Clinical trial NCT04265755
Conditions: Migraine
Keywords: Episodic and Chronic Migraine Link between clinical response and biomarker Phase 4
Sponsor: Amgen
Start date: 2020-10-26; Completion date: 2023-01-18
Enrollment: 1406 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To explore the relationship between clinical response to erenumab and genetic biomarkers

Detailed description:
This is a phase 4 open-label study aiming to explore the relationship between clinical response to erenumab and genetic biomarkers.

Subjects with episodic or chronic migraine will be treated with Erenumab 70mg or 140mg for a 4-week baseline/screening period, followed by a 24-week treatment period.

Subjects will collect migraine-related parameters daily using an eDiary and blood samples will be collected for biomarker research. All analysis will be descriptive in nature.

Arms: arm 1: Erenumab packed in a SureClick® Autoinjector Pen (AI)
Interventions: intervention 1: Erenumab
Intervention descriptions: intervention 1: Erenumab 70 mg or 140 mg packed in a SureClick® Autoinjector Pen (AI).

Protocol documents:
Prot_000.pdf: 
Product:  Erenumab 
Protocol Number:  20190006 
Date:  23 February 2022 
Page 1 of 76 
CONFIDENTIAL  
FORM-001520, v.22, 05 February 2018 
 
Title Page 
Protocol Title: 
Biomarker and Genetic Predictors of Erenumab 
Treatment Response, a Phase 4 Investigational 
Open-label Study (INTERROGATE) 
Short Protocol Title: 
INTERROGATE 
Protocol Number: 
20190006 
Investigational Product: 
Erenumab 
Trade Name: 
AIMOVIG 
Sponsor 
Name of Sponsor: 
Amgen, Inc 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA, 91320, USA 
Telephone Number: 
+1 (805) 447-1000 
Protocol 
Approver 
Name: 
, MD 
Function: 
Governance Body Chair 
Key 
Sponsor 
Contact 
Name: 
, MD/PhD 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA, 91320, USA 
Telephone Number: 
 
Email Address: 
 
EudraCT Number: 
2019-002331-28 
NCT Number: 
NCT04265755 
Protocol Date: 
Document Version 
Date 
Original 
05 September 2019 
Amendment 1 (v2.0) 
01 February 2021 
Superseding 
Amendment 1 (v3.0) 
15 March 2021 
Amendment 2 (v4.0) 
23 February 2022 
Version/Date: 
Data Element Standards Version 
6.2 
This protocol was developed, reviewed, and approved in accordance with Amgen’s standard 
operating procedures. 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  23 February 2022 
Page 2 of 76 
CONFIDENTIAL  
FORM-001520, v.22, 05 February 2018 
 
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; Iceland sites, 354 570 1900; 
Denmark sites, 45 39 61 75 00; Amgen’s general number in the US, 1-805-447-1000. 
Investigator’s Agreement: 
I have read the attached protocol entitled Biomarker and Genetic Predictors of Erenumab 
Treatment Response, a Phase 4 Investigational Open-label Study (INTERROGATE), dated 
23 February 2022, and agree to abide by all provisions set forth therein.   
I agree to comply with the International Council for Harmonisation (ICH) Tripartite Guideline on 
Good Clinical Practice (GCP), Declaration of Helsinki, and applicable national or regional 
regulations/guidelines.   
I agree to ensure that the confidential information contained in this document will not be used 
for any purpose other than the evaluation or conduct of the clinical investigation without the 
prior written consent of Amgen Inc. 
 
_______________________________ 
Signature 
 
_______________________________ ____________________________ 
Name of investigator 
 
 
 
Date (DD Month YYYY) 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  23 February 2022 
Page 3 of 76 
CONFIDENTIAL  
FORM-001520, v.22, 05 February 2018 
 
Table of Contents 
Table of Contents ................................................................................................................... 3 
1. 
Protocol Summary ................................................................................................................. 7 
1.1 
Protocol Synopsis ...................................................................................................... 7 
1.2 
Study Schema .......................................................................................................... 10 
1.3 
Schedule of Activities .............................................................................................. 11 
2. 
Introduction ......................................................................................................................... 16 
2.1 
Study Rationale ....................................................................................................... 16 
2.2 
Background ............................................................................................................. 16 
2.2.1 
Disease .................................................................................................. 16 
2.2.2 
Amgen Investigational Product Background:  Erenumab  .................... 17 
2.3 
Benefit/Risk Assessment ......................................................................................... 17 
3. 
Objectives, Endpoints and Hypotheses................................................................................ 18 
3.1 
Objectives and Endpoints ....................................................................................... 18 
3.2 
Hypothesis............................................................................................................... 21 
4. 
Study Design......................................................................................................................... 21 
4.1 
Overall Design ......................................................................................................... 21 
4.2 
Number of Subjects ................................................................................................ 22 
4.2.1 
Replacement of Subjects ....................................................................... 22 
4.2.2 
Number of Sites ..................................................................................... 22 
4.3 
End of Study ............................................................................................................ 22 
4.3.1 
End of Study Definition ......................................................................... 22 
4.3.2 
Study Duration for Subjects .................................................................. 22 
4.4 
Justification for Investigational Product Dose ........................................................ 23 
4.5 
Patient Input on Study Design ................................................................................ 23 
5. 
Study Population .................................................................................................................. 23 
5.1 
Inclusion Criteria ..................................................................................................... 23 
5.2 
Exclusion Criteria..................................................................................................... 23 
5.3 
Subject Enrollment .................................................................................................. 25 
5.4 
Screen Failures ........................................................................................................ 25 
6. 
Treatments ........................................................................................................................... 25 
6.1 
Treatment Procedures ............................................................................................ 26 
6.1.1 
Investigational Products ........................................................................ 26 
6.1.2 
Non-investigational Products ................................................................ 26 
6.1.3 
Medical Devices..................................................................................... 27 
6.1.4 
Other Protocol-required Therapies ....................................................... 27 
6.1.5 
Other Treatment Procedures ................................................................ 27 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  23 February 2022 
Page 4 of 76 
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FORM-001520, v.22, 05 February 2018 
 
6.1.6 
Product Complaints ............................................................................... 27 
6.1.7 
Excluded Treatments, Medical Devices, and/or Procedures 
During Study Period .............................................................................. 28 
6.2 
Method of Treatment Assignment ......................................................................... 28 
6.3 
Blinding ................................................................................................................... 28 
6.4 
Dose Modification ................................................................................................... 28 
6.4.1 
Dose-cohort Study Escalation/De-escalation and Stopping 
Rules ...................................................................................................... 28 
6.4.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ............................................... 29 
6.4.2.1 
Amgen Investigational Product:  Erenumab ..................... 29 
6.5 
Preparation/Handling/Storage/Accountability ....................................................... 29 
6.6 
Treatment Compliance ........................................................................................... 29 
6.7 
Treatment of Overdose ........................................................................................... 29 
6.8 
Prior and Concomitant Treatment .......................................................................... 29 
6.8.1 
Prior Treatment ..................................................................................... 29 
6.8.2 
Concomitant Treatment ........................................................................ 30 
7. 
Discontinuation Criteria ....................................................................................................... 30 
7.1 
Discontinuation of Study Treatment ...................................................................... 30 
7.2 
Discontinuation From the Study ............................................................................. 31 
7.2.1 
Reasons for Removal From Washout, Run-in or Invasive 
Procedures ............................................................................................ 31 
7.2.2 
Reasons for Removal From Study ......................................................... 31 
7.3 
Lost to Follow-up .................................................................................................... 32 
8. 
Study Assessments and Procedures..................................................................................... 32 
8.1 
General Study Periods ............................................................................................. 32 
8.1.1 
Screening ............................................................................................... 32 
8.1.2 
Baseline Period ...................................................................................... 33 
8.1.3 
Treatment Period .................................................................................. 33 
8.1.4 
End of Study .......................................................................................... 33 
8.2 
Description of General Study Assessments and Procedures .................................. 33 
8.2.1 
General Assessments ............................................................................ 34 
8.2.1.1 
Informed Consent ............................................................. 34 
8.2.1.2 
Demographics ................................................................... 34 
8.2.1.3 
Medical History ................................................................. 34 
8.2.2 
Efficacy Assessments ............................................................................. 35 
8.2.2.1 
Clinical Outcome Assessments and Electronic 
Diaries ............................................................................... 35 
8.2.3 
Safety Assessments ............................................................................... 35 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  23 February 2022 
Page 5 of 76 
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8.2.3.1 
Adverse Events and Serious Adverse Events .................... 36 
8.2.3.2 
Safety Monitoring Plan ..................................................... 38 
8.2.4 
Clinical Laboratory Assessments ........................................................... 39 
8.2.4.1 
Pregnancy Testing ............................................................. 39 
8.2.5 
Biomarkers ............................................................................................ 39 
8.2.5.1 
Biomarker Research .......................................................... 39 
8.2.5.2 
Optional CGRP Biomarker Substudy ................................. 40 
9. 
Statistical Considerations ..................................................................................................... 40 
9.1 
Sample Size Determination ..................................................................................... 40 
9.2 
Analysis Sets, Subgroups, and Covariates ............................................................... 41 
9.2.1 
Analysis Sets .......................................................................................... 41 
9.2.1.1 
Full Analysis Set ................................................................ 41 
9.2.1.2 
Observed Data Analysis Set .............................................. 41 
9.2.1.3 
Efficacy Analysis Set .......................................................... 41 
9.2.1.4 
Safety Analysis Set ............................................................ 41 
9.2.2 
Covariates .............................................................................................. 41 
9.2.3 
Subgroups .............................................................................................. 41 
9.2.4 
Handling of Missing and Incomplete Data ............................................ 42 
9.3 
Statistical Analyses .................................................................................................. 42 
9.3.1 
Planned Analyses................................................................................... 43 
9.3.1.1 
Primary Analysis ............................................................... 43 
9.3.2 
Methods of Analyses ............................................................................. 43 
9.3.2.1 
General Considerations .................................................... 43 
9.3.2.2 
Efficacy Analyses ............................................................... 43 
9.3.2.3 
Safety Analyses ................................................................. 44 
10. 
References ........................................................................................................................... 45 
11. 
Appendices ........................................................................................................................... 46 
11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms .................................. 47 
11.2 
Appendix 2.  Clinical Laboratory Tests .................................................................... 49 
11.3 
Appendix 3.  Study Governance Considerations ..................................................... 50 
11.3.1 
Regulatory and Ethical Considerations ................................................. 50 
11.3.2 
Recruitment Procedures ....................................................................... 51 
11.3.3 
Informed Consent Process .................................................................... 51 
11.3.4 
Data Protection/Subject Confidentiality ............................................... 52 
11.3.5 
Publication Policy .................................................................................. 53 
11.3.6 
Investigator Signatory Obligations ........................................................ 53 
11.3.7 
Data Quality Assurance ......................................................................... 54 
11.3.8 
Source Documents ................................................................................ 55 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  23 February 2022 
Page 6 of 76 
CONFIDENTIAL  
FORM-001520, v.22, 05 February 2018 
 
11.3.9 
Study and Site Closure........................................................................... 56 
11.3.10 
Compensation ....................................................................................... 56 
11.4 
Appendix 4.  Safety Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting ...................................................................... 57 
11.4.1 
Definition of Adverse Event .................................................................. 57 
11.4.2 
Definition of Serious Adverse Event ...................................................... 58 
11.4.3 
Definition of Adverse Device Effect ...................................................... 58 
11.4.4 
Recording Adverse Events and Serious Adverse Events ....................... 59 
11.4.5 
Evaluating Adverse Events and Serious Adverse Events ....................... 60 
11.4.6 
Reporting of Serious Adverse Event ...................................................... 61 
11.4.7 
Adverse Device Effects:  Recording, Evaluating and 
Reporting .............................................................................................. 61 
11.5 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy and 
Lactation Information ............................................................................................. 69 
11.5.1 
Definition of Females of Childbearing Potential ................................... 69 
11.5.2 
Unacceptable Methods of Birth Control for Female 
Subjects ................................................................................................. 70 
11.5.3 
Collection of Pregnancy Information .................................................... 70 
11.5.4 
Collection of Lactation Information ...................................................... 71 
11.6 
Appendix 6.  Sample Storage and Destruction ....................................................... 75 
 
List of Tables 
Table 1.  Schedule of Activities ...................................................................................................... 11 
Table 2.  CGRP Biomarker Substudy Schedule of Assessments ..................................................... 15 
Table 3.  Study Treatments ............................................................................................................ 26 
Table 4.  Imputation for Incomplete Start Date of an Adverse Event or Concomitant 
Medication ........................................................................................................... 42 
Table 5.  Analyte Listing ................................................................................................................. 49 
 
