected during OLTP before the data cutoff 
date for the primary analysis will also be summarized. 
With: 
The primary hypothesis will be tested once the last subject in the nonopioid-treated cohort 
has completed the week 24/ET assessments during the DBTP, and all data for the primary 
endpoint has been collected.  At this time, the DBTP treatment assignment for this cohort 
will be unblinded to the sponsor. If data collection for all subjects in the opioid-treated cohort 
for the DBTP is also complete, the DBTP treatment assignment for this cohort will also be 
unblinded.  Otherwise, the unblinding of treatment assignment for this cohort and the 
analysis of the DBTP data for opioid-treated cohort will be done in the final analysis.  
Study subjects and investigators will remain blinded to original DBTP treatment assignment 
until study completion.  All efficacy analyses and safety analyses will be conducted for the 
DBTP.  However, safety data collected during OLTP before the data cutoff date for the 
primary analysis will also be summarized. 
Section:  10.4.1.2, Final Analysis 
Replace: 
The final analysis will be performed after all subjects (nonopioid-treated and opioid-treated) 
have completed the study through the OLTP last visit or were discontinued from the study. 
With: 
The final analysis will be performed after all subjects (nonopioid-treated and opioid-treated) 
have completed the study through the week 52/EOS visit. 
Section: 10.4.2.1,General Considerations, Paragraph 5,6,7,8 
Add: 
Formal statistical analyses using statistical models and hypothesis testing will be performed 
for the nonopioid-treated cohort only. 
Summary statistics will be computed by treatment group and visit.  For continuous 
endpoints, the following descriptive statistics will be computed: number of observations, 
means, medians, standard deviations, standard errors, first and third quartiles, minimums 
and maximums, and 2-sided 95% CIs of the means (CIs will be provided for efficacy 
Approved 
 
 


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endpoints only).  For categorical endpoints, the summaries will contain the number and 
percentage of subjects in each category. 
The dichotomous efficacy endpoints will be analyzed using the stratified Cochran-Mantel-
Haenszel (CMH) test after the missing data is imputed as nonresponse.  Continuous 
secondary endpoints will be analyzed using a linear mixed effects model including treatment 
group, baseline value, stratification factor, scheduled visit, and the interaction of treatment 
group with scheduled visit, without any imputation for missing data at the monthly level.   
The 2 erenumab dose groups will be compared with placebo for the primary and secondary 
efficacy endpoints in the nonopioid-treated cohort using a simple fixed sequence procedure 
with study-wise type I error rate α = 0.05.  The order of the endpoints to be tested is 
prespecified below. If any test is not significant at the α = 0.05 level, then no further testing 
will be performed.   
Primary and secondary endpoints in erenumab 140 mg versus placebo: 
1. Absence of MOH at month 6 (week 24) of DBTP (140 mg) 
2. Change from baseline in mean monthly AHMD over months 4, 5, and 6 (week 13 
through 24) of the DBTP (140 mg) 
3. Sustained MOH remission during DBTP (140 mg)  
Primary and secondary endpoints in erenumab 70 mg versus placebo: 
4. Absence of MOH at month 6 (week 24) of the DBTP (70 mg) 
5. Change from baseline in mean monthly AHMD over months 4, 5, and 6 (week 13 
through 24) of the DBTP (70 mg) 
6. Sustained MOH remission during DBTP (70 mg)  
Patient reported outcome-related secondary endpoints for the non-EU region 
7. Change from the baseline in mean monthly average physical impairment domain scores 
as measured by the MPFID over months 4, 5, and 6 (week 13 through 24) of the DBTP 
(140 mg) 
8. Change from the baseline in mean monthly average impact on everyday activities 
domain scores as measured by the MPFID over months 4, 5, and 6 (week 13 through 
24) of the DBTP (140 mg) 
9. Change from the baseline in mean monthly average physical impairment domain scores 
as measured by the MPFID over months 4, 5, and 6 (week 13 through 24) of the DBTP 
(70 mg) 
Approved 
 
 


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10. Change from the baseline in mean monthly average impact on everyday activities 
domain scores as measured by the MPFID over months 4, 5, and 6 (week 13 through 
24) of the DBTP (70 mg) 
OR 
Patient reported outcome-related secondary endpoints for the EU region 
7. Change from baseline in mean HIT-6 score over months 4, 5, and 6 (week 13 through 
24) of the DBTP (140 mg) 
8. Change from baseline in mean HIT-6 score over months 4, 5, and 6 (week 13 through 
24) of the DBTP (70 mg) 
Section:  10.4.2.2,Efficacy Analyses 
Add: 
Endpoint 
Statistical Analysis Methods 
Primary 
The primary comparison of absence of MOH at month 6 (week 24) 
between each erenumab dosing group and placebo will be analyzed using 
a stratified CMH test after the missing data are imputed as nonresponse.  
The proportion of subjects with absence of MOH will be reported for each 
treatment group.  The odds ratio between each erenumab group and 
placebo, the corresponding 95% Cl and p-value will be reported.   
Section:  12.1, Appendix 1.  List of Abbreviations and Definitions of Terms 
Add: 
Acute headache 
medication 
Acute headache medications include:  
• 
Triptan-based migraine medications 
• 
Ergotamine-based migraine medications 
• 
Non-opioid acute headache medications 
• 
Non-opioid butalbital containing medications 
• 
Opioid-containing acute headache medications 
• 
Opioid-containing butalbital containing medications 
CBD 
Cannabidiol 
CM-MOH 
Chronic migraine subjects who met thresholds for medication overuse 
headache 
IRT 
interactive response technology that is linked to a central 
computer in real time as an interface to collect and process 
information 
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Date:  27 May 2020 
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Medication overuse 
(per protocol) 
Mean monthly acute headache medication days above the following 
thresholds  
• 
Triptans, ergotamine, opioids/opioid-containing medication, 
combination therapies: ≥ 10 days per study month  
• 
Simple analgesics and NSAIDS only: ≥ 15 days per study 
month of simple analgesics and NSAIDs 
MOH (protocol defined) Mean monthly acute headache medication days over 3 consecutive 
study months at or above ICHD-3 defined thresholds AND mean 
monthly qualified headache days of any severity ≥ 14 days over the 
same consecutive study months 
Study month 
generally 4 weeks 
Section:  12.1, Appendix 1.  List of Abbreviations and Definitions of Terms 
Delete: 
Acute migraine-specific 
medication day 
Any day in which a migraine-specific medication was administered in 
association to a headache day 
BMI 
Body mass index 
Headache day (acute 
headache medication 
day) 
A qualified headache day for which any acute headache medication 
has been administered in association with a headache episode 
Interactive Voice 
Response System 
(IVRS) 
telecommunication technology that is linked to a central computer in 
real time as an interface to collect and process information  
Interactive Web 
Response System 
(IWRS)  
web based technology that is linked to a central computer in real time 
as an interface to collect and process information  
MAR 
Missing at random 
MI 
Multiple imputation 
MNAR 
Missing not at random 
Opioid medication day 
Any day in which an opioid/opioid containing medication was 
administered in association to a headache day 
Section:  12.1, Appendix 1.  List of Abbreviations and Definitions of Terms 
Replace: 
Acute medication day 
Any eDiary day in which an acute headache medication intake is 
reported. Acute medication day is inclusive but not limited to acute 
headache medication days 
CM 
Chronic migraine 
Headache day 
(moderate to severe) 
A qualified headache day that subjects indicate its peak severity 
as being moderate or severe 
Approved 
 
 


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Date:  27 May 2020 
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With: 
Acute headache 
medication day 
Any calendar day in which an acute headache medication intake is 
reported.  
CM 
(per ICHD-3) 
Chronic migraine 
defined as headache occurring on 15 or more days/month for 
more than 3 months, which, on at least 8 days/month, has the 
features of migraine headache. 
A. Headache (migraine-like or tension-type-like) on ≥15 
days/month for >3 months, and fulfilling criteria B and C 
B. Occurring in a patient who has had at least five attacks 
fulfilling criteria B-D for Migraine without aura and/or 
criteria B and C for Migraine with aura 
C. On ≥8 days/month for >3 months, fulfilling any of the 
following: 
1.criteria C and D for Migraine without aura 
2.criteria B and C for Migraine with aura 
3.believed by the patient to be migraine at onset and 
relieved by a triptan or ergot derivative 
D. Not better accounted for by another ICHD-3 diagnosis 
Headache day 
(moderate to severe) 
A qualified headache day that subjects indicate its peak severity as 
being of at least moderate severity 
Section:  12.2, Appendix 2.  Clinical Laboratory Tests, paragraph 1 
Replace: 
The tests detailed in Table 12-1 will be performed by the central laboratory, except urine 
pregnancy testing.  Hematology testing after screening and chemistry testing during the 
OLTP will be at the discretion of the investigator. 
With: 
The tests detailed in Table 12-1 will be performed by the central laboratory, except urine 
pregnancy testing.  During the Baseline period and through the DBTP, hematology and 
chemistry testing will be at the discretion of the investigator, as well as chemistry 
testing during the OLTP. 
Approved 
 
 


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Date:  27 May 2020 
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Section:  12.2, Appendix 2.  Clinical Laboratory Tests, Table 12-1.  Analyte Listing, deleted 
footnote d for HIV of other labs, and replaced footnote of cholesterol, HDL, and LDL of 
Central Laboratory Chemistry from e to d 
Replace: 
Central Laboratory:  
Chemistrya 
 Central Laboratory:  Hematologyb 
Other Labsc 
Sodium 
Potassium 
Chloride 
Bicarbonate  
Total protein 
Calcium 
Adjusted calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Uric acid 
LDH 
Cholesterole 
HDLe 
LDLe 
Triglycerides  
Total bilirubin 
Direct bilirubin 
ALP 
AST (SGOT) 
ALT (SGPT) 
Albumin 
 RBC 
Hemoglobin 
Hematocrit 
MCV  
MCH 
MCHC 
RDW 
Reticulocytes 
Platelets 
WBC 
Differential 
• Neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes  
 
Central Laboratory:  
Urine drug screening 
Pharmacogenetic 
studies (optional)  
Biomarker development 
Hep B surface antigen 
Hep C antibody 
HIVd 
 
Local Laboratory: 
Pregnancy testing-urine 
Footnotes defined on next page 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood 
urea nitrogen; HDL = high density lipoprotein; Hep = hepatitis; HIV = human immunodeficiency virus; 
LDH = lactate dehydrogenase; LDL = low density lipoprotein; MCH = mean corpuscular hemoglobin; 
MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; RBC = red blood cell 
count; RDW = Red cell distribution width; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum 
glutamic-pyruvic transaminase; WBC = white blood cell count 
a During the OLTP, chemistry testing will be at the discretion of the investigator and performed at central 
laboratories. 
b After screening, hematology testing will be at the discretion of the investigator and performed at central 
laboratories 
c Performed at either central or local laboratories, as noted. 
d HIV assessment is recommended. 
e To be tested at screening only. 
Approved 
 
 


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Date:  27 May 2020 
Page 55 of 61 
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With: 
Central Laboratory:  
Chemistrya 
 Central Laboratory:  Hematologyb 
Other Labsc 
Sodium 
Potassium 
Chloride 
Bicarbonate  
Total protein 
Calcium 
Adjusted calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Uric acid 
LDH 
Cholesterold 
HDLd 
LDLd 
Triglycerides  
Total bilirubin 
Direct bilirubin 
ALP 
AST (SGOT) 
ALT (SGPT) 
Albumin 
 RBC 
Hemoglobin 
Hematocrit 
MCV  
MCH 
MCHC 
RDW 
Reticulocytes 
Platelets 
WBC 
Differential 
• Neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes  
 
Central Laboratory:  
Urine drug screening 
Pharmacogenetic 
studies (optional)  
Biomarker development 
Hep B surface antigen 
Total Hep B core 
antibody 
Hep C antibody 
HIV 
 
Local Laboratory: 
Pregnancy testing-urine 
Footnotes defined on next page 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood 
urea nitrogen; HDL = high density lipoprotein; Hep = hepatitis; HIV = human immunodeficiency virus; 
LDH = lactate dehydrogenase; LDL = low density lipoprotein; MCH = mean corpuscular hemoglobin; 
MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; RBC = red blood cell 
count; RDW = Red cell distribution width; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum 
glutamic-pyruvic transaminase; WBC = white blood cell count 
a During the Baseline Period, DBTP, and OLTP, chemistry testing will be at the discretion of the investigator 
and performed at central laboratories. 
b During the Baseline Period and DBTP, hematology testing will be at the discretion of the investigator and 
performed at central laboratories 
c Performed at either central or local laboratories, as noted. 
d To be tested at screening only. 
Section:  12.3, Appendix 3.  Study Governance Considerations, Informed Consent Process 
Replace: 
A subject who is rescreened is not required to sign another informed consent form if the 
rescreening occurs within 30 days from the previous informed consent form signature date. 
Approved 
 
 


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Date:  27 May 2020 
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With: 
A subject who is rescreened is not required to sign another informed consent form if the 
rescreening occurs within 60 days from the previous informed consent form signature date. 
Section:  12.3, Appendix 3.  Study Governance Considerations, Data Quality Assurance 
Delete: 
Amgen (or designee) will perform Self-Evident Corrections to obvious data errors in the 
clinical trial database.  Self-Evident Corrections will be documented in the CRF Standard 
Instructions and the CRF Specific Instructions, both of these will be available through the 
electronic data capture (EDC) system.  Examples of obvious data errors that may be 
corrected by Amgen (or designee) include deletion of obvious duplicate data (ie, the same 
results sent twice with the same date with different visit, (eg, week 4 and early termination) 
and updating a specific response if the confirming datum is provided in the “other, specify” 
field (eg, for race, reason for ending study). 
Section:  12.3, Appendix 3.  Study Governance Considerations, Source Documents 
Replace: 
Source documents may also include data captured in the Interactive Voice Response 
System (IVRS) / Interactive Web Response System (IWRS) system (if used, such as subject 
ID and randomization number) and CRF entries if the CRF is the site of the original 
recording (ie, there is no other written or electronic record of data, such as paper 
questionnaires for a clinical outcome assessment). 
With: 
Source documents may also include data captured in the IRT system (if used, such as 
subject ID and randomization number) and CRF entries if the CRF is the site of the original 
recording (ie, there is no other written or electronic record of data, such as paper 
questionnaires for a clinical outcome assessment). 
Section:  12.4, Appendix 4.  Safety Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting 
Add: 
The Common Terminology Criteria for Adverse Events, version 4.03 which is available at the 
following location:   
Approved 
 
 


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Date:  27 May 2020 
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Section:  12.5, Appendix 5.  Contraceptive Guidance and Collection of Pregnancy and 
Lactation Information, Male Subjects With Partners Who Become Pregnant, bullet 1 
Replace: 
• 
In the event a male subject fathers a child during treatment, and for an additional 
12 weeks after discontinuing protocol-required therapies, the information will be 
recorded on the Pregnancy Notification Worksheet.  The worksheet (see Figure 
12-2) must be submitted to Amgen Global Patient Safety within 24 hours of the site’s 
awareness of the pregnancy.  (Note:  Sites are not required to provide any 
information on the Pregnancy Notification Worksheet that violates the country or 
regions local privacy laws). 
With: 
• 
In the event a male subject fathers a child during treatment, and for an additional 
16 weeks after the last dose of study drug, the information will be recorded on the 
Pregnancy Notification Worksheet.  The worksheet (see Figure 12-2) must be 
submitted to Amgen Global Patient Safety within 24 hours of the site’s awareness of 
the pregnancy.  (Note:  Sites are not required to provide any information on the 
Pregnancy Notification Worksheet that violates the country or regions local privacy 
laws). 
Section:  12.8, Appendix 8.  Substudy:  Qualitative Interview Substudy to ‘A Phase 4, 
Randomized, Double-blind, Placebo-controlled, Parallel group Study to Evaluate the Efficacy 
and Safety of Erenumab in Adults With Chronic Migraine and Medication Overuse 
Headache, Substudy Design, paragraph 1 
Replace: 
Qualitative interviews will be conducted with subjects who opt in to this optional substudy. 
Interviews will be conducted via entry interviews, conducted within 5 days of the first IP 
dose, and exit interviews, conducted within 5 days of the week 24 visit or within 
approximately 5 days of the early termination (ET) visit. 
With: 
Qualitative interviews will be conducted with subjects who opt in to this optional substudy. 
Interviews will be conducted via entry interviews, conducted within 7 days of the first IP 
dose, and exit interviews, conducted within 7 days of the week 24 visit or within 
approximately 14 days of the early termination (ET) visit.  If possible, within 7 days from 
early termination notification will be targeted.  
Approved 
 
 


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Date:  27 May 2020 
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Section:  12.8, Appendix 8.  Substudy:  Qualitative Interview Substudy to ‘A Phase 4, 
Randomized, Double-blind, Placebo-controlled, Parallel group Study to Evaluate the Efficacy 
and Safety of Erenumab in Adults With Chronic Migraine and Medication Overuse 
Headache, Summary of Substudy Subject Eligibility Criteriia 
Replace: 
1) Unable to complete entry interview within five (5) days from first IP dose; 
2) Unable to complete exit interview within five (5) days prior to week 24 visit or within 
approximately five (5) days post early termination visit; 
With: 
1) Unable to complete entry interview within seven (7) days from first IP dose; 
2) Unable to complete exit interview within seven (7) days prior to week 24 visit or within 
approximately 14 days post early termination visit; 
Section:  12.8, Appendix 8.  Substudy:  Qualitative Interview Substudy to ‘A Phase 4, 
Randomized, Double-blind, Placebo-controlled, Parallel group Study to Evaluate the Efficacy 
and Safety of Erenumab in Adults With Chronic Migraine and Medication Overuse 
Headache, Substudy Duration and Substudy Procedures, paragraph 1 
Replace: 
Subjects are required to participate in two telephone interviews, lasting approximately 
one-hour each. Entry interviews will be conducted within five (5) days from first IP dose; exit 
interviews will be conducted in close proximity with the week 24 or early termination visits 
(within 5 days prior to week 24 visit or within approximately 5 days post early termination 
visit). 
With: 
Subjects are required to participate in two telephone interviews, lasting approximately 
one-hour each. Entry interviews will be conducted within seven (7) days from first IP dose; 
exit interviews will be conducted in close proximity with the week 24 or early termination 
visits (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). 
Approved 
 
 


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Date:  27 May 2020 
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Section:  12.8, Appendix 8.  Substudy:  Qualitative Interview Substudy to ‘A Phase 4, 
Randomized, Double-blind, Placebo-controlled, Parallel group Study to Evaluate the Efficacy 
and Safety of Erenumab in Adults With Chronic Migraine and Medication Overuse 
Headache, Substudy Duration and Substudy Procedures, paragraph 3 
Replace: 
At participating sites, randomized subjects that successfully dosed with IP will be provided 
an option to opt in to the qualitative interview substudy and be provided with additional 
information about the substudy. Clinical site staff will explain the substudy objectives and 
procedures to the subject and obtain a supplementary written informed consent. The subject 
will sign two copies of the consent form. Sites will send a wet-ink version of the informed 
consent to Evidera 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. 
With: 
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 randomization and successful dosing with IP, 
depending on site preference. Clinical site staff will explain the substudy objectives and 
procedures to the subject and obtain a supplementary written informed consent. The subject 
will sign two copies of the consent form. Sites will send a wet-ink version of the informed 
consent to Evidera 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. 
Section:  12.8, Appendix 8.  Substudy:  Qualitative Interview Substudy to ‘A Phase 4, 
Randomized, Double-blind, Placebo-controlled, Parallel group Study to Evaluate the Efficacy 
and Safety of Erenumab in Adults With Chronic Migraine and Medication Overuse 
Headache, Substudy Duration and Substudy Procedures, paragraph 6-7 
Replace: 
Patients will take part in a telephone-based entry interview at the start of treatment (no later 
than 5 days from first IP dose), lasting approximately one-hour. Subjects will be specifically 
Approved 
 
 


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asked about their experiences with functioning during and in between migraine attacks 
before receiving the initial study dose. 
During the exit interview portion of the substudy, the subjects will take part in a final 
telephone interview, approximately one-hour in duration (within 5 days prior to week 24 visit 
or within approximately 5 days post early termination visit). Subjects will be specifically 
asked to compare their experience from the end of the DBTP or early termination visit 
around changes in functioning during and in between migraine attacks after receiving the 
preventive treatment for migraine. After open ended questions, if subjects do not mention 
the impacts they noted at entry interview, the interviewer will probe on those impacts. The 
interviews will also explore what aspects of improvement or worsening of their migraine (eg, 
frequency, severity, duration) drove the changes, as well as the ‘meaningfulness’ of 
change/no change reported by the patient. 
With: 
Patients will take part in a telephone-based entry interview at the start of treatment (no later 
than 7 days from first IP dose), lasting approximately one-hour. Subjects will be specifically 
asked about their experiences with functioning during and in between migraine attacks 
before receiving the initial study dose. 
During the exit interview portion of the substudy, the subjects will take part in a final 
telephone interview, approximately one-hour in duration (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). Subjects will be specifically asked to 
compare their experience from the end of the DBTP or early termination visit around 
changes in functioning during and in between migraine attacks after receiving the preventive 
treatment for migraine. After open ended questions, if subjects do not mention the impacts 
they noted at entry interview, the interviewer will probe on those impacts. The interviews will 
also explore what aspects of improvement or worsening of their migraine (eg, frequency, 
severity, duration) drove the changes, as well as the ‘meaningfulness’ of change/no change 
reported by the patient. 
Section:  12.8, Appendix 8.  Substudy:  Qualitative Interview Substudy to ‘A Phase 4, 
Randomized, Double-blind, Placebo-controlled, Parallel group Study to Evaluate the Efficacy 
Approved 
 
 


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and Safety of Erenumab in Adults With Chronic Migraine and Medication Overuse 
Headache, Substudy Sample Size, paragraph 2 
Delete: 
The substudy sample will be a subset of up to 30 subjects who will be recruited from up to 
six (6) Amgen-identified clinical sites participating in the clinical trial 20170703 across the 
United States. 
Approved 
 
 


Product:  Erenumab 
Protocol Number:  20170703 
Date:  19 April 2019 
Page 1 of 112 
CONFIDENTIAL 
 
 
Amendment 1 
Protocol Title:  A Phase 4, Randomized, Double-blind, Placebo-controlled, 
Parallel-group Study to Evaluate the Efficacy and Safety of Erenumab in Adults 
With Chronic Migraine and Medication Overuse Headache 
 
Amgen Protocol Number Erenumab 20170703 
EudraCT Number 2018-003342-16 
 
Amendment Date: 
19 April 2019 
Rationale: 
This protocol is being amended to: 
 
Modify primary, secondary, and exploratory endpoints  
 
Simplify study procedures to reduce patient burden and emulate per label 
monitoring requirements 
 
Simplify eligibility requirements 
 
Make editorial and administrative edits 

SAP_003.pdf: 
Product:  Erenumab (AMG 334) 
Protocol Number:  20170703 
Date:  10 December 2022 
 
 
Page 1 of 53 
CONFIDENTIAL 
 
 
Statistical Analysis Plan 
 
Protocol Title: 
A Phase 4, Randomized, Double-blind, 
Placebo-controlled, Parallel-group Study to Evaluate the 
Efficacy and Safety of Erenumab in Adults With Chronic 
Migraine and Medication Overuse Headache 
Short Protocol Title: 
A Phase 4 Randomized Controlled Study to Evaluate the 
Efficacy and Safety of Erenumab in Adults With 
Medication Overuse Headache 
Protocol Number: 
20170703 
NCT Number: 
NCT03971071 
Authors: 
  
Sponsor: 
Amgen Inc. 
One Amgen Center Drive  
Thousand Oaks, CA 91320 
SAP Date: 
Document Version 
Date 
Original (v1.0) 
Amendment 1 (v2.0) 
13 January 2020 
10 December 2022 
 


Product:  Erenumab (AMG 334) 
Protocol Number:  20170703 
Date:  10 December 2022 
 
 
Page 2 of 53 
CONFIDENTIAL 
 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
13JAN2020 
NA 
Amendment 1 (v2.0) 
10DEC2022 
 Section 4.2 updated to 
o 
Include an additional subgroup 
analysis by prior history of depression 
o 
Clarify the medication categories of 
migraine preventive medications  
 Section 5.1 updated to  
o 
Include ditans as acute migraine-
specific medications and acute 
headache medication 
o 
Include the definition of concomitant 
migraine preventive medication 
o 
Clarify the exclusion of gepant-based 
medication in the derivation of MOH  
o 
Remove the definition of information 
day  
o 
Clarify the table of prorations of 
monthly frequency variable in days 
o 
Include the definition of treatment-
related treatment-emergent adverse 
events 
o 
Clarify the calculation of a headache 
last for multiple days and multiple 
qualified headaches within the same 
day 
o 
Clarify the definition of complete 
response of MPFID 
 Section 5.2 updated to include the 
definition of primary completion date 
 Section 5.3 updated to 
o 
Clarify the handling of measurements 
with multiple individual items 
o 
Include the definition of pre-OLTP 
o 
Clarify the definition of study day 1 in 
Section 5.3 
 Table 5-1 updated to clarify the definition of 
the start date of Week 44 and baseline 
period 
 Table 5.6 updated to clarify the analysis 
visit window of HRU 
 Section 6.2 updated the definition of 
efficacy analysis set to include all 
endpoints 
 Section 7 updated to describe database 
disposition 
 Section 8.3 updated to clarify missing HRU 
dates imputation, missing items in eCOA, 


Product:  Erenumab (AMG 334) 
Protocol Number:  20170703 
Date:  10 December 2022 
 
 
Page 3 of 53 
CONFIDENTIAL 
 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
and missing endpoints evaluations at 
postbaseline during OLTP 
 Section 8.7 updated to clarify TFLs will be 
produced and validated in accordance with 
SOP-430399 
 Section 9.1 updated to include descriptive 
summary of primary, secondary and 
change from baseline in mean monthly 
opioid/opioid-containing medication days 
for the ‘observed’ opioid-treated cohort as 
sensitivity analyses 
 Section 9.2 and 9.3 included summary of 
protocol deviations related to COVID-19 
measures 
 Section 9.4 updated to include additional 
summary of baseline characteristics 
 Table 9-1, Table 9-2, and Section 9.5 
updated to include additional sensitivity 
analyses to examine the derived values of 
concomitant oral migraine preventive 
medications with respect to the primary 
and secondary endpoints 
 Section 9.5 updated to include breslow-test 
for the analysis of dichotomized endpoints, 
ANCOVA for continuous endpoints 
collected at one or two timepoints 
postbaseline, and the analysis of BDI-II 
and PGIC 
 Section 9.6 updated to include exposure-
adjusted subject incidence for the DBTP, 
serious TEAE occuring on or after the 
COVID infection, device-related AEs and 
the EOI COVID-19 SMQ (Narrow) 
 Section 10 updated to specify the addition 
of ditans in the list of acute headache 
medication and changes in definition of 
efficacy analysis set 
 Section 12 updated to clarify the scope of 
this Statistical Analysis Plan will not include 
the data for biomarker development and 
optional interview-based substudy 
 Editorial/changes were made throughout 
the document to improve overall clarity 


Product:  Erenumab (AMG 334) 
Protocol Number:  20170703 
Date:  10 December 2022 
 
 
Page 4 of 53 
CONFIDENTIAL 
 
 
Table of Contents 
Table of Contents ............................................................................................................ 4 
1. 
Introduction ............................................................................................................. 9 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 9 
2.1 
Objectives and Endpoints ............................................................................ 9 
2.2 
Hypotheses and/or Estimations ................................................................. 16 
3. 
Study Overview .................................................................................................... 17 
3.1 
Study Design ............................................................................................. 17 
3.2 
Sample Size .............................................................................................. 17 
3.3 
Adaptive Design ........................................................................................ 18 
4. 
Covariates and Subgroups ................................................................................... 18 
4.1 
Planned Covariates ................................................................................... 18 
4.2 
Subgroups ................................................................................................. 18 
5. 
Definitions ............................................................................................................. 19 
5.1 
Definition of Terms Included in Study Endpoints ....................................... 19 
5.1.1 
Efficacy Endpoints Based on Daily eDiary Collection ................. 19 
5.1.2 
Efficacy Endpoints Based on Monthly Collection ....................... 25 
5.1.3 
Safety Endpoints ....................................................................... 27 
5.2 
Study Dates .............................................................................................. 28 
5.3 
Study Points of Reference ......................................................................... 29 
5.4 
Study Time Intervals ................................................................................. 30 
5.4.1 
Study Periods ............................................................................ 30 
5.4.2 
Monthly Intervals for Efficacy Endpoints Derived From 
Daily Diary Collection ................................................................ 30 
5.4.3 
Analysis Visits for Endpoints Based on Monthly 
Collection .................................................................................. 32 
5.5 
Subject Disposition .................................................................................... 34 
5.6 
Arithmetic Calculations .............................................................................. 35 
5.7 
Disease Characteristics ............................................................................. 36 
6. 
Analysis Sets ........................................................................................................ 36 
6.1 
Full Analysis Set........................................................................................ 37 
6.2 
Efficacy Analysis Set ................................................................................. 37 
6.3 
Safety Analysis ......................................................................................... 37 
6.4 
Open-label Treatment Period Analysis Set ................................................ 37 
7. 
Planned Analyses ................................................................................................. 37 
7.1 
Primary Analysis ....................................................................................... 37 
7.2 
Final Analysis ............................................................................................ 38 
8. 
Data Screening and Acceptance ........................................................................... 38 
8.1 
General Principles ..................................................................................... 38 