List of Figures 
Figure 1-1.  Study Schema .............................................................................................................. 10 
Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Form .................................. 63 
Figure 11-2.  Pregnancy and Lactation Notification Worksheet .................................................... 73 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  23 February 2022 
Page 7 of 76 
CONFIDENTIAL  
FORM-001520, v.22, 05 February 2018 
 
1. 
Protocol Summary 
1.1 
Protocol Synopsis 
Protocol Title:  Biomarker and Genetic Predictors of Erenumab Treatment Response, a Phase 4 
Investigational Open-label Study (INTERROGATE) 
Short Protocol Title:  INTERROGATE 
Study Phase:  4 
Indication:  episodic or chronic migraine 
Rationale 
Migraine is a clinically heterogeneous disorder with polygenic influences that can be 
summarized as a migraine polygenic risk score (mPRS).  It is thought that the spectrum of 
pathophysiologies (eg, presence of aura, menstrual relatedness), the variable temporal onset 
and severity of disease, and responsiveness/non-responsiveness to acute or prophylactic 
migraine medications might reflect the fact that many different genes contribute to migraine 
risk and its phenotypic manifestations.  Preliminary post-hoc analysis of erenumab-treated 
subjects with episodic or chronic migraine (EM or CM) has revealed an association of mPRS with 
several disease characteristics, such as the use of acute migraine-specific and prophylactic 
medications.  The overarching objective of this study is to explore the potential association of 
several biomarker platforms, including DNA (single-nucleotide polymorphisms [SNPs], including 
those comprising the mPRS), RNA, proteomics, and plasma calcitonin gene-related peptide 
(CGRP) levels, with erenumab treatment response.   
Objective(s)/Endpoint(s) 
 
Objectives 
Endpoints 
Primary 
 
To explore the relationship between clinical 
response to erenumab and genetic 
biomarkers 
 
Achievement of at least a 50% reduction from 
baseline in mean monthly migraine days 
(MMD) over months 4, 5, and 6 in relation to 
each individual genome-wide significant 
single-nucleotide polymorphism (SNP) 
contributing to the migraine polygenic risk 
score (mPRS) 
 
Hypotheses 
No formal hypothesis testing will be performed.  All analyses will be descriptive in nature. 
Overall Design 
This is a phase 4 open-label study that will enroll subjects with EM or CM without a 
predetermined allocation ratio.  The study will comprise the following periods: 
 
A screening period of up to 3 weeks (21 days) for the assessment eligibility criteria.  The 
screening visit may be performed on the same day as the baseline visit 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  23 February 2022 
Page 8 of 76 
CONFIDENTIAL  
FORM-001520, v.22, 05 February 2018 
 
 
A baseline period of 4 weeks (28 up to 35 days) to collect data on migraine headaches and 
acute headache medication use using electronic diary (eDiary) and to assess compliance in 
eDiary usage at day 1 visit 
 
A 24-week open-label treatment period 
Subjects will be screened at the screening visit, and if eligible, subjects may enter the baseline 
period at the same visit as screening or may begin baseline procedures up to 3 weeks after the 
screening visit.  At completion of the baseline period, those who meet the eligibility criteria and 
demonstrate  75% compliance with eDiary use will be enrolled and will enter the open-label 
treatment period to receive either erenumab 70 mg or 140 mg subcutaneously (SC) every 4 
weeks (Q4W) at the discretion of the investigator. 
Number of Subjects 
Approximately 1400 subjects will be enrolled in the study; all subjects are to receive erenumab 
70 mg or 140 mg SC Q4W at the discretion of the investigator.  One dose adjustment is allowed 
at week 12 visit. 
Summary of Subject Eligibility Criteria 
Subjects eligible for study include those who are age  18 years, have a history of migraine (with 
or without aura) for  12 months before screening, have  4 headache days that meet criteria as 
migraine days per month on average across the 3 months before screening, and demonstrate  
75% compliance in eDiary usage during baseline period. 
For a full list of eligibility criteria, please refer to Section 5.1 to Section 5.2. 
Treatments 
Erenumab will be used according to the summary of product characteristics.  The dose of 
erenumab, either 70 mg or 140 mg SC Q4W, is to be determined at the investigator’s discretion 
and may be adjusted once during the study at the week 12 visit.  Erenumab will be packaged in a 
SureClick Autoinjector/Pen (AI)/Pens containing 1 mL of 70 mg/mL or 140 mg/mL of erenumab 
for SC injection.  The site staff is to dispense erenumab AI/Pens to subjects at the day 1 visit (for 
treatment on day 1, week 4, and week 8) and week 12 visit (for treatment at weeks 12, 16, and 
20).  At the day 1 and week 12 visit erenumab will be administered on site to subjects by site 
staff or by subject self-administration as the last procedure of the visit.  Administration will be 
performed by the subject or designee in a non-investigator site setting (eg, at home) at weeks 4, 
8, 16, and 20. 
Procedures 
After signing the informed consent and meeting the entry criteria to be assessed before the 
baseline period, subjects are to use an eDiary to collect migraine-related parameters daily at 
home during the baseline period.   
During the open-label treatment period, subjects will continue with their daily eDiary use and 
additionally complete the Migraine Functional Impact Questionnaire version 2.0 at required 
visits.  Blood samples will be collected for biomarker research.  Subjects who participate in the 
CGRP biomarker substudy will have 3 additional blood samples collected at weeks 4, 12, and 24.   
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 8.2 and the Schedule of Activities in Section 1.3. 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  23 February 2022 
Page 9 of 76 
CONFIDENTIAL  
FORM-001520, v.22, 05 February 2018 
 
Statistical Considerations 
The primary analysis will occur after all subjects have completed their week 24 or end of study 
visit. 
For the primary endpoint, a genome-wide association study (GWAS) of Icelandic and Danish 
data will be performed using logistic regression for binary phenotypes. Assuming an additive 
model, GWAS will be performed for the overall sample and by pre-specified subgroups, in 
addition to other phenotypes of interest that may be defined from the study data. Age and sex 
will be used as covariates in Icelandic associations and age, sex, and 10 principal components 
will be used as covariates (to account for population structure) in Danish data. We use linkage 
disequilibrium (LD)-score regression to account for inflation in test statistics due to cryptic 
relatedness and stratification. A likelihood-ratio test will be used to compute all P-values. The 
Icelandic and Danish GWAS will be meta-analyzed using a fixed effects model. Weighted 
Bonferroni adjustment will be used to maintain a family-wise error rate of 0.05 (2-sided) for the 
primary endpoint. Using summary statistics from these studies (excluding GWAS data from 
Denmark and Iceland), mPRS will be calculated for the individuals participating in the clinical 
trial by summing their identified risk alleles, weighted by effect sizes and accounting for linkage 
disequilibrium using the LDPred software package. This genetic marker analysis will include 
subjects with non-missing clinical responses (responder [yes/no] based on at least a 50% 
reduction from baseline in mean MMD over months 4, 5, and 6). 
For a full description of statistical analysis methods, please refer to Section 9. 
Sponsor Name: 
Amgen, Inc 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  23 February 2022 
Page 10 of 76 
CONFIDENTIAL  
FORM-001520, v.22, 05 February 2018 
 
1.2 
Study Schema 
Figure 1-1.  Study Schema 
Day 1
Week 24
Open-label Treatment Period (24 weeks)
70 mg or 140 mg SC Q4W
Week 12
Baseline 
Perioda
(28 up to 35 
days)
End of Study
Screening 
(-7 weeks) a
Biomarker sample 
collection for all subjects
Q4W = once every 4 weeks; SC = subcutaneous;
aScreening and baseline visits may be performed on the same day. 
bSubstudy subjects only.
cSite staff is to dispense doses at the day 1 visit (for treatment on day 1, week 4, and week 8) and week 12 visit (for treatment at weeks 12, 16, and 20). 
Erenumab dose 
dispensationc
Visits
Biomarker sample collection 
for subjects in substudy
Week 4b
Screening 
Perioda
(Up to 21 days)
Baseline
(-4 weeks)
 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  23 February 2022 
Page 11 of 76 
CONFIDENTIAL  
FORM-001520, v.22, 05 February 2018 
 
1.3 
Schedule of Activities 
 
Table 1.  Schedule of Activities 
Screeninga 
(up to 21 
days before 
baseline) 
Baselinea 
(28 [+7] 
days before 
day 1) 
Open-label Treatment Period (24 weeks) 
Notes 
Day 1 
visit 
Wk 4 
( 7 
days) 
Wk 8 
( 7 
days) 
Wk 
12 
( 7 
days) 
Wk 
16  
( 7 
days) 
Wk 
20  
( 7 
days) 
Wk 
24/EOSb 
( 7 days) 
GENERAL AND SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
X 
X 
 
 
 
 
 
 
Compliance with eDiary usage will be assessed prior to 
enrollment on day 1 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
Neurological medical 
history 
X 
 
 
 
 
 
 
 
 
 
Gastro-intestinal 
medical history 
X 
 
 
 
 
 
 
 
 
Includes gastro-intestinal procedures and surgeries 
medical history 
Headache and migraine 
frequency medical 
history 
X 
 
 
 
 
 
 
 
 
 
Prior migraine 
prophylactic 
medications review 
X 
X 
 
 
 
 
 
 
 
Includes all prior migraine prophylactic medications that 
ended 2 months before screening with no limit back in 
time. 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  23 February 2022 
Page 12 of 76 
CONFIDENTIAL  
FORM-001520, v.22, 05 February 2018 
 
Screeninga 
(up to 21 
days before 
baseline) 
Baselinea 
(28 [+7] 
days before 
day 1) 
Open-label Treatment Period (24 weeks) 
Notes 
Day 1 
visit 
Wk 4 
( 7 
days) 
Wk 8 
( 7 
days) 
Wk 
12 
( 7 
days) 
Wk 
16  
( 7 
days) 
Wk 
20  
( 7 
days) 
Wk 
24/EOSb 
( 7 days) 
Prior/concomitant 
therapies review 
X 
X 
X 
 
 
X 
 
 
X 
Includes all prior medications (other than prior migraine 
prophylactic medications) that were being taken/used 
within 120 days prior to screening through the signing of 
the informed consent and all concomitant medications 
including migraine prophylactic medications. 
Most recent date of 
menses 
X 
 
X 
 
 
X 
 
 
X 
Females of childbearing potential only 
Page 1 of 2 
Footnotes after last page of table 
 
Screeninga 
(up to 21 
days before 
baseline) 
Baselinea 
(28 [+7] 
days 
before 
day 1) 
Open-label Treatment Period (24 weeks) 
Notes 
Day 1 
visit 
Wk 4  
( 7 
days) 
Wk 8 
( 7 
days) 
Wk 12 
( 7 days) 
Wk 16  
( 7 
days) 
Wk 20  
( 7 
days) 
Wk 
24/EOSb 
( 7 days) 
SAFETY ASSESSMENTS 
Adverse events 
 
 
Adverse events collected from day 1 to EOS 
 
Serious adverse 
events 
Serious adverse events collected from screening to EOS 
Adverse device 
effects 
 
 
Adverse device effects collected from day 1 to EOS 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  23 February 2022 
Page 13 of 76 
CONFIDENTIAL  
FORM-001520, v.22, 05 February 2018 
 
Screeninga 
(up to 21 
days before 
baseline) 
Baselinea 
(28 [+7] 
days 
before 
day 1) 
Open-label Treatment Period (24 weeks) 
Notes 
Day 1 
visit 
Wk 4  
( 7 
days) 
Wk 8 
( 7 
days) 
Wk 12 
( 7 days) 
Wk 16  
( 7 
days) 
Wk 20  
( 7 
days) 
Wk 
24/EOSb 
( 7 days) 
LABORATORY ASSESSMENTS 
Urine pregnancy test  
X 
 
X 
 
 
X 
 
 
X 
Females of childbearing potential only.  Additional 
on-treatment pregnancy testing may be performed 
at the investigator’s discretion if there is suspicion 
that a female subject may be pregnant or per local 
laws and regulations. 
Hematology 
 
 
X 
 
 
X 
 
 
X 
 
BIOMARKER ASSESSMENTS 
Sample collection for 
biomarker research 
 
 
X 
 
 
X 
 
 
X 
Samples include DNA, RNA, CGRP, and proteomics 
analyses.  DNA and CGRP samples will be collected 
at day 1 visit only. However, DNA samples may be 
collected at a subsequent visit, if sample collection 
is not performed on day 1. 
CLINICAL OUTCOME ASSESSMENTS 
Instructions in eDiary 
use 
  