Product:  Erenumab (AMG 334) 
Protocol Number:  20170703 
Date:  10 December 2022 
 
 
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CONFIDENTIAL 
 
 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 38 
8.3 
Handling of Missing and Incomplete Data ................................................. 38 
8.3.1 
Missing Baseline Evaluation ...................................................... 39 
8.3.2 
Missing Post-baseline Evaluation in Double-blind 
Treatment Period ...................................................................... 39 
8.3.3 
Missing Post-baseline Evaluation in Open-label 
Treatment Period ...................................................................... 40 
8.4 
Detection of Bias ....................................................................................... 40 
8.5 
Outliers ..................................................................................................... 40 
8.6 
Distributional Characteristics ..................................................................... 41 
8.7 
Validation of Statistical Analyses ............................................................... 41 
9. 
Statistical Methods of Analysis.............................................................................. 41 
9.1 
General Considerations ............................................................................. 41 
9.2 
Subject Accountability ............................................................................... 43 
9.3 
Important Protocol Deviations ................................................................... 43 
9.4 
Demographic and Baseline Characteristics ............................................... 44 
9.5 
Efficacy Analyses ...................................................................................... 45 
9.5.1 
Analyses of Primary Efficacy Endpoint ...................................... 47 
9.5.2 
Analyses of Secondary Efficacy Endpoints ................................ 48 
9.5.3 
Analyses of Exploratory Efficacy Endpoints in Double-
blind Treatment Period .............................................................. 48 
9.5.4 
Analyses of Exploratory Efficacy Endpoints in Open-
label Treatment Period .............................................................. 48 
9.6 
Safety Analyses ........................................................................................ 48 
9.6.1 
Analyses of Primary Safety Endpoint(s)  .................................... 48 
9.6.2 
Adverse Events ......................................................................... 49 
9.6.3 
Vital Signs ................................................................................. 50 
9.6.4 
Exposure to Investigational Product .......................................... 50 
9.6.5 
Exposure to Concomitant Medication ........................................ 50 
9.7 
Other Analyses ......................................................................................... 50 
9.7.1 
Analyses of Health Economic Endpoints ................................... 50 
10. 
Changes From Protocol-specified Analyses.......................................................... 50 
11. 
Literature Citations / References ........................................................................... 51 
12. 
Data Not Covered by This Plan............................................................................. 52 
13. 
Appendices ........................................................................................................... 53 


Product:  Erenumab (AMG 334) 
Protocol Number:  20170703 
Date:  10 December 2022 
 
 
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CONFIDENTIAL 
 
 
List of Tables 
Table 5-1.  Monthly Interval for Efficacy Endpoints Derived From Daily Diary 
Collection ................................................................................................ 31 
Table 5-2.  HIT-6 and MFIQ Analysis Visit Windows ...................................................... 33 
Table 5-3.  MIDAS Analysis Visit Windows .................................................................... 33 
Table 5-4.  ASC-12/GAD-7/BDI-II/Sleep Questionnaire Analysis Visit 
Windows ................................................................................................. 33 
Table 5-5.  PGIC Analysis Visit Windows ...................................................................... 33 
Table 5-6.  HRU Questionnaire Analysis Visit Windows ................................................ 33 
Table 5-7.  Vital Signs Analysis Visit Windows .............................................................. 34 
Table 9-1.  Primary Efficacy Endpoint Summary Table .................................................. 46 
Table 9-2.  Secondary Efficacy Endpoints Summary Table ........................................... 46 


Product:  Erenumab (AMG 334) 
Protocol Number:  20170703 
Date:  10 December 2022 
 
 
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CONFIDENTIAL 
 
 
List of Abbreviations and Definition of Terms 
 
Abbreviation or Term 
Definition/Explanation 
AHMD 
Acute headache medication day 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ASC 
Allodynia symptom checklist 
BDI-II 
Beck Depression Inventory - II 
BMI 
Body mass index 
CM 
Chronic migraine 
CM-MOH 
Chronic migraine subjects who met thresholds for medication overuse 
headache 
CMH 
Cochran-Mantel-Haenszel 
COA 
Clinical outcomes assessment 
CRF 
CTCAE 
Case Report Form 
Common Terminology Criteria for Adverse Events 
DBTP 
Double-blind treatment period 
EAS 
Efficacy analysis set 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eDiary  
Electronic diary 
EM 
Episodic Migraine 
Enrollment 
When the investigator decides that the subject has met Part 1 and 
Part 2 eligibility criteria, and follows procedures for subject 
randomization, and a randomization number has been assigned 
ET 
Early termination 
EU 
European Union 
FAS 
Full analysis set 
GAD-7 
Generalized Anxiety Disorder 7-item scale 
HIT-6  
Headache Impact Test-6 
HRU 
Health resource utilization 
ICH 
International Council for Harmonisation 
ICHD-3 
International Classification of Headache Disorders, 3rd Edition 
Interactive Voice 
Response System 
(IVRS) 
telecommunication technology that is linked to a central computer in 
real time as an interface to collect and process information  
IP 
Investigational Product 
LSM 
Least squares mean 
MFIQ 
Migraine Functional Impact Questionnaire 


Product:  Erenumab (AMG 334) 
Protocol Number:  20170703 
Date:  10 December 2022 
 
 
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CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
MHD 
Monthly headache days 
MIDAS 
Migraine Disability Assessment   
MMD 
Monthly migraine days 
MO 
Medication overuse 
MOH 
Medication overuse headache 
MPFID 
Migraine Physical Function Impact Diary 
NCT 
National Clinical Trials  
NSAID 
Nonsteroidal anti-inflammatory drug 
OLTP 
Open-label treatment period 
PFS 
Prefilled syringe 
PGIC 
Patient’s Global Impression of Change 
QM 
every 4 weeks  
Randomization 
A subject is randomized to a treatment assignment  
SAS 
Safety analysis set 
SAP 
Statistical analysis plan 
Study month 
Generally 4 weeks 
 


Product:  Erenumab (AMG 334) 
Protocol Number:  20170703 
Date:  10 December 2022 
 
 
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CONFIDENTIAL 
 
 
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 for study 20170703 dated 27 May 
2020. The scope of this plan includes the primary analysis and the final analysis that are 
planned and will be executed by the Amgen Global Biostatistical Science department 
unless otherwise specified. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
To evaluate the effect of erenumab 
compared with placebo on achieving 
medication overuse headache (MOH) 
remission during the double-blind 
treatment period (DBTP) 
 Absence of MOH at month 6 as defined 
by mean monthly acute headache 
medication days (AHMD) < 10 days 
over months 4, 5, and 6 (week 13 
through 24) OR mean monthly 
headache days (MHD) < 14 days over 
months 4, 5, and 6 (week 13 through 
24) of the DBTP where AHMD include 
any eDiary day in which an acute 
headache medication intake is reported 
Primary Estimand 
The estimand for the primary efficacy endpoint consists of: 
 
The target population, which includes subjects diagnosed with chronic migraine 
(CM) and MOH who have a history of at least 1 preventive treatment failure and do 
not use opioid medication for more than 4 days per month 
 
The endpoint, which is the absence of MOH at month 6 as defined by mean 
monthly AHMD < 10 days over months 4, 5, and 6 (week 13 through 24) OR 
mean MHD < 14 days over months 4, 5, and 6 (week 13 through 24) of the DBTP 
 
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of investigational product (IP), regardless of adherence to 
treatment 
 
The summary measure, which is the odds ratio of absence of MOH between each 
erenumab dose group (ie, 70 mg or 140 mg) and the placebo group 
Secondary 
 
To evaluate the effect of erenumab 
compared with placebo in reducing 
AHMD during the DBTP 
 Change from baseline in mean monthly 
AHMD over months 4, 5, and 6 (week 
13 through 24) of the DBTP 


Product:  Erenumab (AMG 334) 
Protocol Number:  20170703 
Date:  10 December 2022 
 
 
Page 10 of 53 
CONFIDENTIAL 
 
 
Objectives 
Endpoints 
The estimand for the secondary objective on AHMD consists of: 
 
The target population, which includes subjects diagnosed with CM and MOH who 
have a history of at least 1 preventive treatment failure and do not use opioid 
medication for more than 4 days per month 
 
The endpoint, which is the change from baseline in mean monthly AHMD over 
months 4, 5, and 6 (week 13 through 24) of the DBTP  
 
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of investigational product (IP) and have at least 1 change 
from baseline in MHD, regardless of adherence to treatment 
 
The summary measure, which is the difference in mean of the endpoint between 
each erenumab dose group (ie, 70 mg and 140 mg) and the placebo group 
 
To evaluate the effect of erenumab 
compared with placebo on sustaining 
MOH remission during the DBTP 
 Sustained MOH remission during 
DBTP, as defined by absence of MOH 
at months 3 (week 12)  and 6 (week 
12) of the DBTP and “absence of 
MOH” is achieved when mean monthly 
AHMD < 10 days OR mean 
MHD < 14 days over the respective 
3-month period  
The estimand for the secondary objective on sustained absence of MOH consists of: 
 
The target population, which includes subjects diagnosed with CM and MOH who 
have a history of at least 1 preventive treatment failure and do not use opioid 
medication for more than 4 days per month 
 
The endpoint, which is the sustained MOH remission during DBTP, as defined by 
absence of MOH over months 1, 2, and 3 (week 1 through week 12) AND over 
months 4, 5, and 6 of the DBTP (week 13 through 24).  Absence of MOH is 
achieved when mean monthly AHMD < 10 days OR mean MHD < 14 days over 
the respective 3-month period 
 
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of investigational product (IP), regardless of adherence to 
treatment 
 
The summary measure, which is the odds ratio of sustained MOH remission 
between each erenumab dose group (ie, 70 mg and 140 mg) and the placebo 
group 
 
To evaluate the effect of erenumab 
compared with placebo on reducing 
the impact of migraines on physical 
impairment and everyday activities as 
measured by the Migraine Physical 
Function Impact Diary (MPFID) during 
the DBTPa 
 Change from baseline in mean monthly 
average physical impairment domain 
scores as measured by the MPFID 
over months 4, 5, and 6 (week 13 
through 24) of the DBTP 
 Change from baseline in mean monthly 
average impact on everyday activities 


Product:  Erenumab (AMG 334) 
Protocol Number:  20170703 
Date:  10 December 2022 
 
 
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CONFIDENTIAL 
 
 
Objectives 
Endpoints 
domain scores as measured by the 
MPFID over months 4, 5, and 6 (week 
13 through 24) of the DBTP 
The estimand for the secondary objective on MPFID consists of: 
 
The target population, which includes subjects diagnosed with CM and MOH who 
have a history of at least 1 preventive treatment failure and do not use opioid 
medication for more than 4 days per month 
 
The endpoints, which include (1) the change from baseline in mean monthly 
average physical impairment domain scores and (2) the change from baseline in 
mean monthly average impact on everyday activities domain scores as measured 
by the MPFID over months 4, 5, and 6 (week 13 through 24) of the DBTP  
 
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of IP and have at least 1 change from baseline in the 
respective domain score, regardless of adherence to treatment 
 
The summary measure, which is the difference in mean of the endpoint between 
each erenumab dose group (ie, 70 mg and 140 mg) and the placebo group 
 To evaluate the effect of erenumab 
compared to placebo on change from 
baseline in headache impact scores 
as measured by the Headache Impact 
Test (HIT-6)a  
 Change from baseline in mean HIT-6 
score over months 4, 5, and 6 (week 
13 through 24) of the DBTP 
The estimand for the secondary objective on HIT-6 consists of: 
 
The target population, which includes subjects diagnosed with CM and MOH who 
have a history of at least 1 preventive treatment failure and do not use opioid 
medication for more than 4 days per month  
 
The endpoint, which is the change from baseline in mean HIT-6 total score over 
months 4, 5, and 6 (week 13 through 24) of the DBTP  
 
The intercurrent event, which is adherence to treatment.  The treatment effect of 
interest will be assessed for all randomized subjects in the target population who 
receive at least 1 dose of investigational product (IP) and have at least 1 change 
from baseline in HIT-6 total score, regardless of adherence to treatment 
 
The summary measure, which is the difference in mean of the endpoint between 
each erenumab dose group (ie, 70 mg and 140 mg) and the placebo group 
Safety 
 To evaluate the safety and tolerability 
of erenumab in subjects with 
CM-MOH 
 Adverse events 
 Vital signs 
a In the EU region including UK, HIT-6 will replace MPFID as a secondary endpoint and MPFID will be 
evaluated as an exploratory endpoint.  In non-EU regions, MPFID will remain as a secondary endpoint 
while HIT-6 will be evaluated as an exploratory endpoint. 
 


Product:  Erenumab (AMG 334) 
Protocol Number:  20170703 
Date:  10 December 2022 
 
 
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Objectives 
Endpoints 
Exploratory (Double-blind treatment period) 
 
To explore the effect of erenumab 
compared with placebo in promoting 
conversion to EM 
 Achievement of conversion to episodic 
migraine (EM) at month 3 defined as 
mean MHD < 14 days over months 1, 
2, and 3 (week 1 through 12) of the 
DBTP 
 Achievement of conversion to EM at 
month 6, defined as mean MHD 
< 14 days over months 4, 5, and 6 
(week 13 through 24) of the DBTP 
 Achievement of conversion to EM over 
6 months, defined as mean 
MHD < 14 days over months 1 through 
6 (week 1 through 24) of the DBTP 
 
To explore the effect of erenumab 
compared with placebo on the change 
of at least moderate pain intensity 
MHD from baseline to the DBTP  
 Change from baseline in MHD of at 
least moderate pain intensity at 
monthly assessment time points  
 Change from baseline in mean at least 
moderate pain intensity MHD over 
months 4, 5, and 6 (week 13 through 
24) of the DBTP 
 Achievement of at least 30%, 50%, and 
75% reductions from baseline in at 
least moderate pain intensity MHD at 
monthly assessment time points 
 Achievement of at least 30%, 50%, and 
75% reduction from baseline in mean 
at least moderate pain intensity MHD 
over months 4, 5, and 6 (week 13 
through 24) of the DBTP  
 
To explore the effect of erenumab 
compared with placebo on the change 
from baseline in monthly migraine 
days (MMD) during the DBTP 
 Change from baseline in MMD at 
monthly assessment time points  
 Change from baseline in mean MMD 
over months 4, 5, and 6 (week 13 
through 24) of the DBTP 
 Achievement of at least a 30%, 50%, 
and 75% reductions from baseline in 
MMD at monthly assessment time 
points  
 Achievement of at least 30%, 50%, and 
75% reductions from baseline in MMD 
mean over months 4, 5, and 6 (week 
13 through 24) of the DBTP 
 
To explore the effect of erenumab 
compared with placebo on the change 
from baseline in average headache 
pain severity during the DBTP 
 Change from baseline in the monthly 
average pain severity score of qualified 
headache days at monthly assessment 
time points 