X 
 
 
 
 
 
 
 
 
eDiary 
 
Daily 
 
MFIQ 
 
 
X 
 
 
 
 
 
X 
 
STUDY TREATMENT 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  23 February 2022 
Page 14 of 76 
CONFIDENTIAL  
FORM-001520, v.22, 05 February 2018 
 
Screeninga 
(up to 21 
days before 
baseline) 
Baselinea 
(28 [+7] 
days 
before 
day 1) 
Open-label Treatment Period (24 weeks) 
Notes 
Day 1 
visit 
Wk 4  
( 7 
days) 
Wk 8 
( 7 
days) 
Wk 12 
( 7 days) 
Wk 16  
( 7 
days) 
Wk 20  
( 7 
days) 
Wk 
24/EOSb 
( 7 days) 
Erenumab 
dispensation/ 
administration at 
study site 
 
 
X 
 
 
X 
 
 
 
Day 1 and week 12 administration may be 
performed by site staff or by subject 
self-administration as the last procedure of the 
visit. 
Investigational product will be dispensed for weeks 
4 and 8 on day 1 and weeks 16 and 20 at week 12. 
Erenumab 
administration at 
non-investigational 
site setting 
 
 
 
X 
X 
 
X 
X 
 
Administration may be performed by the subject or 
designee in a non-investigative site setting (eg, at 
home) at weeks 4, 8, 16, and 20. 
Site staff 
reconciliation of 
dispensed erenumab 
 
 
 
 
 
X 
 
 
X 
Subject is to return empty AI/Pens and boxes at the 
wk 12 and wk 24 visits.  
Page 2 of 2 
AI = autoinjector; CGRP = calcitonin gene-related peptide; eDiary = electronic diary; EOS = end of study; MFIQ = Migraine Functional Impact Questionnaire;  
Wk = Week 
a Baseline may start on the same day as the screening visit. 
b A subject who discontinues the study during the open-label treatment period (before week 24) is to complete the assessments of the week 24/EOS visit. 


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Table 2.  CGRP Biomarker Substudy Schedule of Assessments 
 
Screeninga 
(up to 21 days 
before 
baseline) 
Baselinea 
(28 [+7] days 
before day 1) 
Open-label Treatment Period (24 weeks) 
Notes 
Day 1 
visit 
Wk 4  
( 7 
days) 
Wk 8  
(7 
days) 
Wk 12 
(7 
days) 
Wk 16  
(7 
days) 
Wk 20  
(7 
days) 
Wk 
24/EOSb 
(7 days) 
SCHEDULE OF ADDITIONAL ACTIVITIES FOR SUBJECTS THAT PARTICIPATE IN THE OPTIONAL CGRP BIOMARKER SUBSTUDY, THESE ACTIVITIES ARE TO BE 
PERFORMED IN ADDITION TO THE ACTIVITIES DETAILED IN TABLE 1) 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
Sample 
collection for 
CGRP 
 
 
 
X 
 
X 
 
 
X 
At Wk 4, Subjects are to be instructed to 
administer erenumab dose at non-
investigative site (eg, home) after the 
visit. 
CGRP = calcitonin gene-related peptide; EOS = end of study; Wk = Week 
a Baseline may start on the same day as the screening visit. 
b A subject who discontinues the study during the open-label treatment period (before week 24) is to complete the assessments of the week 24/EOS visit 
 


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2. 
Introduction 
2.1 
Study Rationale 
Migraine is a clinically heterogeneous disorder with polygenic influences that can be 
summarized as a polygenic risk score (PRS) (Chalmer et al, 2018).  A given individual’s migraine 
PRS (mPRS), derived from the presence/absence of independent single-nucleotide 
polymorphisms [SNPs], has been demonstrated to be significantly associated with migraine risk 
(Gormley et al, 2016), with higher scores indicating higher risk.  The mPRS SNPs are largely 
common (30 of the 38 of the primary SNP signals have an allele frequency  10%) with small 
effect sizes, but together contribute to genetic predisposition for migraine.  It is thought that the 
spectrum of pathophysiologies (eg, presence of aura, menstrual relatedness), the variable 
temporal onset and severity of disease, and responsiveness/non-responsiveness to acute or 
prophylactic migraine medications might reflect the fact that many different genes contribute to 
migraine risk and its phenotypic manifestations.  Preliminary post-hoc analysis of erenumab-
treated subjects with episodic or chronic migraine (EM or CM) has revealed an association of 
mPRS with several disease characteristics, such as the use of acute migraine-specific and 
prophylactic medications.  The overarching objective of this study is to explore the potential 
association of several biomarker platforms including (DNA [SNPs, including those comprising the 
mPRS], RNA, proteomics, and plasma calcitonin gene-related peptide [CGRP] levels) with 
erenumab treatment response. 
2.2 
Background 
2.2.1 
Disease 
Migraine is a disabling disorder characterized by primary recurrent headaches (referred to as 
attacks) lasting 4 to 72 hours (if not treated) with at least 2 of the following pain characteristics:  
unilateral, pulsating, moderate or severe intensity, or aggravated by routine physical activity.  
Migraine attacks are often accompanied by nausea, vomiting, and sensitivity to light 
(photophobia) and sound (phonophobia).  Migraine has 2 major subtypes:  migraine with aura 
(visual, sensory, and/or speech symptoms that occur just before or at the onset of migraine 
headache) and migraine without aura per the International Headache Classification Disorders 
(ICHD)-III. 
Migraine affects more than 10% of the world’s population (Robbins and Lipton, 2010), and the 
prevalence of migraine is approximately 11.7% in the United States, 14.6% in Canada, and 14.7% 
in Europe (Stovner and Andree, 2010; Lipton et al, 2007). 


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The patient burden and disability, as well as the societal impact, increase with higher attack 
frequency, which is why often the migraine spectrum is usually described according to 
frequency of migraine days per month, with 2 broad categories based on frequency of attacks:  
EM is typically defined as 0 to 14 migraine days per month (Katsarava et al, 2012) and CM as 15 
or more headache days per months, at least 8 of which have to be typical migraine days 
(Headache Classification Committee of the International Headache Society, 2018).  While all 
migraine patients can be treated with acute medications, not all migraine patients are 
appropriate for prophylactic treatment.  Although there is no clear consensus on a minimal 
number of migraine days or attacks to start migraine prophylaxis, there is agreement in that it 
should be considered whenever there is significant disability induced by the attacks (Evers et al, 
2006; Antonaci et al, 2010).  Reports suggest that out of the approximately 25% of migraine 
patients in need of migraine prevention, only half of them are actually treated with migraine 
prophylactic treatments (Lipton et al, 2007). 
2.2.2 
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).   
As of the date of approval of this protocol, erenumab (70 mg and 140 mg administered 
subcutaneously [SC] once every 4 weeks [Q4W] [or once every month {QM}]) has been 
approved in approximately 40 countries including the United States (US) and European Union 
(EU). 
A detailed description of the chemistry, pharmacology, efficacy, and safety of erenumab is 
provided in the Erenumab investigator’s Brochure and regional label.   
2.3 
Benefit/Risk Assessment 
Benefits 
Globally, the totality of data from phase 2 and phase 3 studies in subjects with CM and EM 
provides substantial evidence for the efficacy and safety of erenumab in adults with migraine.  
The key benefits of erenumab include reduction in frequency of monthly migraine days (MMDs), 


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reduction in acute migraine-specific medication use, as well as improvements in a range of other 
patient-reported outcomes (PROs), favorable tolerability, low treatment discontinuation rates, 
convenience (QM injections with the option of self-administration), and rapid onset of effect.   
Risks 
The safety profile of erenumab has been favorable in clinical trials and in the post-marketing 
setting. A limited number of adverse drug reactions (injection site reactions, constipation, 
muscle spasm, and pruritus) have been identified at low frequencies (< 5%) in clinical trials. In 
the long-term use of erenumab, the safety profile remained consistent through 5 years of open-
label treatment. In post-marketing settings, hypersensitivity reactions (including rash, 
angioedema and anaphylactoid reactions), and constipation with serious complications have 
been reported. In addition, oral sores (eg, stomatitis, mouth ulceration, oral mucosal blistering), 
alopecia and rash (eg, rash papular, exfoliative rash, rash erythematous, urticaria, blister) have 
been observed in post-marketing surveillance. 
The above benefit risk assessment supports the conduct of this open-label clinical trial.  
Reference should be made to the investigator’s Brochure and regional label for further data on 
erenumab. 
3. 
Objectives, Endpoints and Hypotheses 
3.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
To explore the relationship between clinical 
response to erenumab and genetic 
biomarkers 
 
Achievement of at least a 50% reduction from 
baseline in mean monthly migraine days 
(MMD) over months 4, 5, and 6 in relation to 
each individual genome-wide significant 
single-nucleotide polymorphism (SNP) 
contributing to the migraine polygenic risk 
score (mPRS) 
 
 
 


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Objectives 
Endpoints 
Exploratory 
 
To describe the relationship between AMSM 
use and mPRS in erenumab-treated subjects 
 
Change from baseline in monthly AMSMD 
over months 4, 5, and 6, in relation to mPRS 
 
To describe the relationship between 
baseline calcitonin gene-related peptide 
(CGRP) levels and clinical response with 
erenumab treatment as assessed by MMD in 
erenumab-treated subjects 
 
Change from baseline in MMD over months 
4, 5, and 6 in relation to baseline CGRP level 
 
Achievement of at least a 50% reduction from 
baseline in mean MMD over months 4, 5, and 
6 in relation to baseline CGRP level 
 
Achievement of at least a 75% reduction from 
baseline in mean MMD over months 4, 5, and 
6, in relation to baseline CGRP level 
 
To describe the relationship between 
baseline CGRP levels and clinical response 
with erenumab treatment as assessed by 
acute migraine-specific medication days 
(AMSMD) in 
erenumab-treated subjects 
 
Change from baseline in AMSMD over 
months 4, 5, and 6, in relation to baseline 
CGRP level 
 
To describe the relationship between mPRS 
and baseline CGRP 
 
mPRS in relation to baseline CGRP level 
 
To describe the relationship between 
baseline CGRP levels and migraine disease 
characteristics 
 
Baseline CGRP level in relation to baseline 
MMD 
 
Baseline CGRP level in relation to baseline 
AMSMD 
 
Baseline CGRP level in relation to baseline 
AHMD 
 
Baseline CGRP level in relation to each MFIQ 
individual domain score (physical function, 
usual activities, social function, and 
emotional function) and overall impact usual 
activities global item score at baseline 
 
Baseline CGRP in relation to presence of aura 
during baseline 
 
Baseline CGRP in relation to baseline mean 
migraine severity 


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Objectives 
Endpoints 
Exploratory (Continued) 
 
To describe the relationship between mPRS 
and migraine disease characteristics 
 
mPRS in relation to baseline MMD 
 
mPRS in relation to baseline AMSMD 
 
mPRS in relation to baseline acute headache 
medication days (AHMD) 
 
mPRS in relation to Migraine Functional 
Impact Questionnaire (MFIQ) individual 
domain scores (physical function, usual 
activities, social function, and emotional 
function) and overall impact usual activities 
global item score at baseline 
 
mPRS in relation to presence of aura during 
baseline 
 
mPRS in relation to baseline mean migraine 
severity  
 
To evaluate the effect of erenumab as 
assessed by change in MMD in erenumab-
treated subjects 
 
Change from baseline in mean MMD over 
months 4, 5, and 6 
 
Change from baseline in MMD at assessment 
timepoints 
 
Achievement of at least a 50% reduction from 
baseline in mean MMD over months 4, 5, and 
6 
 
Achievement of at least a 50% reduction from 
baseline in MMD at assessment timepoints 
 
Achievement of at least a 75% reduction from 
baseline in mean MMD over months 4, 5, and 
6 
 
Achievement of at least a 75% reduction from 
baseline in mean MMD at assessment 
timepoints 
 


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Objectives 
Endpoints 
Exploratory (Continued) 
 
To evaluate the effect of erenumab as 
assessed by change in AMSMD in erenumab-
treated subjects 
 
Change from baseline in mean monthly 
AMSMD over months 4, 5, and 6 
 
Change from baseline in monthly AMSMD at 
assessment timepoints 
 
To evaluate the effect of erenumab as 
assessed by change in monthly AHMD in 
erenumab-treated subjects 
 