Product:  Erenumab (AMG 334) 
Protocol Number:  20170703 
Date:  10 December 2022 
 
 
Page 13 of 53 
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Objectives 
Endpoints 
 Change from baseline in the mean 
monthly average pain severity score of 
qualified headache days over months 
4, 5, and 6 (week 13 through 24) of 
the DBTP 
 To explore the effect of erenumab 
compared with placebo on the change 
from baseline in migraine-free days 
during the DBTP 
 Change from baseline in monthly 
migraine-free days at monthly 
assessment time points of the DBTP 
 Change from baseline in mean monthly 
migraine-free days over months 4, 5, 
and 6 (week 13 through 24) of the 
DBTP 
 To explore migraine-related disability 
metrics as measured by the migraine 
functional impact questionnaire (MFIQ) 
 Change from baseline in MFIQ domain 
scores and overall impact on usual 
activities global item score at 
assessment time points 
 To explore migraine-related disability 
and productivity as measured by the 
Migraine Disability Assessment 
(MIDAS) Questionnaire 
 Change from baseline in MIDAS total 
score, absenteeism score and 
presenteeism score at assessment 
time points during DBTP  
 Cumulative (sum of) changes from 
baseline in MIDAS total score, 
absenteeism score and presenteeism 
score over 6 months during DBTP 
 To explore the effect of erenumab 
compared with placebo on the change 
from baseline in health resource 
utilization (HRU) 
 Occurrence of at least 1  
headache-related hospitalization or 
outpatient HRU during the DBTP 
 Occurrence of at least 1  
headache-related hospitalization during 
the DBTP 
 Occurrence of at least 1  
headache-related outpatient HRU 
during the DBTP 
 Occurrence of at least 1  
headache-related outpatient 
emergency room visit during the DBTP 
 Occurrence of at least 1  
headache-related outpatient urgent 
care visit during the DBTP 
 Occurrence of at least 1 
headache-related outpatient clinic visit 
during the DBTP 
 To explore the effect of erenumab 
compared with placebo on the change 
 Change from baseline in Generalized 
Anxiety Disorder 7-item scale (GAD-7) 
score at assessment time points 


Product:  Erenumab (AMG 334) 
Protocol Number:  20170703 
Date:  10 December 2022 
 
 
Page 14 of 53 
CONFIDENTIAL 
 
 
Objectives 
Endpoints 
from baseline in depression and 
anxiety symptoms 
 
 
 Change from baseline in Beck 
Depression Inventory-II (BDI-II) score 
at assessment time points 
 To explore the effect of erenumab 
compared with placebo on the change 
from baseline in measures of sleep 
quality 
 Change from baseline in each of the 
sleep questionnaire domain scores at 
assessment time points 
 To explore the effect of erenumab 
compared with placebo on the subject’s 
assessment of the change in clinical 
status since the start of treatment 
 Change in clinical status as measured 
by the Patient’s Global Impression of 
Change (PGIC) as assessed by the 
subject at month 6 of the DBTP 
 To explore the effect of erenumab 
compared to placebo on the change 
from baseline in allodynia symptoms 
 Change from baseline in Allodynia 
Symptoms Checklist-12 (ASC-12) 
score at assessment time points 
Exploratory (Open-label treatment period) 
 To explore the rate of MOH relapse in 
the end of open-label treatment 
period (OLTP) 
 MOH relapse at year 1, defined as both 
mean monthly AHMD ≥ 10 days over 
months 11, 12, and 13 (week 41 
through 52) AND mean MHD ≥ 14  
days over months 11, 12, and 13  
(week 41 through 52) in subjects who 
achieved MOH remission at month 6 of 
the DBTP 
Note: This endpoint will be analyzed 
among subjects who were treated 
with erenumab throughout the entire 
study 
 To explore absence of MOH at end of 
OLTP 
 Absence of MOH at end of study as 
defined by mean monthly AHMD < 10 
days over months 11, 12, and 13 
(week 41 through 52) OR mean 
MHD < 14 days over months 11, 12, 
and 13 (week 41 through 52) 
 To explore sustainability of MOH 
remission during OLTP 
 Sustained absence of MOH over 1 year 
as defined by absence of MOH over 
the DBTP (months 1, 2, and 3 [week 1 
through 12], OR months 4, 5, and 6 
[week 13 through 24]) AND OLTP 
(months 11, 12, and 13) [week 41 
through 52]. 
Note:  “Absence of MOH” is achieved 
when mean monthly AHMD < 10 days 
OR mean MHD < 14 days over the 
respective 3-month period 
This endpoint will be analyzed 
among subjects who were treated 


Product:  Erenumab (AMG 334) 
Protocol Number:  20170703 
Date:  10 December 2022 
 
 
Page 15 of 53 
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Objectives 
Endpoints 
with erenumab throughout the entire 
study 
 To explore change in AHMD, MMD, 
and MHD of at least moderate pain 
intensity 
 Change from baseline in mean AHMD, 
MMD and MHD of at least moderate 
pain intensity at assessment time 
points  
 Change from week 24 (OLTP baseline) 
in mean AHMD, MMD, and MHD of at 
least moderate pain intensity at 
assessment time points during OLTP 
 To explore everyday activities as 
measured by the MPFID 
 Change from baseline in monthly 
average impact on everyday activities 
score as measured by the MPFID at 
assessment time points 
 Change from week 24 (OLTP baseline) 
in monthly average impact on everyday 
activities score as measured by the 
MPFID at assessment time points 
during OLTP 
 To explore physical impairment as 
measured by the MPFID 
 Change from baseline in monthly 
average physical impairment score as 
measured by the MPFID at 
assessment time points 
 Change from week 24 (OLTP baseline) 
in monthly average physical 
impairment score as measured by the 
MPFID at assessment time points 
during OLTP 
 To explore the daily activity impact of 
headache as measured by the HIT-6 
 Change from baseline in HIT-6 total 
score at week 52 
 Change from week 24 (OLTP baseline) 
in HIT-6 total score at week 52 
 To explore migraine-related disability 
metrics as measured by MFIQ 
 Change from baseline in MFIQ domain 
scores and overall impact on usual 
activities global item score at week 52 
 Change from week 24 (OLTP baseline) 
in MFIQ domain scores and overall 
impact on usual activities global item 
score at week 52 
 To explore migraine-related disability 
and productivity as measured by the 
MIDAS Questionnaire 
 Change from baseline in MIDAS total 
score, absenteeism score and 
presenteeism score at week 52 
 Change from week 24 (OLTP baseline) 
in MIDAS total score, absenteeism 
score, and presenteeism score at 
week 52 
Exploratory (Opioid-treated Cohort Only)a 


Product:  Erenumab (AMG 334) 
Protocol Number:  20170703 
Date:  10 December 2022 
 
 
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Objectives 
Endpoints 
 To explore the effect of erenumab 
compared with placebo in reducing 
consumption of opioids in subjects 
stratified to the opioid-treated cohort 
during DBTP 
 Change from baseline in monthly 
opioid/opioid-containing medication 
days at assessment time points during 
DBTP 
 Change from baseline in mean 
monthly opioid/opioid-containing 
medication days over months 4, 5 
and 6 (week 13 through 24) of the 
DBTP 
 To explore the effect of erenumab 
compared with placebo in reducing 
consumption of opioids in subjects 
stratified to the opioid-treated cohort 
during OLTP 
 Change from baseline in monthly 
opioid/opioid-containing medication 
days at assessment time points during 
OLTP 
a In addition to these objectives/endpoints, all primary, secondary, and exploratory objectives/endpoints 
will be evaluated for the opioid-treated cohort. 
 
2.2 
Hypotheses and/or Estimations 
The primary clinical hypothesis of Study 20170703 is that preventive treatment with 
monthly injections of erenumab is superior to placebo in achieving MOH remission for 
subjects with CM-MOH in the nonopioid-treated cohort who have a history of at least 1 
preventive treatment failure as measured by the absence of the MOH status based on 
the mean over months 4, 5, and 6 (week 13 through 24) of the DBTP. 
The secondary clinical hypotheses of Study 20170703 are that preventive treatment with 
monthly injections of erenumab is superior to placebo in reducing AHMDs over months 4 
to 6 (week 13 through 24) of the DBTP; sustaining MOH remission during the entire 
DBTP; reducing migraine-related impact on physical functioning and everyday activities 
as measured by Migraine Physical Function Impact Diary (MPFID) physical function and 
everyday activities domains (non-EU) or migraine-related impact on physical functioning 
as measured by the Headache Impact Test 6 (HIT-6) (EU only). 
For subjects with CM-MOH allocated to the opioid-treated cohort, an additional 
exploratory clinical hypothesis of Study 20170703 is that preventive treatment with 
monthly injections of erenumab could help reduce opioid use as measured by the mean 
change in monthly opioid medication days from baseline over months 4, 5, and 6 (week 
13 through 24) of the DBTP. Formal statistical testing does not apply to this exploratory 
clinical hypothesis. 


Product:  Erenumab (AMG 334) 
Protocol Number:  20170703 
Date:  10 December 2022 
 
 
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3. 
Study Overview 
3.1 
Study Design 
Study 20170703 is a phase 4, randomized, double-blind, double-dummy, parallel-group, 
placebo-controlled study to evaluate the safety and efficacy of erenumab against 
placebo in a CM population with MOH and prior history of treatment failure.  Subjects will 
be enrolled based on fulfillment of the International Classification of Headache 
Disorders, 3rd Edition (ICHD-3) CM and MOH criteria and will not be advised to early 
discontinue acute medication.  During randomization, subjects will be separated into 2 
distinct cohorts based on their opioid medication use at baseline.  Subjects with an 
opioid medication use  4 days per month during the baseline period will be allocated to 
the opioid-treated cohort.  Subjects with an opioid medication use of  4 days per month 
during the baseline period will be allocated to the nonopioid-treated cohort.  The 
randomization process on the nonopioid-treated cohort will be balanced based on the 
following stratum: 
 
Concomitant oral migraine preventive treatment initiated before screening and 
taken during baseline (Yes or No). 
Subjects allocated to the opioid treated cohort will be analyzed separately as an 
exploratory cohort.  
During the DBTP, subjects will be randomized in a 1:1:1 fashion to either placebo, 
erenumab 70 mg SC every 4 weeks, or erenumab 140 mg SC every 4 weeks. Subjects 
who successfully complete the 24-week DBTP of the study will be offered an opportunity 
to continue in an OLTP of 28-weeks duration. Subjects who received erenumab 
treatment during the DBTP will continue to receive the same erenumab dose during the 
OLTP. Subjects who received placebo during the DBTP will be allocated in a 1:1 ratio to 
receive either erenumab 70 mg or 140 mg SC QM during the OLTP. All subjects will 
remain blinded to their original DBTP treatment assignment. 
3.2 
Sample Size 
The sample size calculation has been performed based on the primary endpoint 
(absence of MOH at month 6) for the nonopioid-treated cohort. 
Based on a subgroup analysis of subjects who failed preventive migraine medication, 
overused acute headache medication, and had at least 14 MHD at baseline in the 
erenumab CM pivotal Study 20120295, 33.1%, 50.5%, and 64.1% of subjects in 
placebo, erenumab 70 mg and erenumab 140 mg treatment group, respectively, 


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achieved absence of MOH at month 3.  Assuming similar response rates over month 4, 
5 and 6 and a conservative scenario that includes a dropout rate of 20% during the 
6-month DBTP, the planned sample size of 183 subjects per group will provide 85% 
power for 70 mg versus placebo and > 99% power for 140 mg versus placebo using a 
2-sample chi-squared test with a 2-sided significance level of 0.05. 
In addition, up to 138 opioid-treated cohort subjects will be randomized to receive 
erenumab or placebo (46 on placebo, 46 on 70 mg, and 46 on 140 mg). 
3.3 
Adaptive Design 
Not applicable. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
All model-adjusted analyses of efficacy endpoints in nonopioid-treated cohort will include 
the following covariates: 
 
Concomitant oral migraine preventive treatment initiated before screening AND taken 
during baseline (Yes or No) 
 
Corresponding baseline value for the endpoint being analyzed (for continuous 
endpoints only) 
4.2 
Subgroups 
The primary and secondary endpoints for the nonopioid cohort will be analyzed in the 
following subgroups:   
 
concomitant oral migraine preventive treatment initiated before screening and taken 
during baseline (Yes or No) 
 
geographic region (North America vs. Other)  
 
BMI (< median vs. ≥ median) 
 
prior history of treatment with onabotulinumtoxinA (Yes or No) 
 
total number of prior treatment failures (1 vs. 2 or more) 
 
total number of prior treatment failures (1 vs. 2 vs. 3 or more)  
 
prior history of depression (Yes or No) 
 
acute headache medication overuse category  
o overuse of triptan (Yes or No) 
o overuse of simple analgesics/NSAIDs (Yes or No) 
o overuse of combination analgesics (Yes or No) 
o overuse of combination therapies (Yes or No) 


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Summary of prior and concomitant migraine preventive medication use is based 
on the following 9 categories: topiramate, other antiepileptics, beta blockers, 
tricyclic antidepressants, other antidepressants, calcium channel 
blockers/calcium antagonists, angiotensin receptor blockers/angiotensin-
converting enzyme (ACE) inhibitors, botulinum toxin, and other drugs used for 
migraine prevention. 
5. 
Definitions 
5.1 
Definition of Terms Included in Study Endpoints 
5.1.1 
Efficacy Endpoints Based on Daily eDiary Collection 
Acute Headache Medication (AHM) 
Acute headache medications include  
 
Triptan-based migraine medications 
 
Ergotamine-based migraine medications 
 
Ditan-based migraine medications 
 
Non-opioid acute headache medications 
 
Non-opioid butalbital containing medications 
 
Opioid-containing acute headache medications 
 
Opioid-containing butalbital containing medications 
Acute Migraine-specific Medication (AMSM) 
A subset of acute headache medication consisting of triptan-based migraine 
medications,  ergotamine-based migraine medications, and ditan-based migraine 
medications. 
Medication Overuse (MO)  
Monthly acute headache medication use meeting at least one of the following criteria: 
 
≥ 10 days of a combination of ergotamines, triptans, opiates or opioid-containing 
meds or opioid combination-analgesic, non-opioid combination-analgesic 
medications or simple analgesics/NSAIDs whilst not satisfying medication 
overuse criteria in any of the below individual medication categories alone 
 
 10 days of opiates or opioid-containing medications or opioid 
combination-analgesics 
 
 10 days of triptans or triptan-containing medications 
 
 10 days of ergotamines or ergotamine-containing medications 
 
≥ 10 days of non-opioid combination-analgesics 


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 
≥ 15 days of simple analgesics/NSAIDs if subjects use simple analgesics/NSAIDs 
ONLY during the monthly interval 
Monthly acute headache medication days for each medication category will be 
calculated using the same proration approach as monthly acute headache 
medication days. 
Concomitant migraine preventive medication 
Migraine preventive medication that were reported in concomitant medication 
CRF, belonged to medication category defined in Section 4.2 and had start date < 
study day 1 AND (end date > day 1 OR missing end date). 
Overuse of Combination Analgesics 
Monthly acute headache medication days meeting at least one of the following criteria: 
 