Change from baseline in mean monthly 
AHMD over months 4, 5, and 6  
 
Change from baseline in monthly AHMD at 
assessment timepoints 
 
To evaluate the effect of erenumab on 
functional impact as assessed by the change 
from baseline MFIQ score in erenumab-
treated subjects 
 
Change from baseline in MFIQ individual 
domain scores (physical function, usual 
activities, social function, and emotional 
function) and overall impact usual activities 
global item score at month 6 
 
To describe the relationship between change 
from baseline in MFIQ score and mPRS in 
erenumab-treated subjects 
 
Change from baseline in MFIQ individual 
domain scores (physical function, usual 
activities, social function and emotional 
function) and overall impact usual activities 
global item score at month 6, in relation to 
mPRS 
 
3.2 
Hypothesis 
No formal hypothesis testing will be performed.  All analyses will be descriptive in nature.   
4. 
Study Design 
4.1 
Overall Design 
This is a phase 4 open-label study that will enroll subjects with EM or CM without a 
predetermined allocation ratio.  The study will comprise of the following periods: 
 
A screening period of up to 3 weeks (21 days) for the assessment eligibility criteria. The 
screening visit may be performed on the same day as the baseline visit 
 
A baseline period of 4 weeks (28 up to 35 days) to collect data on migraine headaches and 
acute headache medication use using electronic diary (eDiary) and to assess compliance in 
eDiary usage at day 1 visit 
 
A 24-week open-label treatment period 
Subjects will be screened at screening visit, and if eligible, subjects may enter the baseline 
period at the same visit as screening or may begin baseline procedures up to 3 weeks after the 
screening visit.  At completion of the baseline period, those who meet eligibility criteria and 
demonstrate  75% compliance with eDiary use will be enrolled and will enter the open-label 
treatment period to receive either erenumab 70 or 140 mg subcutaneously (SC) every 4 weeks 
(Q4W) at the discretion of the investigator. 


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Day 1 and week 12 administration may be performed by site staff or by subject 
self-administration.  Site staff will dispense the doses at day 1 and week 12 necessary to 
continue erenumab monthly treatment between visits (ie, subject is to take home doses for 
week 4, 8, 16, and 20 for administration at non-investigative site [eg, home]), as detailed in 
Table 1.  Subjects may contact the site at any time in between scheduled visits, and the 
investigator will determine if an additional unscheduled onsite visit is necessary.  
The overall study design is described by a study schema in Section 1.2.  The endpoints are 
defined in Section 3.1. 
4.2 
Number of Subjects 
Approximately 1400 subjects will be enrolled in the study; all subjects are to receive erenumab, 
either 70 mg or 140 mg SC Q4W, determined at the investigator’s discretion and may be 
adjusted once during the study at the week 12 visit. 
Subjects in this clinical investigation shall be referred to as “subjects”.  For the sample size 
justification, see Section 9.1. 
4.2.1 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
4.2.2 
Number of Sites 
Approximately 2 to 4 investigative sites in Europe will be included in the study.  Sites that do not 
enroll subjects within 6 months of site initiation may be closed. 
4.3 
End of Study 
4.3.1 
End of Study Definition 
End of Study: An individual subject is considered to have completed the study if he/she has 
completed the last scheduled procedure shown in the Schedule of Activities (Table 1). 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. 
4.3.2 
Study Duration for Subjects 
The study duration including screening/baseline period and 24-week open-label treatment 
period is approximately 28 to 33 weeks.  


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4.4 
Justification for Investigational Product Dose 
Erenumab 70 mg and 140 mg SC Q4W are approved in Europe and the United States for the 
prevention of migraine in adults.  Regulatory approval was granted on the basis of established 
superiority against placebo for each dose in 4 independent randomized clinical studies (1 CM 
and 3 EM) (Sun et al, 2106; Goadsby et al, 2017; 
Tepper et al, 2017; Dodick et al, 2018). 
4.5 
Patient Input on Study Design 
Patient input was not solicited in the study design. 
5. 
Study Population 
Investigators will be expected to maintain a screening log of all potential study candidates that 
includes limited information about the potential candidate (eg, date of screening).   
Eligibility criteria will be evaluated during screening.  
Before any study-specific activities/procedures, the appropriate written informed consent must 
be obtained (see Section 11.3). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions will not be provided. 
5.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
Before baseline period 
101 
Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures. 
102 
Age  18 years upon entry into screening  
103 
History of migraine (with or without aura) for  12 months before screening according 
to the International Headache Society (IHS) Classification ICHD-3 (Headache 
Classification Committee of the International Headache Society, 2018) based on medical 
records and/or patient self-report 
104 
 4 headache days that meet criteria as migraine days per month on average across the 
3 months before screening 
After baseline period 
105 
Must have demonstrated  75% compliance in eDiary usage during baseline period   
5.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 


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Disease Related 
201 
 50 years of age at migraine onset 
202 
History of cluster headache or hemiplegic migraine headache 
203 
Inability to differentiate between migraine from other headaches  
Other Medical Conditions 
204 
The subject is at risk of self-harm or harm to others as evidenced by past suicidal 
behavior 
205 
History or evidence of any other clinically significant disorder, condition or disease (with 
the exception of those outlined above) that, in the opinion of the investigator or Amgen 
physician, if consulted, would pose a risk to subject safety or interfere with the study 
evaluation, procedures or completion 
Prior/Concomitant Therapy 
206 
Previously received erenumab (Aimovig) 
207 
Received an anti-CGRP monoclonal antibody within 3 months prior to the start of the 
baseline period   
215 
Initiation, discontinuation, or change of dosing of migraine prophylactic medications 
within 2 months prior to the start of the baseline period, during the baseline period or 
planned during the study. Refer to Section 6.1.7 for additional information.  
Prior/Concurrent Clinical Study Experience 
208 
Currently receiving treatment in another investigational device or drug study, or less 
than 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. 
Other Exclusions 
209 
Female subjects of childbearing potential with a positive pregnancy test assessed at 
screening or day 1 by a urine pregnancy test.   
210 
Female subject is pregnant or breastfeeding or planning to become pregnant or 
breastfeed during treatment and for an additional 16 weeks after the last dose of 
investigational product.   
211 
Female subjects of childbearing potential unwilling to use 1 acceptable method of 
effective contraception during treatment and for an additional 16 weeks after the last 
dose of investigational product.  Refer to Section 11.5 for additional contraceptive 
information. 
212 
Evidence of current pregnancy or breastfeeding per subject self-report or medical 
records  
213 
Subject has known sensitivity to any of the products or components to be administered 
during dosing. 
214 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures (eg, Clinical Outcome 
Assessments) to the best of the subject and investigator’s knowledge. 


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5.3 
Subject Enrollment 
Before subjects begin participation in any study-specific activities/procedures, Amgen requires a 
copy of the site’s written institutional review board/independent ethics committee (IRB/IEC) 
approval of the protocol, informed consent form (ICF), and all other subject information and/or 
recruitment material, if applicable (see Section 11.3). 
The subject must personally sign and date the IRB/IEC and Amgen approved informed consent 
before commencement of study-specific procedures. 
A subject is considered enrolled when the investigator decides that the subject has met all 
eligibility criteria.  This should occur on day 1, after completion of the baseline period.  The 
investigator is to document this decision and date, in the subject’s medical record and in/on the 
enrollment electronic case report form (eCRF). 
Each subject who enters into the screening period for the study (defined as when the subject 
signs the ICF) receives a unique subject identification number before any study-related 
activities/procedures are performed.  The subject identification number will be assigned 
sequentially following format provided by Amgen.  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 the initial assignment, including if a subject is rescreened. 
5.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are 
not subsequently enrolled in the study.  A minimal set of screen failure information will be 
collected that includes demography, screen failure details, eligibility criteria, medical history, 
prior therapies, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once if in the opinion of the investigator, the reason for the initial screen failure has 
been resolved or is no longer applicable.  Refer to Section 8.1.1. 
6. 
Treatments 
Study treatment is defined as any investigational product(s), non-investigational product(s), 
placebo, or medical device(s) intended to be administered to a study subject according to the 
study protocol. 


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Note that in several countries, investigational product and non-investigational product are 
referred to as investigational medicinal product and non-investigational medicinal product, 
respectively. 
The Investigational Product Instruction Manual (IPIM), a document external to this protocol, 
contains detailed information regarding the storage, preparation, destruction, and 
administration of each treatment shown in Table 3 below. 
6.1 
Treatment Procedures 
6.1.1 
Investigational Products 
Table 3.  Study Treatments 
Study Treatment 
Name 
Amgen Investigational Product:a 
Erenumab 
Dosage Formulation 
Erenumab will be packaged in a SureClick AI/Pen containing 1 mL of 70 mg/mL 
or 140 mg/mL of erenumab.   
Unit Dose 
Strength(s)/ 
Dosage Level(s) and 
Dosage Frequency 
Erenumab 70 mg or 140 mg will be administered Q4W.  Dose is to be 
determined at the investigator’s discretion and may be adjusted once during 
the study at the week 12 visit. 
Route of 
Administration 
SC injection 
Accountability 
The quantity, start date, and lot number of investigational product are to be 
recorded on each subject’s eCRF. 
Dosing Instructions 
Site staff is to dispense erenumab AI/Pens to subjects at the day 1 visit (for 
treatment on day 1, week 4, and week 8) and week 12 visit (for treatment at 
weeks 12, 16, and 20).   
At the day 1 and week 12 visit erenumab will be administered to subjects by 
site staff or by subject self-administration as the last procedure of the visit. 
Administration will be performed by the subject or designee in a 
non-investigator site setting (eg, at home) at weeks 4, 8, 16, and 20.   
At week 4, subjects participating in the CGRP biomarker substudy are to be 
instructed to administer erenumab dose at non-investigative site (eg, home) 
after the visit. 
 
Refer to the IPIM for investigational product details.  
Device 
AI/Pen 
AI = autoinjector; eCRF = electronic case report form; IPIM = Investigational Product Instruction Manual; Q4W = once 
every 4 weeks; SC = subcutaneous. 
a Erenumab will be manufactured and packaged by Amgen and distributed using Amgen clinical study drug 
distribution procedures. 
6.1.2 
Non-investigational Products 
Non-investigational products will not be used in this study.  


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6.1.3 
Medical Devices 
The following investigational medical device(s) provided by Amgen for use in this study is the 
erenumab SureClick Autoinjector Pen (AI/Pen) (Table 3). 
The erenumab SureClick AI/Pen is a single-use disposable, handheld mechanical “spring-based” 
device for fixed dose SC injection of erenumab 1 mL deliverable volume. 
Additional details are provided in the IPIM.   
Other non-investigational medical devices may be used in the conduct of this study as part of 
standard care. 
Non-investigational medical devices (eg, syringes, sterile needles), that are commercially 
available are not usually provided or reimbursed by Amgen (except, for example, if required by 
local regulation).  The investigator will be responsible for obtaining supplies of these devices. 
6.1.4 
Other Protocol-required Therapies 
Other-protocol-required therapies will not be used in this study. 
6.1.5 
Other Treatment Procedures 
Other treatment procedures will not be conducted in this study. 
6.1.6 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges deficiencies 
related to the identity, quality, durability, reliability, safety, effectiveness, or performance of a 
drug, combination product, or device after it is released for distribution to market or clinic by 
either (1) Amgen or (2) distributors or partners for whom Amgen manufactures the material.  
This includes all components distributed with the drug, such as packaging drug containers, 
delivery systems, labeling, and inserts. 
This includes any investigational/non-investigational product(s), device(s), or combination 
product(s) provisioned and/or repackaged/modified by Amgen, including the erenumab AI/Pen.   
Any product complaint(s) associated with an investigational product(s), non-investigational 
products devices(s), or combination product(s) supplied by Amgen are to be reported according 
to the instructions provided in the IPIM. 


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6.1.7 
Excluded Treatments, Medical Devices, and/or Procedures During Study 
Period 
Concomitant treatment with migraine prophylactic medications are allowed under the following 
conditions: 
 
 
Drug regimen (ie, formulation, frequency of use, route, and dose) is stable for ≥ 2 months 
(for oral migraine prophylactic medications) or ≥ 2 cycles (for botulinum toxin) prior to the 
start of the baseline period 
 
Drug regimen is at a generally accepted dose, frequency, and route for its use in migraine 
 
Drug regimen is not anticipated to change during baseline period or throughout the study 
 
Allowable medications include:  
 
Antiepileptics (eg, divalproex sodium, sodium valproate, topiramate, carbamazepine, 
levetiracetam) 
 
Angiotensin receptor blockers (eg, candesartan) or ACE inhibitors (eg, lisinopril) 
 
Beta blockers 
 
Calcium channel blockers (eg, verapamil, amlodipine, cinnarizine) or calcium antagonists (eg, 
flunarizine) 
 
Tricyclic antidepressants  
 
Other antidepressants (eg, serotonin-norepinephrine reuptake inhibitors, selective 
serotonin-reuptake inhibitors)  
 
Botulinum toxin (in the head and/or neck region) 
 
Other drugs used for migraine prevention (eg, clonidine, guanfacine, methysergide, 
cyproheptadine, pizotifen), except for anti-CGRP medications which are excluded. 
6.2 
Method of Treatment Assignment 
Subjects who meet eligibility criteria will be assigned to treatment with either 70 mg or 140 mg 
SC Q4W, determined by the investigator’s discretion and may be adjusted once during the study 
at the week 12 visit. 
The treatment assignment date is to be documented in the subject’s medical record and on the 
enrollment eCRF. 
6.3 
Blinding 
This is an open-label study; blinding procedures are not applicable. 
6.4 
Dose Modification 
6.4.1 
Dose-Cohort Study Escalation/De-escalation and Stopping Rules 
Dose-cohort study escalation/de-escalation and stopping rules do not apply to this study.   


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6.4.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, Permanent 
Discontinuation 
6.4.2.1 
Amgen Investigational Product:  Erenumab 
Dose adjustments between 70 mg and 140 mg erenumab are permitted at the week 12 visit per 
investigator discretion.  The reason for change of planned dose of erenumab is to be recorded 
on each subject’s eCRF(s). 
At any time during the study, the investigator may discontinue investigational product 
administration for any subject who experiences a severe or life-threatening adverse event 
reported by the investigator to be related to investigational product.  Refer to Section 8.2.3.1 for 
details regarding adverse event reporting.   
6.5 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, or 
return of the investigational product or device during the study are provided in the IPIM. 
6.6 
Treatment Compliance 
Subject administration of investigational product will occur at sites at scheduled visits or at a 
non-investigator site setting (eg, at home).  Noncompliance is to be documented in the medical 
file and will be reflected in the eCRF.  Noncompliant subjects are to be 
re-educated on the importance of adhering to the investigational product administration 
schedule and reminded that repeated cycles of noncompliance could be a reason for 
discontinuation of study treatment.   
6.7 
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.   
6.8 
Prior and Concomitant Treatment 
6.8.1 
Prior Treatment 
All prior prophylactic migraine therapies ever taken and ending prior to start of baseline will be 
collected, including reason for ending therapy.   
For all other prior therapies that were being taken/used from 120 days before screening 
through the signing of the informed consent, therapy name, start date, and stop date will be 
collected. 


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6.8.2 
Concomitant Treatment 
Throughout the study, investigators may prescribe any concomitant medications or treatments 
deemed necessary to provide adequate supportive care. Refer to Section 6.1.7 for restrictions 
regarding migraine prophylactic medication. 
Concomitant therapies are to be collected from the signing of informed consent through the 
end of study in the concomitant medication eCRF. 
7. 
Discontinuation Criteria 
Subjects have the right to withdraw from investigational product and/or 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 protocol procedures, or the study as a whole at any time prior to study 
completion for the reasons listed in Sections 7.1, 7.2.1, and 7.2.2. 
7.1 
Discontinuation of Study Treatment 
Subjects (or a legally acceptable representative) can decline to continue receiving investigational 
product and/or procedures at any time during the study but continue participation in the study.  
If this occurs, the investigator is to discuss with the subject the appropriate processes for 
discontinuation from investigational product and must discuss with the subject the possibilities 
for continuation of the Schedule of Activities (see Table 1) including different options of follow-
up (eg, in person, by phone/mail, through family/friends, in correspondence/communication 
with other treating physicians, from the review of medical records) and collection of data, 
including endpoints, adverse events, and device-related events, and must document this 
decision in the subject’s medical records.  Subjects who have discontinued investigational 
product and/or procedures should not be automatically removed from the study.  Whenever 
safe and feasible, it is imperative that subjects remain on-study to ensure safety surveillance 
and/or collection of outcome data. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) by a 
separate protocol or as provided for by the local country’s regulatory mechanism, based on 
parameters consistent with Section 11.3. 
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 


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 
decision by sponsor 
 
lost to follow-up 
 
death 
 
ineligibility determined 
 
Protocol deviation 
 
non-compliance  
 
adverse event 
 
subject request 
 
pregnancy 
7.2 
Discontinuation From the Study 
Withdrawal of consent for a study means that the subject does not wish to receive further 
protocol-required therapies or procedures, and the subject does not wish to or is unable to 
continue further study participation.  Subject data up to withdrawal of consent will be included 
in the analysis of the study, and where permitted, publicly available data can be included after 
withdrawal of consent.  The investigator is to discuss with the subject appropriate procedures 
for withdrawal from the study, and must document the subject’s decision to withdraw in the 
subject’s medical records.   
If a subject withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the investigator must notify Amgen accordingly (see Section 11.6 for further 
details).  Refer to the Schedule of Activities (Table 1) for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
7.2.1 
Reasons for Removal From Washout, Run-in or Invasive Procedures 
Wash-out, run-in, or invasive procedures do not apply to this study.   
7.2.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
decision by sponsor 
 
withdrawal of consent from study 
 
death 
 
lost to follow-up 


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7.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
 
The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or is able to continue in 
the study. 
 
In cases in which the subject is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the subject (where possible, 3 telephone calls and, 
if necessary, a certified letter to the subject’s last known mailing address or local equivalent 
methods).  These contact attempts are to be documented in the subject’s medical record. 
 
If the subject continues to be unreachable, he/she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up.  
 
For subjects who are lost to follow-up, the investigator can search publicly available records 
where permitted to ascertain survival status.  This ensures that the data set(s) produced as 
an outcome of the study is/are as comprehensive as possible. 
8. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities (see 
Table 1 ). 
As protocol waivers or exemptions are not allowed if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the subject is to continue or discontinue study 
treatment. 
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct. 
8.1 
General Study Periods 
8.1.1 
Screening 
Informed consent must be obtained before completing any screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  After the subject has signed the 
ICF, the site will assign subject identification numbers sequentially following format provided by 
Amgen and screen the subject in order to assess eligibility for participation. 


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All screening and baseline evaluations must be completed and reviewed to confirm that 
potential subjects meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for screening 
failure, (see Section 5.4) as applicable. 
8.1.2 
Baseline Period 
The baseline period can begin after confirmation that all initial eligibility criteria have been met.  
This can be the same day as the screening visit or within 3 weeks (21 days) of the screening visit.  
The baseline period will end 1 day before the day 1 visit and must be at least 28 days and no 
more than 35 days in duration.  The compliance in eDiary usage during the baseline period will 
be assessed on day 1.  A subject will either be screen-failed if not demonstrating  75% 
compliance in eDiary usage, or enrolled into the open-label treatment period.  Subjects who 
have screen failed may be eligible for rescreening only once, if in the opinion of the investigator, 
the reason for the initial screen failure has been resolved or is no longer applicable. Once the 
subject is rescreened, a new screening window will begin.  Subjects will retain the same subject 
identification number assigned at the original screening.  If the rescreening period begins more 
than 45 days after the original signing of the informed consent form, all screening procedures, 
including informed consent, must be repeated. 
8.1.3 
Treatment Period 
Visits will occur per the Schedule of Activities (Table 1).  The date of the first dose of erenumab 
is defined as day 1.  All subsequent doses and study visits will be scheduled based on the day 1 
date.  Study visits after day 1 may be completed within  7 days of the scheduled visit.  At the 
day 1 and week 12 visit erenumab will be administered on site to subjects by site staff or by 
subject self-administration as the last procedure of the visit.  All other doses of erenumab are to 
be administered by subject or designee at a non-investigative site setting (eg, at home). 
8.1.4 
End of Study 
The end of study visit occurs at week 24 ( 7 days) or when subject discontinues from the study 
before the week 24 visit.  All assessments will be performed at the end of study visit as per 
Schedule of Activities (Table 1). 
8.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required time 
points. 


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8.2.1 
General Assessments  
8.2.1.1 
Informed Consent 
All subjects or their legally authorized representative must sign and personally date the IRB/IEC 
approved informed consent before any study-specific procedures are performed. 
8.2.1.2 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected in order to 
study their possible association with subject safety and treatment effectiveness. 
8.2.1.3 
Medical History 
The investigator or designee will collect a complete medical history that started within 120 days 
prior to screening.  Medical history will include information on the subject's concurrent medical 
conditions.  Record all findings on the medical history eCRF.  In addition to the medical history, 
migraine history must date back to the original diagnosis.  The current severity will be collected 
for each condition that has not resolved. 
Targeted medical history is to be recorded in the neurologic medical history eCRF, 
gastro-intestinal medical history eCRF, gastro-intestinal procedures and surgeries medical 
history and headache and migraine frequency medical history eCRF.  The current severity will be 
collected for each condition that has not resolved. 
 


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8.2.2 
Efficacy Assessments 
8.2.2.1 
Clinical Outcome Assessments and Electronic Diaries 
8.2.2.1.1 
Electronic Diary 
The eDiary will collect migraine-related parameters daily at home, including the following: 
 
presence or absence of a migraine 
 
presence or absence of aura 
 
use of acute headache medications and whether the acute headache medication is a triptan 
 
worst headache severity 
At the baseline visit (after confirming the subject’s eligibility), the site staff will instruct the 
subject on eDiary use (eg, accessing the application, navigating screens, transmitting data, 
contacting the help desk for technical assistance).  The subject will be instructed to interact with 
the eDiary every day.  At the day 1 visit, the investigator will use the subject’s eDiary to review 
all data entered during the baseline period and confirm the relevant inclusion and exclusion 
criteria.   
8.2.2.1.2 
Migraine Functional Impact Questionnaire 
The Migraine Functional Impact Questionnaire (MFIQ) version 2.0 is a self-administered 26-item 
instrument measuring the impact of migraine on broader functioning including 4 domains:  
Impact on Physical Functioning (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 are to complete the MFIQ using paper forms as specified in the Schedule of Activities 
(Table 1), and site staff will record entries onto eCRFs.   
8.2.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities see 
(Table 1). 


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8.2.3.1 
Adverse Events and Serious Adverse Events 
8.2.3.1.1 
Time Period and Frequency for Collecting and Reporting Safety Event 
Information 
8.2.3.1.1.1 
Adverse Events 
The adverse event grading scale to be used for this study will be the Common Terminology 
Criteria for Adverse Events (CTCAE) v4.03 and is described in Section 11.4. 
The investigator is responsible for ensuring that all adverse events observed by the investigator 
or reported by the subject that occur after the first dose of investigational product through the 
end of study are reported using the Events eCRF. 
8.2.3.1.1.2 
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 
end of study are reported using the Events eCRF. 
All serious adverse events will be collected, recorded and reported to the sponsor or designee 
within 24 hours, of the investigator’s awareness of the event, as indicated in Section 11.4.  The 
investigator will submit any updated serious adverse event data to the sponsor within 24 hours 
of it being available. 
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.  For any adverse event that applies to this situation, comprehensive 
documentation of the event’s severity must be recorded in the subject medical records. 
8.2.3.1.1.3 
Serious Adverse Events After the Protocol-required Reporting Period 
After End of Study, there is no requirement to actively monitor study subjects after the study 
has ended with regards to study subjects treated by the investigator.  However, if the 
investigator becomes aware of serious adverse events suspected to be related to 
investigational product, then these serious adverse events will be reported to Amgen within 
24 hours following the investigator’s awareness of the event. 
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. 


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Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases and handled accordingly based on 
relationship to investigational product.  
The method of recording, evaluating, and assessing causality of adverse events, adverse device 
effects, and serious adverse events and the procedures for completing and transmitting serious 
adverse event reports are provided in Section 11.4. 
8.2.3.1.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events and/or serious adverse 
events.  Open-ended and non-leading verbal questioning of the subject is the preferred method 
to inquire about adverse event occurrence. 
8.2.3.1.3 
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 7.3).  Further information on 
follow-up procedures is given in Section 11.4. 
All new information for previously reported serious adverse events must be sent to Amgen 
within 24 hours following knowledge of the new information.  If specifically requested, the 
investigator may need to provide additional follow-up information, such as discharge 
summaries, medical records, or extracts from the medical records.  Information provided about 
the serious adverse event must be consistent with that recorded on the Event eCRF. 
8.2.3.1.4 
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. 