 10 days of opioid-containing combination-analgesics 
 
≥ 10 days of non-opioid combination-analgesics 
Medication Overuse Headache (MOH; Over 3 Months)  
Mean monthly AHMD ≥ 10 days AND mean MHD  14 days over 3 consecutive study 
months, excluding gepant-based medication in the derivation. 
Absence of MOH (Over 3 Months) 
Mean monthly AHMD < 10 days OR mean MHD < 14 days over 3 consecutive study 
months, excluding gepant-based medication in the derivation. 
Sustained MOH Remission (Over 6 Months During DBTP) 
Mean monthly AHMD < 10 days OR mean MHD < 14 days over 3 consecutive study 
months at both time points (months 1, 2, and 3 [week 1 to week 12], AND months 4, 
5, and 6 [week 13 through 24]), excluding gepant-based medication in the 
derivation. 
Absence of MOH at End of Study 
Mean monthly AHMD < 10 days OR mean MHD < 14 days over months 11, 12 and 13 
(week 41 through 52), excluding gepant-based medication in the derivation. 
Sustained Absence of MOH (Sustained MOH Remission) Over 1 Year  
Absence of MOH over the DBTP (months 1, 2, and 3 [week 1 through 12], OR months 
4, 5, and 6 [week 13 through 24]) AND OLTP (months 11,12 and 13 [week 41 through 
52]), excluding gepant-based medication in the derivation. 
Conversion to Episodic Migraine (EM) (Over 3 Months) 
Mean MHD < 14 days over 3 consecutive study months 


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Achievement of Conversion to Episodic Migraine (EM) (Over 6 Months During 
DBTP) 
Mean MHD <14 days over months 1 through 6 (week 1 through 24) of the DBTP. 
Qualified Headache  
A qualified headache is defined as 
 
A headache of duration ≥ 4 hours, or 
 
A headache of duration < 4 hours during which an acute headache medication is 
administered 
Headache Day 
A calendar day (00:00 to 23:59) in which the subject experiences ≥ 1 qualified headache 
or takes ≥ 1 acute migraine-specific medication (ie, triptan, ergotamine, ditan) during 
aura  
Qualified Migraine Headache 
A qualified migraine headache is defined as  
 
A headache lasting for ≥ 4 hours, and meeting ≥ 1 of the following criteria (a 
and/or b): 
a) ≥ 2 of the following pain features:  
 
Unilateral 
 
Throbbing 
 
Moderate to severe (ie, headache pain intensity ≥ 4) 
 
Exacerbated with exercise/physical activity 
b) ≥ 1 of the following associated symptoms:  
 
Nausea 
 
Vomiting  
 
Photophobia and phonophobia 
 
A headache during which an acute migraine-specific medication (ie, triptan,  
ergotamine, ditan) is administered regardless of the headache duration, pain 
features, and associated symptoms 
Migraine Day 
A calendar day (00:00 to 23:59) in which the subject experiences ≥ 1 qualified migraine 
headache or takes ≥ 1 acute migraine-specific medication (ie, triptan, ergotamine, 
ditan) during aura. 


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Migraine-free Day  
A calendar day (00:00 to 23:59) of a diary day in which the subject does not experience 
any headache pain or any symptoms including aura, nausea, vomiting, phonophobia, 
and photophobia, and does not take any acute headache medication. 
Acute Headache Medication Day 
A calendar day (00:00 to 23:59) in which the subject takes ≥ 1 acute headache 
medication. 
Opioid Medication Day 
A calendar day (00:00 to 23:59) in which an opioid/opioid containing medication was 
administered.  
Headache Pain Intensity 
Worst or peak pain intensity collected on a headache ranges from 1 to 10 with a higher 
score indicating more severe pain.  Pain intensity are categorized into mild (1 to 3), 
moderate (4 to 6), and severe (7 to 10). 
Headache Day of at Least Moderate Pain Intensity 
A calendar day (00:00 to 23:59) in which the subject experiences ≥ 1 qualified headache 
with the worse or peak pain intensity of ≥ 4. 
Diary Day 
A calendar day (00:00 to 23:59) with complete headache, aura, and acute headache 
medication data recorded in the eDiary device. 
Monthly Frequency Variable in Days 
Number of days of interest during one monthly interval as defined in Table 5-1. Monthly 
frequency variables include: 
 
Monthly migraine days (MMD) 
 
Monthly headache days (MHD) 
 
Monthly migraine-free days 
 
Monthly opioid/opioid-containing medication days 
 
Monthly acute headache medication days (AHMD) 
 
Monthly headache days with at least moderate pain intensity 
 
Monthly acute migraine-specific medication days 
The following proration rule will be applied to all monthly frequency variables for 
analysis. If a subject misses diary on a day when a headache is ongoing, that day will 
still be included in MHD calculation as only headache duration is required to identify a 


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headache day. For other endpoints which are derived using headache symptoms and 
medication information, days without diary completion will not be included in the 
proration.  
Within 
Each 
Monthly 
Interval 
Monthly Frequency Variable 
≥ 14 
diary 
days 
For monthly headache days with at least moderate pain intensity, prorate to 
28-day equivalent without rounding 
𝑵𝒖𝒎𝒃𝒆𝒓 𝒐𝒇 𝒐𝒃𝒔𝒆𝒓𝒗𝒆𝒅 𝒉𝒆𝒂𝒅𝒂𝒄𝒉𝒆 𝒅𝒂𝒚𝒔 𝒘𝒊𝒕𝒉
 𝒂𝒕 𝒍𝒆𝒂𝒔𝒕 𝒎𝒐𝒅𝒆𝒓𝒂𝒕𝒆 𝒑𝒂𝒊𝒏 𝒘𝒊𝒕𝒉𝒊𝒏 𝒆𝒂𝒄𝒉 𝒎𝒐𝒏𝒕𝒉𝒍𝒚 𝒊𝒏𝒕𝒆𝒓𝒗𝒂𝒍
𝑵𝒖𝒎𝒃𝒆𝒓 𝒐𝒇 𝒅𝒊𝒂𝒓𝒚 𝒅𝒂𝒚𝒔 𝒐𝒓 𝒅𝒂𝒚𝒔 𝒘𝒊𝒕𝒉 𝒉𝒆𝒂𝒅𝒂𝒄𝒉𝒆 𝒑𝒂𝒊𝒏 𝒊𝒏𝒕𝒆𝒏𝒔𝒊𝒕𝒚
 𝒄𝒐𝒍𝒍𝒆𝒄𝒕𝒆𝒅 𝒘𝒊𝒕𝒉𝒊𝒏 𝒆𝒂𝒄𝒉 𝒎𝒐𝒏𝒕𝒉𝒍𝒚 𝒊𝒏𝒕𝒆𝒓𝒗𝒂𝒍
 𝒙 𝟐𝟖 
For monthly migraine-free days, prorate to 28-day equivalent without 
rounding 
𝑵𝒖𝒎𝒃𝒆𝒓 𝒐𝒇 𝒇𝒓𝒆𝒒𝒖𝒆𝒏𝒄𝒚 𝒅𝒂𝒚𝒔 𝒘𝒊𝒕𝒉𝒊𝒏 𝒆𝒂𝒄𝒉 𝒎𝒐𝒏𝒕𝒉𝒍𝒚 𝒊𝒏𝒕𝒆𝒓𝒗𝒂𝒍
𝑵𝒖𝒎𝒃𝒆𝒓 𝒐𝒇 𝒅𝒊𝒂𝒓𝒚 𝒅𝒂𝒚𝒔 𝒐𝒓 𝒉𝒆𝒂𝒅𝒂𝒄𝒉𝒆 𝒅𝒂𝒚𝒔 𝒐𝒓 
𝒂𝒄𝒖𝒕𝒆 𝒉𝒆𝒂𝒅𝒂𝒄𝒉𝒆 𝒎𝒆𝒅𝒊𝒄𝒂𝒕𝒊𝒐𝒏 𝒅𝒂𝒚𝒔
 𝒘𝒊𝒕𝒉𝒊𝒏 𝒆𝒂𝒄𝒉 𝒎𝒐𝒏𝒕𝒉𝒍𝒚 𝒊𝒏𝒕𝒆𝒓𝒗𝒂𝒍
 𝒙 𝟐𝟖 
For monthly acute migraine-specific medication days and monthly 
opioid/opioid-containing medication days, prorate to 28-day equivalent 
without rounding 
𝑵𝒖𝒎𝒃𝒆𝒓 𝒐𝒇 𝒇𝒓𝒆𝒒𝒖𝒆𝒏𝒄𝒚 𝒅𝒂𝒚𝒔 𝒘𝒊𝒕𝒉𝒊𝒏 𝒆𝒂𝒄𝒉 𝒎𝒐𝒏𝒕𝒉𝒍𝒚 𝒊𝒏𝒕𝒆𝒓𝒗𝒂𝒍
𝑵𝒖𝒎𝒃𝒆𝒓 𝒐𝒇 𝒅𝒊𝒂𝒓𝒚 𝒅𝒂𝒚𝒔 𝒐𝒓 𝒂𝒄𝒖𝒕𝒆 𝒉𝒆𝒂𝒅𝒂𝒄𝒉𝒆 𝒎𝒆𝒅𝒊𝒄𝒂𝒕𝒊𝒐𝒏 𝒅𝒂𝒚𝒔
 𝒘𝒊𝒕𝒉𝒊𝒏 𝒆𝒂𝒄𝒉 𝒎𝒐𝒏𝒕𝒉𝒍𝒚 𝒊𝒏𝒕𝒆𝒓𝒗𝒂𝒍
 𝒙 𝟐𝟖 
For other frequency variables, prorate to 28-day equivalent without rounding 
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑓𝑟𝑒𝑞𝑢𝑒𝑛𝑐𝑦 𝑑𝑎𝑦𝑠 𝑤𝑖𝑡ℎ𝑖𝑛 𝑒𝑎𝑐ℎ 𝑚𝑜𝑛𝑡ℎ𝑙𝑦 𝑖𝑛𝑡𝑒𝑟𝑣𝑎𝑙
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑖𝑎𝑟𝑦 𝑑𝑎𝑦𝑠 𝒐𝒓 𝒇𝒓𝒆𝒒𝒖𝒆𝒏𝒄𝒚 𝒅𝒂𝒚𝒔 𝑤𝑖𝑡ℎ𝑖𝑛 𝑒𝑎𝑐ℎ 𝑚𝑜𝑛𝑡ℎ𝑙𝑦 𝑖𝑛𝑡𝑒𝑟𝑣𝑎𝑙 𝑥 28 
Note: diary days with complete headache, aura, and acute headache medication 
data is required to derive endpoints related to symptoms, pain intensity and acute 
medication use. 
< 14 
diary 
days 
Set to missing 
Monthly Average Variable Based on Qualified Headaches 
Monthly average headache pain intensity based on qualified headache will be 
calculated as below: 


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Within Each Monthly Interval 
Monthly Average Variable 
≥ 14 diary days 
Sum of the headache pain intensity values from all qualified 
headaches during a monthly interval as defined in Table 5-1 
divided by the total number of qualified headaches in that 
monthly interval 
Set to 0 if no qualified headache reported 
< 14 diary days 
Set to missing 
A headache lasts for multiple days will be separated to multiple qualified 
headaches by midnight. Multiple qualified headaches within the same day will be 
calculated as separate qualified headaches. 
Monthly Average Variable Based on Daily PRO Scores 
Monthly average variables derived from daily MPFID assessment include  
 
Monthly average physical impairment domain score  
 
Monthly average impact on everyday activities domain score  
Days With Complete Response 
Within Each Monthly Interval 
Monthly Average Variable 
≥ 14 days 
Sum of values from daily assessment during a monthly 
interval as defined in Table 5-1 divided by the number of 
days with complete response.   
< 14 days 
Set to missing 
Complete response is defined as the completion of a MPFID questionnaire with all 
questions answered. The latest record of the duplicate MPFIDs will be used for the 
calculation of monthly MPFIDs. 
Migraine Physical Function Impact Domains and Everyday Activities 
The MPFID is a self-administered 13-item instrument measuring physical functioning.  It 
has 2 domains, Impact on Everyday Activities (7 items) and Physical Impairment 
(5 items), and 1 stand-alone global question which provides an assessment of overall 
impact on everyday activities.  
Subjects respond to items using a 5-point scale, with difficulty items ranging from 
"Without any difficulty" to "Unable to do" and frequency items ranging from "None of the 
time" to "All of the time".  These are assigned scores from 1 to 5, with 5 representing the 
greatest burden.  For each domain, the scores will be calculated as the sum of the item 
responses and the sum will be rescaled to a 0 to 100 scale, with higher scores 
representing greater impact of migraine (ie, higher burden).  There will be a score for 


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each of the 2 domains and a third score for the stand-alone item.  The recall period is 
the past 24 hours.  Subjects will complete the MPFID daily using the eDiary. 
5.1.2 
Efficacy Endpoints Based on Monthly Collection 
Headache Impact Test (HIT-6) 
The scoring of the HIT-6 total score will be performed using the Optum Scoring 
Software.  The HIT-6 total scores ranging from 36 to 78 can be categorized into 
4 grades, representing little or no impact (49 or less), some impact (50 to 55), substantial 
impact (56 to 59), and severe impact (60 to 78) due to headache.  Subjects will complete 
the HIT-6 using the eDiary. 
Migraine Functional Impact Questionnaire (MFIQ) 
The MFIQ is a self-administered 26-item instrument measuring the impact of migraine on 
broader functioning including 4 domains, Impact on Physical Functioning (5 items), 
Impact on Usual Activities (10 items), Impact on Social Functioning (5 items), and Impact 
on Emotional Functioning (5 items). In addition, there is 1 stand-alone global item 
assessing the overall impact on usual activities. Subjects respond to items using a 5-
point scale assigned scores from 1 to 5, with 5 representing the greatest burden. Each 
domain scores will be calculated as the sum of the item responses, and the sum will be 
rescaled to a 0 to 100 scale, with higher scores representing greater burden. The recall 
period is the past 7 days.  Subjects will complete the MFIQ using the eDiary. 
Allodynia Symptoms Checklist 12 items (ASC-12) 
The ASC-12 is a subject reported outcome measure used to assess the frequency of 
allodynia symptoms.  The checklist will ask subjects to assess how often they 
experience increased pain or an unpleasant sensation on their skin during their most 
severe type of headache while engaging in each of the following: combing their hair, 
pulling their hair back (eg, ponytail), shaving their face, wearing eyeglasses, wearing 
contact lenses, wearing earrings, wearing a necklace, wearing tight clothing, taking a 
shower (when the shower water hits their face), resting their face or head on a pillow, 
exposure to heat (eg, cooking, washing their face with hot water), and exposure to cold 
(eg, using an ice pack, washing their face with cold water). 
The subject answers each question using the following categories: “Does not apply to 
me”, “Never”, “Rarely”, “Less than half of the time”, “Half the time or more”.  Responses 
to each question are assigned a score.  A positive response to answer options 1 to 3 is 
scored as 0, a positive response to answer option 4 is scored as a 1, and a positive 


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response to answer option 5 is scored a 2.  The final grading is based on the sum of the 
12 items. Subjects will complete the ASC-12 using the eDiary. 
Migraine Disability Assessment Questionnaire (MIDAS)  
The MIDAS Questionnaire is a 5-item self-administered questionnaire that sums the 
number of productive days lost over the past 3 months in 2 settings: the workplace and 
the home.  The MIDAS also assesses disability in family, social, and leisure activities.  
The MIDAS score is the sum of missed days due to a headache from paid work, 
housework, and nonwork (family, social, leisure) activities; and days at paid work or 
housework where productivity was reduced by at least half.  The recall period is 
3 months.  
The score is categorized into 4 severity grades: grade I = 0 to 5 (defined as minimal or 
infrequent disability), grade II = 6 to 10 (mild or infrequent disability), grade III = 11 to 
20 (moderate disability), and grade IV = 21 and over (severe disability).  Two other 
questions (A and B) are not scored, but were designed to provide the physician with 
clinically relevant information on headache frequency and pain severity. Subjects will 
complete the MIDAS using the eDiary. 
Generalized Anxiety Disorder 7-item Questionnaire (GAD-7) 
The GAD-7 is a self-administered 7-item instrument that uses some of the 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.  Subjects will complete the GAD-7 using the eDiary. 
Patient Global Impression of Change (PGIC) 
The PGIC is a subject-reported outcome that evaluates general aspects of a subject’s 
health and assesses if there has been an improvement or decline in clinical status.  The 
PGIC employs a 7-point Likert scale that ranges from (1) ‘Very much improved’ to (7) 
‘Very much worse’.  Subjects will complete the PGIC using the eDiary. 


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American Registry for Migraine Research (ARMR) Sleep Questionnaire 
The ARMR sleep questionnaire is a novel self-administered 10-item patient-reported 
outcome that measures parameters of sleep quantity, sleep quality and daytime 
sleepiness and their relationship with migraine symptomatology and treatment over a 
3-month recall period. Items 1 to 3 of the questionnaire evaluate parameters of sleep 
quantity as a discrete time variable. Items 4-6 and 8-10 evaluate several behaviors that 
denote poor sleep quality and excessive daytime sleepiness using a five-level Likert 
scale that ranges from ‘strongly disagree’ to ‘strongly agree’. For each question, ‘not 
applicable’ options are also provided and are not scored. Each item may be scored 
separately or in combination within the same domain.  Item 7 refers to lifetime sleep 
disorders history and will only be collected at day 1 post randomization visit. Subjects 
will complete the ARMR sleep questionnaire using the eDiary. 
Beck Depression Inventory (BDI)-II 
The Beck Depression Inventory (BDI)-II is a 21-item questionnaire that assesses 
severity of depression.  Each item is scored from 0 to 3.  The total score is categorized 
into 4 severity grades: minimal depression (0 – 13), mild depression (14 – 19), moderate 
depression (20 – 28), and severe depression (29 – 63).   
Sites will be able to activate baseline period BDI-II on the eDiary at the end of the 
subject’s baseline period, after at least 28 full calendar days have passed 
(inclusive of the day the subject was set-up on the eDiary device). 
5.1.3 
Safety Endpoints 
Serious Adverse Event (SAE) 
An event categorized as “Adverse Event” on the Events eCRF starting on or after 
signing of the informed consent and up to the End of Study date with the indicator flag 
“Serious” equal to “Yes”. 
Treatment-emergent Adverse Event 
An event categorized as “Adverse Event” on the Events eCRF starting on or after first 
dose of investigational product, as determined by “Did event start before first dose of 
investigational product” equal to “No” or missing, and up to the End of Study date. 
Serious Treatment-emergent Adverse Event 
A treatment-emergent adverse event with the indicator flag “Serious” equal to “Yes” on 
the Events eCRF. 


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Treatment-emergent Adverse Device Effect 
A treatment-emergent adverse event with the indicator flag “Is there a reasonable 
possibility that the event may have been caused by the investigational device” equal to 
“Yes” on the Events eCRF. 
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 setup and ready for entry  
Randomization (Enrollment) Date in DBTP 
Randomization (Enrollment) Date in DBTP is the date on which a subject is assigned to 
one of the treatments through the Interactive Voice Response System (IVRS) in the 
DBTP. 
First (DBTP) IP Dose Date 
The first (DBTP) IP dose date is the date on which a subject is administered the first 
dose of IP during the DBTP following randomization as recorded on the IP 
Administration eCRF. The first IP dose date may be the same day or after the 
randomization date.  
Last DBTP IP Dose Date 
Last DBTP IP Dose Date is the date on which a subject is administered the last dose of 
IP during the DBTP as recorded on the IP Administration eCRF. 
First OLTP IP Dose Date 
The first OLTP IP Dose Date is the date on which a subject is administered the first dose 
of IP in the OLTP following completion of the DBTP as recorded on the IP Administration 
eCRF. 


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Last OLTP IP Dose Date 
Last OLTP IP Dose Date is the date on which a subject is administered the last dose of 
IP during the OLTP as recorded on the IP Administration eCRF. 
Last IP Dose Date 
Last IP Dose Date is the date on which a subject is administered the last dose of IP, 
which can be during the DBTP or OLTP, as recorded on the IP Administration eCRF. 
End of Study (EOS) Date 
End of study (EOS) date is defined as the last date on which the subject participates in 
the study as recorded on the End of Study eCRF. 
Primary Completion Date 
The primary completion date is defined as the date when the last subject is 
assessed or receives an intervention for the final collection of data for the primary 
endpoint(s), for the purposes of conducting the primary analysis, whether the 
study concluded as planned in the protocol or was terminated early. 
For this study, the primary completion date is the date when the last subject in the 
nonopioid-treated cohort has completed the assessments for week 24 (month 6) 
or discontinues study. 
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) before the first dose of investigational product.  In cases where 
baseline measurements are taken on the same day as IP, it will be assumed that these 
measurements are taken prior to IP being administered.  For subjects who are 
randomized but not dosed after the randomization, the baseline of the study is defined 
as the last non-missing measurement prior to or on the date of randomization. 
For measurements with multiple individual items, such as MFIQ and ARMR, all 
individual items from the same set of measurement will be used for analysis. 
Pre-OLTP Baseline  
Pre-OLTP baseline is defined as the last non-missing measurement for the 
endpoint of interest taken before the first dose of OLTP IP. In cases where the 


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measurements are taken on the same day as the first dose of OLTP IP, it will be 
assumed that these measurements are taken prior to IP being administered. For 
endpoints derived based on daily eDiary data, the pre-OLTP baseline is the last 
non-missing monthly measurement before the first dose of OLTP IP. 
Study Day 1 
Study day 1 is defined as the first IP dose date regardless on or after randomization 
date. For subjects who are randomized but never received any dose, the study day 1 
is defined as the date of randomization. 
Study Day 
Study Day is defined as the number of days from study day 1. 
Before Study Day 1: 
Study Day = (Date of Interest – Date of Study Day 1) 
On or after Study Day 1: 
Study Day = (Date of Interest – Date of Study Day 1) + 1 
Therefore, the day prior to Study Day 1 is -1. 
5.4 
Study Time Intervals 
5.4.1 
Study Periods 
The following data will be categorized into treatment periods.  Any data occurred after 
EOS date will not be included in the analysis.   
Efficacy Assessments at Scheduled Visits, Vitals 
 
DBTP:  Study Day 1 to minimum (first OL dose date, EOS date) 
 
OLTP:  (First OL dose date + 1) to EOS date 
Adverse Events, Concomitant Medications 
 
DBTP:  Study Day 1 to minimum (first OL dose date – 1, EOS date) 
 
OLTP:  First OL dose date to EOS date 
5.4.2 
Monthly Intervals for Efficacy Endpoints Derived From Daily Diary 
Collection 
The (4-week) monthly intervals for efficacy endpoints derived from daily 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.  Any 
eDiary data occurring after EOS date will not be included in the analysis. 


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Applicable efficacy endpoints utilizing the monthly intervals in Table 5-1 include: 
 
Monthly migraine days (MMD) 
 
Monthly headache days (MHD) 
 
Monthly migraine-free days 
 
Monthly opioid/opioid-containing medication days 
 
Monthly acute headache medication days (AHMD) 
 
Monthly headache days with at least moderate pain intensity 
 
Monthly acute migraine-specific medication days 
 
Monthly average headache pain intensity 
 
Monthly average MPFID physical impairment domain score  
 
Monthly average MPFID impact on everyday activities domain score 
Table 5-1.  Monthly Interval for Efficacy Endpoints Derived From Daily Diary 
Collection 
Study Period 
Assessment 
Timepoint 
Monthly Interval 
Start Date (Day) 
End Date (Day) 
Baseline Period 
Baseline 
Device ready for 
entry date d 
Day prior to study day 1 
Double-blind 
Treatment Period 
Week 4 (Month 1) 
Study Day 1  
Week 4 dose date – 1 b 
Week 8 (Month 2) 
Week 4 dose date a 
Week 8 dose date – 1 b 
Week 12 (Month 3) 
Week 8 dose date a 
Week 12 dose date – 1 b 
Week 16 (Month 4) 
Week 12 dose date a 
Week 16 dose date – 1 b 
Week 20 (Month 5) 
Week 16 dose date a 
Week 20 dose date – 1 b 
Week 24 (Month 6) 
Week 20 dose date a 
Week 24 dose date – 1 b 
Open-label 
Treatment Period 
Week 44 (Month 11) 
Week 40 visit date c 
Week 44 dose date – 1 b 
Week 48 (Month 12) 
Week 44 dose date a  Week 48 dose date – 1 b 
Week 52 (Month 13) 
Week 48 dose date a  Start date (day) + 27 
a Start Date (Day) = End date (day) of previous monthly interval + 1 if IP dose date is not available 
b End Date (Day) = Start date (day) of current monthly interval + 27 if IP dose date is not available 
c eDiary will be re-activated at the week-40 visit during OLTP irrespective of IP dose status. Week 40 visit 
date will be determined by week 40 dose date. If week 40 dose date is missing, week 40 clinic visit 
date will be used instead. If dose date or clinic visit date of the week was missing, the target date of 
the week would be used to determine the start date or end date. 
d Start Date of baseline period= the first eDiary date If device ready for entry date is not available 


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5.4.3 
Analysis Visits for Endpoints Based on Monthly Collection 
Since the actual visit for a subject may not exactly coincide with their targeted visit date, 
the actual visit date is mapped to the analysis visit as in Table 5-2 to Table 5-7.   
By-visit data collected on or before the first OLTP dose date belong to DBTP.  Data 
collected after the first OLTP dose date, not including the safety follow-up visit, belong to 
OLTP.  Any data occurred after EOS date will not be included in the analysis except 
antibody data.   
For by-visit summaries, if more than one visit with non-missing measurement (including 
the unscheduled visits, ie, CPEVENT = ‘UNSCHED’) fall within the same visit window, 
the following rules will be applied according to the order described below for selecting 
one visit per visit window for summary:  
1. Scheduled visit will be used regardless of the distance from the target day.  
Unscheduled visit will only be used when there is no measurement from 
scheduled visit in the visit window.   
2. The visit closest to the target day 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 5-2.  HIT-6 and MFIQ Analysis Visit Windows 
Study Period 
Analysis Visit 
Target 
Day 
Visit Window (Study Day) 
Double-blind 
Treatment Period 
Day 1 (Baseline) 
1 
Last measurement prior or on Day 1 
Week 4 (Month 1) 
29 
16 to 43 
Week 8 (Month 2) 
57 
44 to 71 
Week 12 (Month 3) 
85 
72 to 99 
Week 16 (Month 4) 
113 
100 to 127 
Week 20 (Month 5) 
141 
128 to 155 
Week 24 (Month 6) 
169 
156 to Week 24 dose date,  
if available, else to 183 
Open-label 
Treatment Period 
Week 52 (Month 13) 
365 
352 to 379 
Table 5-3.  MIDAS Analysis Visit Windows 
Study Period 
Analysis Visit 
Target Day 
Visit Window (Study Day) 
Double-blind 
Treatment Period 
Day 1 (Baseline) 
1 
Last measurement ≤ Day 1 
Week 12 (Month 3) 
85 
72 to 99 
Week 24 (Month 6) 
169 
156 to Week 24 dose date,  
if available, else to 183 
Open-label 
Treatment Period 
Week 52 (Month 13) 
365 
352 to 379 
Table 5-4.  ASC-12/GAD-7/BDI-II/Sleep Questionnaire Analysis Visit Windows 
Study Period 
Analysis Visit 
Target Day 
Visit Window (Study Day) 
Double-blind 
Treatment Period 
Day 1 (Baseline) 
1 
Last measurement ≤ Day 1 
Week 12 (Month 3) 
85 
72 to 99 
Week 24 (Month 6) 
169 
156 to Week 24 dose date,  
if available, else to 183 
Table 5-5.  PGIC Analysis Visit Windows 
Study Period 
Analysis Visit 
Target Day 
Visit Window (Study Day) 
Double-blind 
Treatment Period 
Week 24 (Month 6) 
169 
156 to Week 24 dose date,  
if available, else to 183 
Table 5-6.  HRU Questionnaire Analysis Visit Windows 
Study Period 
Analysis Visit 
Target Day 
Visit Window (Study Day) 
Double-blind 
Treatment Period 
Day 1 (Baseline) 
1 
Last measurement ≤ Day 1 
Week 24 (Month 6) 
- 
2 to Week 24/ET visit date,  
if available, else to 183 


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Table 5-7.  Vital Signs Analysis Visit Windows 
Study Period 
Analysis Visit 
Target Day 
Visit Window (Study Day) 
Double-blind 
Treatment Period 
Day 1 (Baseline) 
1 
Last measurement ≤ Day 1 
Week 4 (Month 1) 
29 
16 to 43 
Week 8 (Month 2) 
57 
44 to 71 
Week 12 (Month 3) 
85 
72 to 99 
Week 16 (Month 4) 
113 
100 to 127 
Week 20 (Month 5) 
141 
128 to 155 
Week 24 (Month 6) 
169 
156 to Week 24 dose date,  
if available, else to 183 
Open-label 
Treatment Period 
Week 40 (Month 10) 
281 
268 to 295 
Week 52 (Month 13) 
365 
352 to 379 
5.5 
Subject Disposition 
Randomized 
Individuals are considered randomized if they have been assigned a randomization 
number.  Randomized individuals are referred to as “subjects”. 
On-study 
Subjects are considered on-study if they have been randomized and have not yet had 
their end of study visit. 
Exposed to Investigational Product 
Subjects are defined as exposed if they receive at least one dose of investigational 
product.  
Completing the Double-blind Investigational Product 
Subjects are defined as completing double-blind investigational product if the primary 
reason for ending IP on End of IP DBTP eCRF is “Completed”. 
Completing the Double-blind Treatment Period 
Subjects are defined as completing the DBTP if they complete week-24 assessment.  It 
will be derived from the End of Double-Blind eCRF page with “Completed” as the 
primary reason for ending study period. 
Completing the Open-label Investigational Product 
Subjects are defined as completing open-label investigational product if the primary 
reason for ending IP on End of IP OLTP eCRF is “Completed”. 