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Individual safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and sponsor policy and forwarded to investigators as 
necessary. 
An investigator who receives an individual safety report describing a serious adverse event or 
other specific safety information (eg, summary or listing of serious adverse events) from the 
sponsor will file it along with the investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
8.2.3.2 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and signal 
management processes. 
8.2.3.2.1 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects and female partners of male 
subjects will be collected after the start of study treatment and until end of study. 
If a pregnancy is reported, the investigator is to inform Amgen within 24 hours of learning of the 
pregnancy and/or lactation and is to follow the procedures outlined in Section 11.5.  Amgen 
Global Patient Safety will follow-up with the investigator regarding additional information that 
may be requested. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered serious adverse events. 
Further details regarding pregnancy and lactation are provided in Section 11.5. 
8.2.3.2.2 
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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Product complaints are described in Section 6.1.6. 
Further details regarding adverse device effects can be found in Section 11.4. 
8.2.4 
Clinical Laboratory Assessments 
Refer to Section 11.2 for the list of clinical laboratory tests to be performed and to the Schedule 
of Activities (Table 1) 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 eCRF. 
All protocol-required laboratory assessments, as defined in Section 11.2, must be conducted in 
accordance with the laboratory manual and the Schedule of Activities (Table 1). 
8.2.4.1 
Pregnancy Testing 
A urine pregnancy test should be completed at screening and before administration of 
investigational product on day 1 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 
11-2).  Refer to Section 11.5 for contraceptive requirements.  
Additional pregnancy testing should be performed at intervals of every 12 weeks ( 7 days) 
during treatment with protocol-required therapies and at the end of study.  
Additional on-treatment pregnancy testing may be performed at the investigator’s discretion or 
as required per local laws and regulations. 
8.2.5 
Biomarkers 
Biomarkers are objectively measured and evaluated indicators of normal biologic processes, 
pathogenic processes, or pharmacologic responses to a therapeutic intervention. 
8.2.5.1 
Biomarker Research 
Samples will be collected for biomarker analysis, eg, to evaluate potential biomarkers that may 
correlate with treatment response.   
Blood samples are to be collected for biomarker development at the time points specified in the 
Schedule of Activities (Table 1).  Blood samples may be tested for genotyping, RNA sequencing, 
proteomics, and plasma CGRP levels.   


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8.2.5.2 
Optional CGRP Biomarker Substudy 
Approximately 315 subjects will provide additional informed consent in order to participate in 
the optional CGRP biomarker substudy.  Subjects participating in this substudy will have an 
additional CGRP sample collected at weeks 4, 12 and 24 as indicated in the CGRP Substudy 
Schedule of Activities (Table 2).  These additional CGRP samples will be used to explore whether 
the changes from baseline in CGRP levels might predict erenumab response. 
Obtain confirmation that the optional substudy ICF has been signed prior to performing optional 
substudy procedures.   
9. 
Statistical Considerations 
9.1 
Sample Size Determination 
The primary objective is the identification of genome-wide significant SNPs contributing to the 
mPRS that are significantly associated with clinical response to erenumab treatment (based on 
achievement of at least a 50% reduction from baseline in mean MMD over months 4, 5, and 
6).  Based on erenumab pivotal EM and CM studies, the  50% response rate with respect to 
MMD reduction is expected to be approximately 50% after 24 weeks of erenumab treatment.  It 
is hypothesized that the mPRS SNPs with genome-wide significance (p  5 x 10-8) have an 
additive effect on clinical response, ie, for each of these mPRS SNPs, each additional copy of the 
allele (with 0 as the reference) is associated with increased clinical response and will result in an 
odds ratio of 1.8 or higher (allelic odds ratio).  Given the currently known 123 migraine SNPs 
with genome-wide significance and a minor allele frequency (MAF) of at least 0.1, a study of 
1400 subjects with 10% dropouts (resulting an effective sample size of 1260 at week 24) is at 
least 90% powered to identify five of the genome-wide significant migraine SNPs that are 
statistically significantly associated with clinical response.  This is based on a two-sided power 
analysis, with Bonferroni adjustment, bootstrapping the data from the pivotal EM 
Study 20120296 (Mikol et al, 2020), using a logistic regression model to predict clinical 
response with each SNP, and adjusting for sex, age, BMI and principal components. 
9.2 
Analysis Sets, Subgroups, and Covariates 
9.2.1 
Analysis Sets 
9.2.1.1 
Full Analysis Set 
The full analysis set (FAS) consists of all subjects who enroll in the study.  Analysis of disposition, 
demographic and baseline characteristics, and important protocol deviations will utilize the FAS. 


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9.2.1.2 
Observed Data Analysis Set 
The observed data analysis set consists of a subset of subjects in FAS who receive at least 1 dose 
of investigational product and have an observed value for the endpoint of interest.  Primary 
analysis of the efficacy endpoints related to the genetic biomarkers will utilize the observed data 
analysis set. 
9.2.1.3 
Efficacy Analysis Set 
The efficacy analysis set (EAS) consists of a subset of subjects in FAS who receive at least 1 dose 
of investigational product and have at least 1 postbaseline change from baseline measurement 
for the endpoint of interest.  Primary analysis of the exploratory efficacy endpoints not involving 
biomarkers will utilize the EAS. 
9.2.1.4 
Safety Analysis Set 
The safety analysis set (SAS) will consist of a subset of subjects in FAS who receive at least 1 
dose of investigational product.  Analysis for safety endpoints and summary of investigational 
product administration will utilize the SAS. 
9.2.2 
Covariates 
All model-adjusted analyses of efficacy endpoints will include the corresponding baseline value 
for the endpoint being analyzed.   
9.2.3 
Subgroups 
The primary endpoint will be summarized in the subgroups defined by the following:  
 
sex (female/male) 
 
aura (yes/no) 
 
menstrual-related migraine (yes/no) 
 
country (Iceland/Denmark) 
 
migraine classification (EM/CM) 
 
prior migraine prophylactic treatment failure (yes/no) 
9.2.4 
Handling of Missing and Incomplete Data 
Subjects may miss specific data points for a variety of reasons.  In general, data could be missing 
because of a subject’s early withdrawal from the study, a missed visit, or inability to evaluate an 
endpoint at a time point.  For this study, efficacy endpoints will be collected via eDiary and 
subjects could miss entering several days of data in each monthly interval.  The general 
procedures outlined below describe how missing data will be handled. 


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For the eDiary data, if at least 14 days of eDiary are collected in the monthly interval, then the 
monthly frequency measurements (eg, migraine days or acute migraine-specific medications 
days [AMSMD]) will be prorated based on the number of days with available information.  If less 
than 14 days of eDiary are collected in the monthly interval, then the monthly frequency 
measurements will be set to missing.  Missing clinical outcome assessments (MFIQ) will not be 
imputed. 
Missing safety endpoints will not be imputed.  Missing or incomplete dates will be listed as 
reported, except for incomplete start date of an adverse event or concomitant medication 
(Table 4). 
Table 4.  Imputation for Incomplete Start Date of an Adverse Event or Concomitant 
Medication 
Missing 
Imputation 
Exception on Adverse Event Start Date 
Day 
01 
Default to study day 1 if an adverse event started 
the same year and month as study day 1 and the 
flag indicates that the adverse event started on or 
after the first dose of investigational product on the 
Events eCRF 
Day/Month 
01 Jan 
Default to study day 1 if an adverse event started 
the same year as study day 1 and the flag 
indicates that the adverse event started on or after 
the first dose of investigational product on the 
Events eCRF 
Day/Month/Year 
None 
— 
eCRF = electronic case report form 
9.3 
Statistical Analyses 
The statistical analysis plan (SAP) will be developed and finalized before database lock.  Below is 
a summary of the timing and methods for the planned statistical analyses.  To preserve study 
integrity, the primary analysis will be conducted and reported following the end-of-study, as 
defined in Section 4.3.1. 
9.3.1 
Planned Analyses 
9.3.1.1 
Primary Analysis 
The primary analysis (or final analysis, as this study has only 1 milestone analysis) will be 
performed after all subjects have completed their week 24 or end of study visit.  The data will be 
cleaned, and the database will be locked for the primary analysis.   


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9.3.2 
Methods of Analyses 
9.3.2.1 
General Considerations 
Summary statistics will be tabulated at each assessment time point, as applicable.  For 
continuous endpoints, the descriptive statistics include the following:  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. 
9.3.2.2 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
A GWAS of Icelandic and Danish data will be performed using logistic regression for 
binary phenotypes.  Assuming an additive model, GWAS will be performed for 
overall sample and by pre-specified subgroups, in addition to other phenotypes of 
interest that may be defined from the study data.  Age and sex will be used as 
covariates in Icelandic associations and age, sex, and 10 principal components will 
be used as covariates (to account for population structure) in Danish data.  Linkage 
disequilibrium (LD)-score regression will be used to account for inflation in test 
statistics due to cryptic relatedness and stratification. A likelihood-ratio test will be 
used to compute all P-values.  The Icelandic and Danish GWAS will be meta-analyzed 
using a fixed effects model.  Weighted Bonferroni adjustment will be used to 
maintain a family-wise error rate of 0.05 (2-sided) for primary endpoint.  Using 
summary statistics from these studies (excluding GWAS data from Denmark and 
Iceland), migraine polygenic risk scores (mPRS) will be calculated for the individuals 
participating in the clinical trial by summing their identified risk alleles, weighted by 
effect sizes and accounting for linkage disequilibrium using the LDPred software 
package.  This analysis is planned to be performed by deCODE and details of the 
analysis are described in deCODE Analysis Plan (Appendix B of the statistical analysis 
plan). 
Exploratory 
The analyses will be described in the statistical analysis plan, which will be finalized 
before database lock. 
 
9.3.2.3 
Safety Analyses 
9.3.2.3.1 
Adverse Events  
Subject incidence of all treatment-emergent adverse events will be tabulated by system organ 
class and preferred term.  Tables of fatal adverse events, serious adverse events, adverse events 
leading to withdrawal from investigational product, and significant treatment-emergent adverse 
events will also be provided.  Subject incidence of device-related events, if applicable, will be 
tabulated by system organ class and preferred term. 


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9.3.2.3.2 
Exposure to Investigational Product 
The total length of investigational product exposure, the total dose of investigational product, 
and the proportion of subjects receiving each dose will be summarized using descriptive 
statistics.   
9.3.2.3.3 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving acute headache medications will be summarized 
by medication category.   


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10. 
References 
Antonaci F, Dumitrache C, De Cillis I, et al  A review of current European treatment guidelines for 
migraine.  J Headache Pain.  2010;11(1):13-19. 
Chalmer MA, Esserlind AL, Olesen J, et al  Polygenic risk score:  use in migraine research.  J 
Headache Pain.  2018;19(1):29. 
Dodick DW, Ashina M, Brandes JL, et al  ARISE: A phase 3 randomized trial of erenumab for 
episodic migraine.  Cephalalgia.  2018;38(6):1026-1037. 
Erenumab investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc.  
Evers S, Afra J, Frese A, et al  EFNS guideline on the drug treatment of migraine - report of an 
EFNS task force.  Eur J Neurol.  2006;13(6):560-572. 
Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S.  
Pathophysiology of Migraine:  A Disorder of Sensory Processing.  Physiol Rev.  2017;97(2):553-
622. 
Goadsby PJ, Lipton RB, Ferrari MD  Migraine—current understanding and treatment.  N Engl J 
Med.  2002;346(4):257-270. 
Gormley P, Anttila V, Winsvold B, et al  Meta-analysis of 375,000 individuals identifies 38 
susceptibility loci for migraine.  Nat Genet.  2016;48(8):856-866. 
Headache Classification Committee of the International Headache Society (IHS).  The 
International Classification of Headache Disorders, 3rd ed (ICHD-3).  Cephalalgia.  
2018;38(1):1-211. 
Katsarava Z, Buse DC, Manack AN, Lipton RB.  Defining the differences between episodic 
migraine and chronic migraine.  Curr Pain Headache Rep.  2012;16:86-92. 
Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF.  AMPP Advisory Group:  
migraine prevalence, disease burden, and the need for preventive therapy.  Neurology.  
2007;68:343-349. 
Mikol DD, Picard H, Klatt J, Wang A, Peng C, Stefansson K. Migraine Polygenic Risk Score Is 
Associated with Severity of Migraine–Analysis of Genotypic Data from Four Placebo-
controlled Trials of Erenumab. Neurology. 2020;94 (15 supplements): 1214. 
Robbins MS, Lipton RB.  The epidemiology of primary headache disorders.  Semin Neurol.  
2010;30(2):107-119. 
Stovner LJ, Andree C.  Prevalence of headache in Europe:  a review for the Eurolight project.  J 
Headache Pain.  2010;11(4):289-299. 
Sun H, Dodick DW, Silberstein S, et al  Safety and efficacy of AMG 334 for prevention of episodic 
migraine:  a randomised, double-blind, placebo-controlled, phase 2 trial.  Lancet Neurol.  
2016;15(4):382-390. 
Tajti J, Uddman R, Möller S, Sundler F, Edvinsson L.  Messenger molecules and receptor mRNA in 
the human trigeminal ganglion.  J Auton Nerv Syst.  1999;76:176-183. 
Tepper S, Ashina M, Reuter U, et al  Safety and efficacy of erenumab for preventive treatment of 
chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial.  Lancet Neurol.  
2017;16(6):425-434. 