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Completing the Open-label Treatment Period 
Subjects are defined as completing the OLTP if they complete the week-52 assessment.  
It will be derived from the End of Open-Label eCRF page with “Completed” as the 
primary reason for ending study period. 
Completing Study 
Subjects are defined as completing study if they complete the entire 52 weeks of study 
evaluation.  It will be derived from the End of Study eCRF page with “Completed” as the 
primary reason for ending study. 
5.6 
Arithmetic Calculations 
Duration of Migraine 
The number of years from the diagnosis date (DXDT) of migraine (migraine with aura or 
migraine without aura, whichever is earlier) to the date informed consent is signed. 
Observed 
Portion  
Missing 
Portion  
Duration of Migraine (Years) 
Year, Month, Day 
NA 
(Informed Consent Date – DXDT) / 365.25 
Year, Month  
Day  
[Year(Informed Consent Date) – Year(DXDT)] +  
[Month(Informed Consent Date) – Month(DXDT)] / 12 a 
Year 
Month, Day 
[Year(Informed Consent Date) – Year(DXDT)] a 
a If it equals 0, add 1/12 years (ie, 1 month) to avoid a disease duration of 0.   
Duration of DB IP Exposure 
If subject enters into OL treatment period,  
Duration = Minimum (Last DB Dose Date + 27, First OL Dose Date - 1) – First 
DB Dose Date + 1 
Otherwise,  
Minimum (Last DB Dose Date + 27, EOS Date) – First DB Dose Date + 1 
Duration of OL IP Exposure 
Minimum (Last OL Dose Date + 27, EOS Date) – First OL 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:  


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(Postbaseline – Baseline) * 100 / Baseline  
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 of the observed monthly change from baseline values for the months 
with non-missing change from baseline values  
Subject Incidence 
The subject incidence for a given event in a given period is defined as the number of 
subjects with at least one reported occurrence of the event divided by the number of 
subjects who entered that period (ie, number of at-risk subjects).  For subjects with 
multiple occurrences of the same event in a given period, the event will only be counted 
once per subject in that period. 
Exposure-adjusted Incidence Rate 
The exposure-adjusted incidence rate for a given event in a given period is defined as 
the number of subjects with at least one reported occurrence of the event in a given 
period divided by total exposure time of all subjects who are at risk for the event.  For 
subjects with a given event, only the time until the onset of each subject’s first event 
contributes to the exposure time.  For subjects without a given event, the exposure time 
is the entire duration of the period.  This incidence rate will be presented as number of 
subjects per 100 subject-years.   
5.7 
Disease Characteristics 
Treatment Failure of Prior Migraine Preventive Medications 
Treatment failure of prior preventative medications is determined by “Reason for 
stopping” as “Lack of Efficacy”, “Adverse Reaction” or “Intolerance” on the Prior Migraine 
Prophylactic Medication eCRF. 
6. 
Analysis Sets 
Each analysis set will be defined separately for the non-opioid-treated cohort and the 
opioid-treated cohort. 


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6.1 
Full Analysis Set 
The full analysis set (FAS) consists of all subjects who were randomized in the study.  
Subjects will be analyzed according to their randomized treatment, regardless of the 
treatment received.  Tabulations of demographic and baseline characteristics, 
disposition, and important protocol deviations (IPD) will utilize this analysis set.   
6.2 
Efficacy Analysis Set 
The efficacy analysis set (EAS) for all efficacy endpoints during DBTP is a subset of 
FAS consisting of subjects who receive at least 1 dose of investigational product during 
DBTP.  The respective EAS will be used to perform the analyses for the efficacy 
endpoints of interest during DBTP.  Subjects will be analyzed according to their 
randomized treatment in DBTP, regardless of the treatment received.  
6.3 
Safety Analysis 
The safety analysis set (SAS) will consist of all randomized subjects who received at 
least 1 dose of investigational product. Subjects will be analyzed according to the 
randomized treatment unless a subject receives the incorrect dose during the entire 
DBTP.  Analysis for safety endpoints and summary of investigational product 
administration will utilize this analysis set. 
6.4 
Open-label Treatment Period Analysis Set 
The open-label analysis set (OLAS) will consist of all subjects who receive at least 
1 dose of erenumab in the OLTP. This analysis set will be used to summarize data 
collected during the OLTP.  
7. 
Planned Analyses 
Data will be subject to ongoing checks for integrity, completeness and accuracy 
in accordance with the Data Management Plan with the expectation that  
outstanding data issues are resolved ahead of the lock to the extent possible for 
the primary analysis and all outstanding data issues are resolved ahead of the 
final lock. The data supporting the primary analysis will be locked to prevent 
further changes. 
7.1 
Primary Analysis 
The primary analysis will be performed when all randomized subjects in the 
nonopioid-treated cohort have completed the week 24/ET assessments during the 
DBTP, and all data are collected for the primary endpoint. All available data up to and 
including the data cutoff date will be cleaned and locked. At the time of primary 


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analysis, the DBTP treatment assignment for this cohort will be unblinded to selected 
staff of the sponsor conducting the analysis. If data collection for all subjects in the 
opioid-treated cohort for the DBTP is also complete, the DBTP treatment assignment for 
this cohort will also be unblinded. Study subjects, investigators, and remaining sponsor 
staff will remain blinded to original DBTP treatment assignment until study completion.  
All efficacy analyses and safety analyses will be conducted for the DBTP.  Safety data 
collected during the OLTP before the data cutoff date for the primary analysis will also 
be summarized. 
7.2 
Final Analysis 
The final analysis will be performed after all subjects (nonopioid-treated and opioid- 
treated) have completed the study through the week-52/EOS visit. The final analysis 
will be performed based on the final cleaned and locked data. 
8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses. This study will use the RAVE 
database as well as eDiary data outside of RAVE database. 
8.3 
Handling of Missing and Incomplete Data 
Subjects may miss specific data points for a variety of reasons.  In general, data could 
be missing due to a subject’s early withdrawal from the study, a missed visit, or inability 
to evaluate an endpoint at a particular point in time.  For this study, efficacy endpoints 
are clinical outcome assessments (COAs) collected via daily eDiary or monthly 
assessments at the office visits. Missing COAs with respect to quality-of-life 
questionnaires (MPFID, HIT-6, MFIQ, MIDAS, Sleep questionnaire, Allodynia symptom 
checklist, BDI-II, GAD-7 and PGIC) will not be imputed. Missing items in each eCOA 
questionnaire will be handled based on the scoring algorithm for each COA. 
Subjects could miss entering several days of data in eDiary within each monthly interval. 
The calculation of monthly measurements about subjects’ migraine and non-migraine 
headaches will be handled using the following method, also described in Section 5.1.1.  
 
For each monthly interval with  14 days of eDiary use:  


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 
Monthly frequency measurements will be prorated to 28-day equivalents.  
Prorated result does not need to be rounded. 
 
Monthly average scores will be calculated as the average of observed scores. 
 
For monthly intervals with  14 days of eDiary use, all monthly measurements will be 
set as missing. 
Missing safety endpoints will not be imputed except for partial AE start dates. Missing 
or incomplete dates will be listed as reported, except for incomplete start date of an AE 
or concomitant medication, which will be imputed as follows: 
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 
— 
Similarly, incomplete dates of HRU will be imputed using the same imputation rule as 
above. 
8.3.1 
Missing Baseline Evaluation 
Missing baseline evaluations will not be imputed. 
All subjects included in the efficacy analysis set will have baseline monthly rate or 
monthly average of migraine and non-migraine headaches related measurements after 
applying proration rule defined in Section 5.1.1 since only subject with ≥ 80% 
compliance of eDiary use during baseline will be eligible for randomization. 
8.3.2 
Missing Post-baseline Evaluation in Double-blind Treatment Period 
Primary analysis of dichotomous efficacy endpoints during the DBTP will be conducted 
using Cochran-Mantel-Haenszel test (CMH) after the missing data are imputed as 
nonresponse. Primary analysis of continuous efficacy endpoints during the DBTP will be 
conducted using the repeated measures linear mixed effects model including observed 
data without imputation. 
For the descriptive summary of mean monthly value calculated using the monthly value 
from each of months 4, 5, and 6 (week 13 through 24) of the DBTP, if a subject has at 
least one monthly value at months 4, 5, and 6 (week 13 through 24), then the subject 
contributes to the summary statistics.   


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If the proportion of missing data in primary endpoint is high (eg, > 20% for primary 
analysis at week 24), further analysis will be performed to  
 
examine the frequency and reason of missing data 
 
determine if there are any patterns in the missing data 
 
distinguish true missing values from other unknown values (eg, due to 
measurement or sample processing error) 
8.3.3 
Missing Post-baseline Evaluation in Open-label Treatment Period 
For the descriptive summary of mean monthly value calculated using the monthly 
value from each of months 11, 12, and 13 (week 41 through 52) of the DBTP, if a 
subject has at least one monthly value at months 11, 12, and 13 (week 13 through 
24), then the subject contributes to the summary statistics.   
 
8.4 
Detection of Bias 
This study has been designed to minimize potential bias by allocating treatment groups 
randomly, assessing endpoints and handling withdrawals without knowledge of the 
treatment. Other factors that may bias the results of the study include:  
 
important protocol deviations likely to impact the analysis and interpretation of 
the efficacy endpoints  
 
inadvertent breaking of the blind before formal unblinding  
 
investigational product dosing non-compliance  
 
the timing of and reasons for early withdrawal from treatment and from study  
The incidence of these factors may be assessed. Important protocol deviations will be 
listed and/or tabulated in the clinical study report (CSR). If necessary, the incidence of 
other factors will be tabulated.  
Any breaking of the blind for individual subjects prior to formal unblinding of the study will 
be documented in the CSR.  
The timing of and reasons for early withdrawal from treatment and from study will be 
tabulated and/or listed. 
8.5 
Outliers 
Histograms will be examined to identify outliers in any of the continuous variables used 
in the analyses. Unexpected and/or unexplained values in categorical data will be 
identified by utilizing frequency tables.  
Outliers due to data entry errors will be corrected by the study team before final 
database lock. The validity of any questionable values or outliers will be confirmed. 


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Outliers or any questionable values with confirmed validity will be included in the 
analyses. However, ad-hoc sensitivity analyses may be conducted to evaluate the 
influence of extreme values in the data. 
8.6 
Distributional Characteristics 
Continuous endpoints of change from baseline value will be analyzed under normality 
assumption. If they deviate appreciably from normality, appropriate transformations or 
the non-parametric alternatives will be used, such as Quade test (Quade D, 1966).  
8.7 
Validation of Statistical Analyses 
Programs will be developed, maintained, and output will be verified in accordance with 
current risk-based quality control procedures.   
Tables, figures, and listings will be produced and validated in accordance with SOP-
430399. Standard macros programs will be used when available.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
higher. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Formal statistical analyses using statistical models and hypothesis testing will be 
performed for the nonopioid-treated cohort only. Descriptive statistics will be produced 
for the opioid-treated cohort. The classification of cohorts (opioid-treated and 
nonopioid-treated) used for the primary analysis will be based on the cohort value 
determined at randomization. As sensitivity analysis, the primary endpoint, 
secondary endpoints, and change from baseline in mean monthly opioid/opioid-
containing medication days will be summarized descriptively for the ‘observed’ 
opioid-treated subjects who reported >4 days of opioid medication use in the 
eDiary data during the last 28 days of baseline period. 
Summary statistics will be computed by treatment group and visit.  For continuous 
endpoints, the following descriptive statistics will be computed: number of observations, 
means, medians, standard deviations, standard errors, first and third quartiles, 
minimums and maximums, and 2-sided 95% CIs of the means (CIs will be provided for 
efficacy endpoints only).  For categorical endpoints, the summaries will contain the 
number and percentage of subjects in each category. 


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The dichotomous efficacy endpoints will be analyzed using the stratified 
Cochran-Mantel-Haenszel (CMH) test after the missing data is imputed as nonresponse.  
Continuous secondary endpoints will be analyzed using a linear mixed effects model 
including treatment group, baseline value, stratification factor, scheduled visit, and the 
interaction of treatment group with scheduled visit, without any imputation for missing 
data at the monthly level. In case more than 10% subjects had stratification error 
within non-opioid treated cohort (ie. stratified incorrectly between the with vs. 
without concomitant oral migraine preventive medication strata), sensitivity 
analysis will be conducted for the model-based analysis for primary and 
secondary endpoints, using the ‘observed’ concomitant oral migraine preventive 
medication reported by site as strata in CMH tests. 
The 2 erenumab dose groups will be compared with placebo for the primary and 
secondary efficacy endpoints in the nonopioid-treated cohort using a simple fixed 
sequence procedure with study-wise type I error rate  = 0.05.  The order of the 
endpoints to be tested is prespecified below. If any test is not significant at the  = 0.05 
level, then no further testing will be performed.   
Primary and secondary endpoints in erenumab 140 mg versus placebo: 
1. Absence of MOH at month 6 of DBTP (140 mg) 
2. Change from baseline in mean monthly AHMD over months 4, 5, and 6 (week 13 
through 24)  of the DBTP (140 mg) 
3. Sustained MOH remission during DBTP (140 mg)  
Primary and secondary endpoints in erenumab 70 mg versus placebo: 
4. Absence of MOH at month 6 of the DBTP (70 mg) 
5. Change from baseline in mean monthly AHMD over months 4, 5, and 6 (week 13 
through 24) of the DBTP (70 mg) 
6. Sustained MOH remission during DBTP (70 mg)  
Patient reported outcome-related secondary endpoints for the non-EU region (United 
States, Australia): 
7. Change from the baseline in mean monthly average physical impairment domain 
scores as measured by the MPFID over months 4, 5, and 6 of the DBTP (140 mg) 
8. Change from the baseline in mean monthly average impact on everyday activities 
domain scores as measured by the MPFID over months 4, 5, and 6 of the DBTP 
(140 mg) 
9. Change from the baseline in mean monthly average physical impairment domain 
scores as measured by the MPFID over months 4, 5, and 6 of the DBTP (70 mg) 