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11. 
Appendices 


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11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms 
 
Abbreviation or Term 
Definition/Explanation 
AHMD 
acute headache medication days 
AI/Pen 
Autoinjector Pen 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AMSMD 
acute migraine-specific medication days 
AST 
aspartate aminotransferase 
BIL 
bilirubin 
CFR 
United States Code of Federal Regulations 
CGRP 
calcitonin gene-related peptide 
CM 
chronic migraine 
CTCAE 
Common Terminology Criteria for Adverse Events 
EAS 
efficacy analysis set 
eCRF 
electronic case report form 
EDC 
electronic data capture 
Enrollment 
defined as the date when the subject has been assessed to pass all 
eligibility criteria after completion of the screening and baseline 
period 
End of Study for Individual 
Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject 
End of Study (primary 
completion) 
defined as the date when the last subject is assessed or receives an 
intervention for the final collection of data for the primary 
endpoint(s), for the purposes of conducting the primary analysis, 
whether the study concluded as planned in the protocol or was 
terminated early  
End of Study (end of trial) 
defined as the date when the last subject across all sites is assessed or 
receives an intervention for evaluation in the study (ie, last subject last 
visit), following any additional parts in the study (eg, long-term follow-
up), as applicable 
End of Treatment 
defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject 
EM 
episodic migraine 
EU 
European Union 
FAS 
full analysis set 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GWAS 
genome-wide association study 
HRT 
hormone replacement therapy 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICHD 
International Headache Classification Disorders 


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Abbreviation or Term 
Definition/Explanation 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IHS 
International Headache Society 
INR 
international normalized ratio 
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD 
intrauterine device 
IUS 
intrauterine hormonal-releasing system 
LD 
linkage disequilibrium 
MAF 
minor allele frequency 
MFIQ 
Migraine Functional Impact Questionnaire 
MMD 
monthly migraine day 
mPRS 
migraine polygenic risk score 
NCT 
National Clinical Trials 
PROs 
patient-reported outcomes 
PRS 
polygenic risk score 
Q4W 
Every 4 weeks 
QM 
once every month 
SAP 
statistical analysis plan 
SAS 
safety analysis set 
SC 
subcutaneous 
SmPC 
summary of product characteristics 
SNP 
single-nucleotide polymorphism 
Source Data 
information from an original record or certified copy of the original 
record containing patient information for use in clinical research.  The 
information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained 
in source documents (original records or certified copies).  (ICH 
Guideline [E6]).  Examples of source data include Subject 
identification, Randomization identification, and Stratification Value. 
Study day 1 
defined as the first day that protocol-specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject 
TBL 
total bilirubin 
ULN 
upper limit of normal 
 


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11.2 
Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 5 will be performed. 
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in Sections 5.1 
to 5.2 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations. 
Table 5.  Analyte Listing 
Hematology 
WBC count 
Differential 
Other Labs 
Urine pregnancy 
Biomarker research samples (DNA, RNA, proteomics, and CGRP analyses) 
Biomarker samples for CGRP biomarker substudy (CGRP analysis) 
CGRP = calcitonin gene-related peptide; WBC = white blood cell 


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11.3 
Appendix 3.  Study Governance Considerations 
11.3.1 
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 (ICF), investigator’s Brochure, and 
other relevant documents (eg, subject recruitment advertisements) must be submitted to an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) by the investigator and 
reviewed and approved by the IRB/IEC.  A copy of the written approval of the protocol and ICF 
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 
United States Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and all other 
applicable local regulations 


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11.3.2 
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.   
11.3.3 
Informed Consent Process 
An initial sample ICF is provided for the investigator to prepare the informed consent document 
to be used at his or her site.  Updates to the sample ICF are to be communicated formally in 
writing from the Amgen Trial Manager to the investigator.  The written ICF 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, or his/her legally 
authorized representative, 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 ICF. 
The investigator is also responsible for asking the subject if the subject has a primary care 
physician and if the subject agrees to have his/her primary care physician informed of the 
subject’s participation in the clinical study unless it is a local requirement.  The investigator shall 
then inform the primary care physician.  If the subject agrees to such notification, the 
investigator is to inform the subject’s primary care physician of the subject’s participation in the 
clinical study.  If the subject does not have a primary care physician and the investigator will be 
acting in that capacity, the investigator is to document such in the subject’s medical record. 
The acquisition of informed consent is to be documented in the subject’s medical records, and 
the ICF 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 


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treatment and/or procedures must also be documented in the subject’s medical records; refer 
to Section 7. 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
The original signed ICF is to be retained in accordance with institutional policy, and a copy of the 
ICF(s) must be provided to the subject or the subject’s legally authorized representative.  
The ICF 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. 
11.3.4 
Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for documents 
submitted to Amgen. 
Subject will be assigned a unique identifier by the sponsor.  Any subject records or datasets that 
are transferred to the sponsor will contain the identifier only; subject names or any information 
which would make the subject identifiable will not be transferred.  
On the electronic case report form (eCRF) demographics page, in addition to the unique subject 
identification number, include the age at time of enrollment. 
For serious adverse events reported to Amgen, subjects are to be identified by their unique 
subject identification number, initials (for faxed reports, in accordance with local laws and 
regulations), and age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed ICFs) 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, 


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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. 
11.3.5 
Publication Policy 
Authorship of any publications resulting from this study will be determined on the basis of the 
Uniform Requirement for Manuscripts Submitted to Biomedical Journals International 
Committee of Medical Journal Editors Recommendations for the Conduct of Reporting, Editing, 
and Publications of Scholarly Work in Medical Journals, which states:  Authorship credit is to be 
based on:  (1) substantial contributions to conception and design, acquisition of data, or analysis 
and interpretation of data; (2) drafting the article or revising it critically for important 
intellectual content; (3) final approval of the version to be published; and (4) agreement to be 
accountable for all aspects of the work in ensuring that questions related to the accuracy or 
integrity of any part of the work are appropriately investigated and resolved.  Authors need to 
meet conditions 1, 2, 3, and 4. 
When a large, multicenter group has conducted the work, the group is to identify the individuals 
who accept direct responsibility for the manuscript.  These individuals must fully meet the 
criteria for authorship defined above.  Acquisition of funding, collection of data, or general 
supervision of the research group, alone, does not justify authorship.  All persons designated as 
authors must qualify for authorship, and all those who qualify are to be listed.   Each author 
must have participated sufficiently in the work to take public responsibility for appropriate 
portions of the content.  All publications (eg, manuscripts, abstracts, oral/slide presentations, 
book chapters) based on this study must be 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. 
11.3.6 
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 


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 
an investigator who provided significant contributions to either the design or interpretation 
of the study 
 
an investigator contributing a high number of eligible subjects 
11.3.7 
Data Quality Assurance 
All subject data relating to the study will be recorded on printed or eCRF unless transmitted to 
the sponsor or designee electronically (eg, laboratory data, centrally or adjudicated data).  The 
investigator is responsible for verifying that data entries are accurate and correct by physically 
or electronically signing the eCRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.   
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.  
Clinical monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements per the sponsor’s monitoring 
plan.  
The investigator agrees to cooperate with the clinical monitor to ensure that any problems 
detected in the course of these monitoring visits, including delays in completing eCRFs, are 
resolved. 
The Amgen representative(s) and regulatory authority inspectors are responsible for contacting 
and visiting the investigator for the purpose of inspecting the facilities and, upon request, 
inspecting the various records of the clinical study (eg, eCRFs and other pertinent data) provided 
that subject confidentiality is respected. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected for audit 
by representatives from Amgen’s Global Research and Development Compliance and Audit 
function (or designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy 


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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. 
11.3.8 
Source Documents 
The investigator is to maintain a list of appropriately qualified persons to whom he/she has 
delegated study duties.  All persons authorized to make entries and/or corrections on eCRFs will 
be included on the Amgen Delegation of Authority Form. 
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator’s site. 
Source documents are original documents, data, and records from which the subject’s eCRF 
data are obtained.  These include but are not limited to hospital records, clinical and office 
charts, laboratory and pharmacy records, diaries, microfiches, radiographs, and 
correspondence.  Source documents may also include data captured in the Interactive Response 
Technology (IRT) system (if used, such as subject ID and randomization number) and eCRF 
entries if the eCRF is the site of the original recording (ie, there is no other written or electronic 
record of data, such as paper questionnaires for a clinical outcome assessment). 
Data reported on the eCRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained.  The 
investigator may need to request previous medical records or transfer records, depending on 
the study.  Also, current medical records must be available. 
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for inspection at 
any time by representatives from Amgen and/or applicable regulatory authorities. 
Elements to include: 
 
Subject files containing completed eCRFs, ICFs, and subject identification list 
 
Study files containing the protocol with all amendments, investigator’s Brochure, copies of 
prestudy documentation, and all correspondence to and from the [IRB/IEC] and Amgen 
 
Investigational product-related correspondence including [Proof of Receipts, Investigational 
Product Accountability Record(s), Return of Investigational Product for Destruction Form(s), 
Final Investigational Product Reconciliation Statement, as applicable 
 
Non-investigational product(s), and/or medical device(s) or combination product(s) 
documentation, as applicable 


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Retention of study documents will be governed by the Clinical Trial Agreement. 
11.3.9 
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. 
11.3.10 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the study are 
described in the Compensation for Injury section of the Informed Consent that is available as a 
separate document. 


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11.4 
Appendix 4.  Safety Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting 
11.4.1 
Definition of Adverse Event 
Adverse Event Definition 
 
An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment.   
 
Note:  An adverse event can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a treatment, combination product, medical device or 
procedure. 
 
Note: Treatment-emergent adverse events will be defined in the statistical analysis plan 
 
Events Meeting the Adverse Event Definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, electrocardiogram, radiological scans, vital signs 
measurements), including those that worsen from baseline, that are considered clinically 
significant in the medical and scientific judgment of the investigator 
(ie, not related to progression of underlying disease). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration even though 
it may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication.  Overdose per se will not be reported as an 
adverse event/serious adverse event unless it is an intentional overdose taken with 
possible suicidal/self-harming intent.  Such overdoses are to be reported regardless of 
sequelae. 
 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an adverse event or serious adverse event.  Such instances will be captured in 
the efficacy assessments.  However, the signs, symptoms, and/or clinical sequelae 
resulting from lack of efficacy will be reported as adverse event or serious adverse event 
if they fulfill the definition of an adverse event or serious adverse event.  
 
Events NOT Meeting the Adverse Event Definition 
 
Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that leads 
to the procedure is the adverse event. 
 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 


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 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
11.4.2 
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. 
11.4.3 
Definition of Adverse Device Effect 
The detection and documentation procedures for adverse device effects described in this 
protocol apply to all Amgen medical devices provided for use in the study (see Section 6.1.3 for 
the list of Amgen medical devices). 


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Adverse Device Effect Definition 
An adverse device effect is any adverse event related to the use of a combination product or 
medical device.  Adverse device effects include adverse events resulting from insufficient or 
inadequate instructions for use, adverse events resulting from any malfunction of the device, 
or adverse events resulting from use error or from intentional misuse of the device. 
A combination product is a product composed of any combination of a drug, a device, and a 
biological product. Each drug, device, and biological product included in a combination 
product is referred to as a “constituent part” of the combination product. 
11.4.4 
Recording Adverse Events and Serious Adverse Events 
Adverse Event and Serious Adverse Event Recording 
 
When an adverse event or serious adverse event occurs, it is the responsibility of the 
investigator to review all documentation (eg, hospital progress notes, laboratory, and 
diagnostics reports) related to the event. 
 