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10. Change from the baseline in mean monthly average impact on everyday activities 
domain scores as measured by the MPFID over months 4, 5, and 6 of the DBTP 
(70 mg) 
OR 
Patient reported outcome-related secondary endpoints for the EU region (including 
United Kingdom): 
11. Change from baseline in mean HIT-6 score over months 4, 5, and 6 (week 13 
through 24) of the DBTP (140 mg) 
12. Change from baseline in mean HIT-6 score over months 4, 5, and 6 (week 13 
through 24) of the DBTP (70 mg) 
Analysis for efficacy endpoints during the OLTP will be summarized separately for 
nonopioid-treated and opioid-treated cohorts. 
9.2 
Subject Accountability 
For the primary analysis at week-24 the disposition of all enrolled subjects will be 
tabulated by the randomized treatment group. The summary will include the number of 
subjects who are randomized, the number and percent of subjects who receive the 
double-blind IP, who complete double-blind IP, discontinue double-blind IP and reasons 
for discontinuing, who complete the 24-week DBTP, and who withdraw prematurely from 
the study before completion of the 24-week DBTP and their reasons for withdrawal. 
Summary of subjects who discontinue investigational product/study due to 
COVID-19 control measures will be included. 
For the primary and final analysis, disposition of the OLTP and the entire study will be 
tabulated, which includes the number and percent of subjects who enter the OLTP, who 
receive the open-label erenumab who complete open-label erenumab, discontinue 
erenumab and reasons for discontinuing, who complete the study, and who withdraw 
prematurely from the study and their reasons for withdrawal. Summary of subjects 
who discontinue investigational product/study due to COVID-19 control measures 
will be included. 
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to database lock. These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the course of the study. Eligibility deviations are defined 
in the protocol. IPDs will be summarized by randomized treatment group. Protocol 


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Deviations (PDs) related to COVID-19 control measures will be summarized 
separately. 
9.4 
Demographic and Baseline Characteristics 
Subject demographic and baseline characteristics will be summarized using descriptive 
statistics by randomized treatment group and overall study population using FAS. If 
multiple races have been reported for a subject, the subject will be categorized as 
multiple races. 
At double-blinded baseline, following demographic and baseline characteristics will be 
summarized:  
 
Age (years) 
 
Sex 
 
Ethnicity 
 
Race 
 
Region (North America vs Others) 
 
Height (cm) 
 
Weight (kg) 
 
Body mass index (BMI, kg/m2) 
 
Targeted neurological disease diagnosis at baseline 
 
Prior history of treatment with onabotulinumtoxinA 
 
Prior history of depression 
 
Disease duration of migraine with or without aura 
 
Disease duration of chronic migraine with or without aura 
 
Age at onset of migraine 
 
Age at onset of chronic migraine 
 
Prior migraine preventive treatment and reasons for discontinuation by 
medication category 
 
Concomitant oral migraine preventive treatment by by medication category 
 
Number of prior migraine preventive treatment failures by medication 
category 
 
Acute headache medication used during baseline period:  
a) Migraine-specific 
b) Non-migraine-specific 
 
Monthly migraine days during baseline period 
 
Monthly migraine-free days during baseline period 
 
Monthly headache days during baseline period 


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 
Monthly headache days with at least moderate pain intensity during baseline 
period 
 
Monthly acute migraine-specific medication days during baseline period 
 
Monthly acute migraine-specific medication days during baseline period among 
baseline users 
 
Monthly acute headache medication days during baseline period 
 
Monthly opioid/opioid-containing medication days (opioid-treated cohort 
only) 
 
Overuse of acute headache medication during the baseline period 
 
Overuse of triptan during the baseline period 
 
Overuse of simple analgesics/NSAIDs during the baseline period 
 
Overuse of combination analgesics during the baseline period 
 
Overuse of combination therapies during the baseline period 
 
Monthly average headache pain intensity during baseline period 
 
Monthly average MPFID physical impairment score during baseline period 
 
Monthly average MPFID overall impact on everyday activities score during 
baseline period 
 
Beck Depression Inventory (BDI)-II total score severity grade 
 
Headache Impact Test (HIT-6) total score 
 
MFIQ impact on physical functioning 
 
MFIQ impact on usual activities 
 
MFIQ overall impact on usual activities 
 
MFIQ impact on social functioning 
 
MFIQ impact on emotional functioning 
 
Allodynia Symptoms as measured by the Allodynia Symptoms Checklist 12-items 
(ASC-12)  
 
Migraine Disability Assessment Questionnaire MIDAS) total score 
 
Migraine Disability Assessment Questionnaire (MIDAS) presenteeism score 
 
Migraine Disability Assessment Questionnaire (MIDAS) total score 
 
Generalized Anxiety Disorder 7-Item Scale (GAD-7) score 
9.5 
Efficacy Analyses 
The primary analysis of efficacy endpoints during the DBTP will utilize the efficacy 
analysis set.  Subjects will be analyzed according to their randomized treatment group 
regardless of the actual treatment received during the study. 


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Table 9-1.  Primary Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and 
Analysis Method  
Sensitivity Analysis 
Absence of MOH at month 6 
(week 24) as defined by mean 
monthly AHMD < 10 days over 
months 4, 5, and 6 (week 13 
through 24) OR mean MHD 
< 14 days over months 4, 5 
and 6 (week 13 through 24) 
where AHMD include any 
eDiary day in which an acute 
headache medication intake is 
reported. 
1. The responder rate of 
subjects with absence of 
MOH by treatment group 
with missing data 
imputed as non-
response imputation 
(NRI) 
2. A stratified CMH test 
with NRI adjusted by 
original stratified values 
3. Breslow-Day test will be 
conducted to test the 
homogeneity of the 
odds ratios across the 
original stratification 
factors 
1. Same as primary 
analysis method but 
using observed 
concomitant oral 
preventive medication 
status as the 
stratification factor. 
2. Same as primary 
analysis method but 
only include subjects 
with observed monthly 
AHMD and MHD in 
each of the month over 
month 4, 5 and 6  
 
Table 9-2.  Secondary Efficacy Endpoints Summary Table 
Endpoint 
Primary Summary and 
Analysis Method 
Sensitivity Analysis 
1. Change from baseline in 
mean monthly AHMD over 
months 4, 5, and 6 (week 
13 through 24) of the 
DBTP 
 
(Note: Result at each 
timepoint during DBTP will 
also be generated in the 
same model.) 
1. Summary statistics by 
visit using observed data 
and 95% CI of mean 
change from baseline at 
each visit by treatment 
group 
2. Least squares means by 
visit using a linear mixed 
effects repeated measure 
model adjusted by 
baseline value, original 
stratification factor, 
scheduled visit, and the 
interaction of treatment 
group with scheduled 
visit, without any 
imputation for missing 
data at monthly level 
3. Treatment difference 
between each erenumab 
dose group and placebo) 
with the 95% CI, and 
p-value from the model 
in #2 
Least squares means by 
visit using a linear mixed 
effects repeated measure 
model adjusted by 
baseline value, observed 
concomitant oral migraine 
preventive medication 
status, scheduled visit, 
and the interaction of 
treatment group with 
scheduled visit, without 
any imputation for missing 
data at monthly level 


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Endpoint 
Primary Summary and 
Analysis Method 
Sensitivity Analysis 
2. Sustained MOH remission 
during DBTP, as defined 
by absence of MOH at 
months 3 (week 12) and 6 
(week 24) of the DBTP, 
and “absence of MOH” is 
achieved when mean 
monthly AHMD < 10 days 
OR mean MHD < 14 days 
over the respective 
3-month period 
Same as primary endpoint 
Same as primary analysis 
method but using 
observed concomitant oral 
preventive medication 
status as stratification 
factor. 
3. Change from baseline in 
mean monthly average 
physical impairment 
domain scores as 
measured by the MPFID 
over months 4, 5, and 6 
(week 13 through 24) of 
the DBTP (non-EU region) 
4. Change from baseline in 
mean monthly average 
impact on everyday 
activities domain scores 
as measured by the 
MPFID over months 4, 5, 
and 6 (week 13 through 
24) of the DBTP (non-EU 
region) 
5. Change from baseline in 
mean HIT-6 total score 
over months 4, 5, and 6 
(week 13 through 24) of 
the DBTP (EU region) 
(Note: Result at each 
timepoint during DBTP will 
also be generated in the 
same model.) 
Same as above 
Same as above 
 
9.5.1 
Analyses of Primary Efficacy Endpoint 
The primary comparison of absence of MOH at month 6 between each erenumab group 
and placebo will be analyzed using a stratified CMH test with nonresponse imputation. 
The proportion of subjects with absence of MOH will be reported for each treatment 
group. The odds ratio between each erenumab group and placebo, the corresponding 
95% Cl and p-value will be reported. Breslow-Day test will be conducted to test the 
homogeneity of the odds ratios across the strata. 


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As a supportive analysis, the primary efficacy endpoint will also be analyzed including 
subjects with observed AHMD and MHD data at each month during months 4, 5, and 6 
(week 13 through 24).   
9.5.2 
Analyses of Secondary Efficacy Endpoints 
The continuous secondary endpoints will be analyzed using a linear mixed effects 
repeated measure model will include treatment group, baseline value, stratification 
factor, scheduled visit, and the interaction of treatment group with scheduled visit, 
without any imputation for missing data. If applicable, the first-order autoregressive 
covariance structure is assumed. Least squares means (LSMs) for each treatment 
group, standard errors, associated 95% confidence intervals, difference of LSMs 
compared to placebo group, associated 95% confidence intervals and nominal two-sided 
p-values will be tabulated by visit.  
The dichotomized secondary endpoint will be analyzed using the same method as for 
the primary endpoint in Section 9.5.1. 
9.5.3 
Analyses of Exploratory Efficacy Endpoints in Double-blind 
Treatment Period 
For exploratory efficacy endpoints during the DBTP, summary statistics and analysis 
method will be conducted in the same way as that for the primary and secondary 
efficacy endpoints as described in Section 9.5.1 and in Section 9.5.2. No sensitivity 
analysis is planned for exploratory endpoints except the sensitivity analysis for 
opioid-treated cohort as specified in section 9.1. For continuous endpoints 
collected only at one or two timepoints post-baseline during the DBTP, analysis of 
covariance (ANCOVA) adjusting baseline value and stratification factor will be 
used instead. BDI-II and PGIC will be summarized by category score using 
observed data. The shift from baseline in severity category score of BDI-II will be 
analyzed at week 12 and week 24 using observed data. 
9.5.4 
Analyses of Exploratory Efficacy Endpoints in Open-label Treatment 
Period 
For the OLTP of the study, descriptive summaries of efficacy endpoints will be tabulated 
by visit based on observed data without imputation.  
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s)  
For safety endpoints during the DBTP, all randomized subjects who received at least 
one dose of investigational product (ie, Safety Analysis Set) will be analyzed based on 


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the randomized treatment unless a subject has received the incorrect dose during the 
entire period of interest (treatment period or study). Safety analyses will be repeated for 
the non-opioid treated cohort, opioid-treated cohort, and overall. For safety analyses of 
vital signs in OLTP, descriptive summaries of change from baseline values will be 
tabulated based on observed data using pre-OLTP baseline. 
No statistical testing comparing treatment groups will be performed in the safety 
analyses. 
9.6.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 25.1 or later will be 
used to code all events categorized as adverse events to a system organ class and a 
preferred term. All AEs will be graded using the Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.03.  All AE summary tables described below will be 
summarized by treatment group using subject incidence for the DBTP and be repeated 
using exposure-adjusted subject incidence for the DBTP and the OLTP. 
The subject incidence of AEs will be summarized by SOC in alphabetical order and PT 
in descending order of frequency for all treatment-emergent adverse events (TEAEs), 
serious AEs, serious TEAE occuring on or after the COVID infection, AEs leading to 
discontinuation of investigational product, fatal AEs, device-related AEs, and adverse 
events of interest (EOI) including  
 
Ischaemic Central Nervous System Vascular Conditions SMQ (Narrow) 
 
Ischaemic Heart Disease SMQ (Narrow and Broad) 
 
Peripheral Arterial Disease AMQ (Narrow) 
 
Hypertension SMQ (Narrow and Broad)  
 
Constipation AMQ (Narrow and Broad) 
 
Alopecias AMQ (Broad) 
 
COVID-19 SMQ (Narrow) 
Subject incidence of EOI (standardized MedDRA queries [SMQ] and/or Amgen medical 
queries [AMQ]) will also be summarized according to their categories by SOC in 
alphabetical order and PT in descending order of frequency.   
Subject incidence of all TEAEs, SAEs, AEs leading to withdrawal of investigational 
product, and fatal AEs will be tabulated by PT in descending order of frequency. In 
addition, summaries of all TEAEs occurring in at least 3% of the subjects by PT in any 
treatment arm will be provided by PT in descending order of frequency. 


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Summaries of all TEAEs and SAEs will be tabulated by SOC, PT, and grade.    
9.6.3 
Vital Signs 
The analyses of vital signs (systolic/diastolic blood pressure (SBP/DBP), and heart rate) 
will include summary statistics of change from baseline over time by treatment group. 
Subject incidence at each time-point within the following defined categories for each 
treatment period:  
 
Increase from baseline ≥ 10 mmHg in DBP with DBP > 90 mmHg 
 
Increase from baseline ≥ 10 mmHg in DBP with DBP ≤ 90 mmHg 
 
Increase from baseline ≥ 20 mmHg in SBP with SBP > 140 mmHg 
 
Increase from baseline ≥ 20 mmHg in SBP with SBP ≤ 140 mmHg 
 
Change from baseline in heart rate of ≥ 15 bpm (increase) or heart rate ≥ 120 bpm  
 
Change from baseline in heart rate of ≤ -15 bpm (decrease) or heart rate ≤ 50 bpm 
9.6.4 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to investigational product 
by treatment group and treatment period. 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 by treatment group. 
9.6.5 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving acute headache medications will be 
summarized by acute headache medication category for each treatment group. 
9.7 
Other Analyses 
9.7.1 
Analyses of Health Economic Endpoints 
Health Resource Utilization Questionnaire (HRU) 
The questionnaire is designed to collect data on HRU.  Specifically, the aim is to capture 
frequency of headache-related hospitalizations and outpatient visits including 
emergency department visits, urgent care visits, and other clinical visits. The recall 
period for the HRU questionnaire is 24 weeks, and the HRU questionnaire will be 
administered on day 1, and week 24 of the DBTP.  The questionnaire assessed at the 
early termination visit before week 24 should only include HRU recalled since the 
previous assessment at day 1 to avoid collecting duplicate information. 
10. 
Changes From Protocol-specified Analyses 
During the development of SAP amendment, it was realized that there are 
protocol-specified analyses that cannot be implemented/performed and the 


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protocol is not required to be amended. Ditans is included in the list of acute 
headache medications in Section 5.1. The definition of efficacy analysis set stated 
in the protocol is not applicable to all efficacy endpoints and has been corrected 
in Section 6.2 to what was intended. These changes will also be documented in 
the clinical study report. 
11. 
Literature Citations / References 
Quade, D. (1966), Rank analysis of covariance, University of North Carolina, Institute of Statistics 
Mimeo Series. No 483. 


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


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13. 
Appendices 
Not applicable