The investigator will then record all relevant adverse event/serious adverse event 
information in the Event electronic case report form (eCRF). 
 
The investigator must assign the following adverse event attributes: 
 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms); 
 
Dates of onset and resolution (if resolved); 
 
Did the event start prior to first dose of investigational product, other protocol-
required therapies; 
 
Severity (or toxicity defined below); 
 
Assessment of relatedness to investigational product(s), other protocol-required 
therapies, devices, and/or study-mandated activity and/or procedures; 
 
Action taken; and 
 
Outcome of event 
 
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record as a single event with the worst severity on the Events eCRF  
 
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to the sponsor in lieu of completion of the Events eCRF page. 
 
If specifically requested, the investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the medical 
records.  In this case, all subject identifiers, with the exception of the subject number, will 
be blinded on the copies of the medical records before submission to Amgen. 
 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis (not the 


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individual signs/symptoms) will be documented as the adverse event/serious adverse 
event. 
11.4.5 
Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The investigator will make an assessment of severity for each adverse event and serious 
adverse event reported during the study.  The assessment of severity will be based on: 
The Common Terminology Criteria for Adverse Events, version 4.03 which is available at the 
following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between investigational product, 
device(s), and 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 post-mortem findings including 
histopathology. 
 
New or updated information will be recorded in the originally completed Event eCRF. 
 
The investigator will submit any updated serious adverse event data to Amgen within 24 
hours of receipt of the information. 
11.4.6 
Reporting of Serious Adverse Event 
Serious Adverse Event Reporting via Electronic Data Collection Tool 
 
The primary mechanism for reporting serious adverse event will be the electronic data 
capture (EDC) system.  
 
If the EDC system is unavailable for more than 24 hours, then the site will report the 
information to Amgen using an electronic Serious Adverse Contingency Report Form (see 
Figure 11-1) within 24 hours of the investigator’s knowledge of the event. 
 
The site will enter the serious adverse event data into the electronic system as soon as it 
becomes available. 
 
After the study is completed at a given site, the EDC system will be taken off-line to 
prevent the entry of new data or changes to existing data. 
 
If a site receives a report of a new serious adverse event from a study subject or receives 
updated data on a previously reported serious adverse event after the EDC has been 
taken off-line, then the site can report this information on a paper Serious Adverse Event 
Report Form (see Figure 11-1). 
 
Once the study has ended, serious adverse event(s) suspected to be related to 
investigational product will be reported to Amgen if the investigator becomes aware of 
a serious adverse event. The investigator should use the paper-based Serious Adverse 
Event Contingency Report Form to report the event. 
11.4.7 
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 Events eCRF page. 


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 
It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by Amgen) at the time of the initial report and 
describes any corrective or remedial actions taken to prevent recurrence of the incident. 
 


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


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Protocol Number:  20190006 
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11.5 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy and 
Lactation Information 
Study-specific contraception requirements for female subjects of childbearing potential are 
outlined in Section 5.2. 
Female subjects of childbearing potential must receive pregnancy prevention counseling and be 
advised of the risk to the fetus if they become pregnant during treatment and for an additional 
16 weeks after the last dose of protocol-required therapies. 
11.5.1 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile.  Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered female of childbearing potential: 
 
premenopausal female with 1 of the following: 
 
documented hysterectomy; 
 
documented bilateral salpingectomy; or 
 
documented bilateral oophorectomy. 
Note:  Site personnel documentation from the following sources is acceptable:  
1) review of subject’s medical records; 2) subject’s medical examination; or 
3) subject’s medical history interview. 
 
premenarchal female 
 
postmenopausal female 
 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT).  However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient. 
 
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the non-hormonal highly effective contraception methods if they wish to continue their 
HRT during the study.  Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment 
Contraception Methods for Female Subjects 
Acceptable Methods of Effective Contraception 
 
combined (estrogen and progestogen containing) or progestogen-only hormonal methods 
given via oral, intravaginal, transdermal, injectable, or implantable route) 
 
intrauterine device (IUD) 


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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) 
11.5.2 
Unacceptable Methods of Birth Control for Female Subjects 
Birth control methods that are considered unacceptable in clinical trials include: 
 
periodic abstinence (calendar, symptothermal, post-ovulation methods) 
 
withdrawal (coitus interruptus) 
 
spermicides only 
 
lactational amenorrhea method 
11.5.3 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
 
Investigator will collect pregnancy information on any female subject who becomes 
pregnant while taking protocol-required therapies through 16 weeks after the last dose of 
protocol-required therapies. 
 
Information will be recorded on the Pregnancy Notification Worksheet (see 
Figure 11-2).  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). 
 
Any termination of pregnancy will be reported to Amgen Global Patient Safety, regardless of 
fetal status (presence or absence of anomalies) or indication for procedure.  


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 
While pregnancy itself is not considered to be an adverse event or serious adverse event, 
any pregnancy complication or report of a congenital anomaly or developmental delay, fetal 
death, or suspected adverse reactions in the neonate will be reported as an adverse event 
or serious adverse event.  Note that an elective termination with no information on a fetal 
congenital malformation or maternal complication is generally not considered an adverse 
event, but still must be reported to Amgen as a pregnancy exposure case. 
 
If the outcome of the pregnancy meets a criterion for immediate classification as a serious 
adverse event (eg, female subject experiences a spontaneous abortion, stillbirth, or 
neonatal death or there is a fetal or neonatal congenital anomaly) the investigator will 
report the event as a serious adverse event. 
 
Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be reported 
to Amgen Global Patient Safety as described in Section 11.4.  While the investigator is not 
obligated to actively seek this information in former study subjects, he or she may learn of a 
serious adverse event through spontaneous reporting.  
 
Any female subject who becomes pregnant while participating will discontinue study 
treatment (see Section 7.1 for details). 
Male Subjects With Partners Who Become Pregnant  
 
In the event a male subject fathers a child during treatment, and for an additional 16 weeks 
after discontinuing protocol-required therapies, the information will be recorded on the 
Pregnancy Notification Worksheet.  The worksheet 
(see Figure 11-2) must be submitted to Amgen Global Patient Safety within 24 hours of the 
site’s awareness of the pregnancy.  (Note:  Sites are not required to provide any information 
on the Pregnancy Notification 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. 
11.5.4 
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 protocol-
required therapies. 


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 
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 212. 
 
With the female subjects signed authorization for release of mother and infant health 
information, the investigator will collect mother and infant health information and complete 
the lactation questionnaire on any female subject who breastfeeds while taking protocol-
required therapies through 16 weeks after discontinuing 
protocol-required therapies. 


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Date:  23 February 2022 
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Figure 11-2.  Pregnancy and Lactation Notification Worksheet 
 


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11.6 
Appendix 6.  Sample Storage and Destruction 
Any blood sample collected according to the Schedule of Activities () 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, and characterize aspects of the molecule 
(eg, mechanism of action/target, metabolites).  Results from this analysis are to be documented 
and maintained, but are not necessarily reported as part of this study.  Samples can be retained 
for up to 20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the treatment 
course, the results of pharmacogenetic, biomarker development, or other exploratory studies 
are not placed in the subject’s medical record and are not to be made available to the subject, 
members of the family, the personal physician, or other third parties, except as specified in the 
informed consent. 
The subject retains the right to request that the sample material be destroyed by contacting the 
investigator.  Following the request from the subject, the investigator is to provide the sponsor 
with the required study and subject number so that any remaining blood samples and any other 
components from the cells can be located and destroyed.  Samples will be destroyed once all 
protocol-defined procedures are completed.  However, information collected from samples 
prior to the request for destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from the 
sample materials and is responsible for the destruction of the sample(s) at the request of the 
subject through the investigator, at the end of the storage period, or as appropriate (eg, the 
scientific rationale for experimentation with a certain sample type no longer justifies keeping 
the sample).  If a commercial product is developed from this research project, the sponsor owns 


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Date:  23 February 2022 
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the commercial product.  The subject has no commercial rights to such product and has no 
commercial rights to the data, information, discoveries, or derivative materials gained or 
produced from the sample.  See Section 11.3 for subject confidentiality. 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  23 February 2022 
Page 1 of 7 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 2 
Protocol Title:  Biomarker and Genetic Predictors of Erenumab Treatment 
Response, a Phase 4 Investigational Open-label Study (INTERROGATE) 
Amgen protocol Number Erenumab 20190006 
NCT04265755 
Amendment Date: 
23 February 2022 
 
Rationale: 
This protocol is being amended to: 
 
Reduce the sample size from 2000 subjects to 1400 subjects throughout the protocol 
as the sites will not be able to achieve the enrollment target and it was determined 
that a lower sample will still provide sufficient analytical power. 
 
Update Sample Size Determination for align with the sample size. 
 
Update section on serious adverse events after the protocol-required reporting 
period, Product Complaints, Adverse Device Effect Definition, Serious Adverse Event 
Reporting via Electronic Data Collection Tool as per the latest template text. 
 
Increase the sample from 200 subjects to 315 subjects in optional CGRP biomarker 
substudy. 
 
Perform administrative and formatting updates. 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  15 March 2021 
Page 1 of 1 
Amgen Proprietary - Confidential 
Amendment 1 
Protocol Title: Biomarker and Genetic Predictors of Erenumab Treatment 
Response, a Phase 4 Investigational Open-label Study (INTERROGATE) 
Amgen Protocol Number Erenumab 20190006 
 
Amendment Date: 
01 February 2021 
Superseding Amendment 
Date: 
15 March 2021 
Rationale: Changes have been made to facilitate enrollment and provide subjects with 
flexibility, including the option to separate screening from the start of the baseline period; 
adding the option for self-administration of the investigational product on day 1, and a 
rescreening option.  Changes were also made to clarify aspects of the protocol, including 
the collection of DNA samples from all subjects; requirements for allowable use of other 
migraine preventive medication; and calcitonin gene-related peptide assessments after 
day 1 to be only conducted in an optional sub-study. Updates were also made to reflect 
current data in the risk and statistical analysis sections. 
The following changes have been made: 
 
The screening and baseline periods have been separated 
 
Statistical analyses have been updated 
 
Notes have been added to the schedule of assessments (SOA) to clarify 
activities 
 
Optional sub-study assessments have been put into a separate SOA 
 
References to some exploratory objectives have been removed 
 
Benefit risk-assessment language has been updated to reflect current 
assessments 
 
End of study language edited to reflect current template format 
 
Exclusion criteria 215 added: “Initiation, discontinuation, or change of dosing of 
migraine prophylactic medications within 2 months prior to the start of the 
baseline period, during the baseline period or planned during the study.” 
 
Screen failure and rescreening language updated: a subject may be rescreened 
once if in the opinion of the investigator, the reason for the initial screen failure 
has been resolved or is no longer applicable 
 
Excluded treatments, medical devices, and/or procedures during the study period 
have been updated 
 
Hepatotoxicity sections have been removed per template language regarding it 
as optional 
 
Sampling has been updated for the plasma calcitonin gene-related peptide 
(CGRP) biomarker substudy 
 
Editorial and administrative updates have been made throughout 
On 15 March 2021, the protocol amendment was superseded to include the following: 
 
To include CGRP samples for biomarker research 
 
Remove abbreviation drug induced liver injury (DILI) from the abbreviation list 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  01 February 2021 
Page 1 of 1 
Amgen Proprietary - Confidential 
Amendment 1 
Protocol Title: Biomarker and Genetic Predictors of Erenumab Treatment 
Response, a Phase 4 Investigational Open-label Study (INTERROGATE) 
Amgen Protocol Number Erenumab 20190006 
 
Amendment Date: 
01 February 2021 
 
Rationale: Changes have been made to facilitate enrollment and provide subjects with 
flexibility, including the option to separate screening from the start of the baseline period; 
adding the option for self-administration of the investigational product on day 1, and a 
rescreening option.  Changes were also made to clarify aspects of the protocol, including 
the collection of DNA samples from all subjects; requirements for allowable use of other 
migraine preventive medication; and calcitonin gene-related peptide assessments after 
day 1 to be only conducted in an optional sub-study. Updates were also made to reflect 
current data in the risk and statistical analysis sections. 
The following changes have been made: 
 
The screening and baseline periods have been separated 
 
Statistical analyses have been updated 
 
Notes have been added to the schedule of assessments (SOA) to clarify 
activities 
 
Optional sub-study assessments have been put into a separate SOA 
 
References to some exploratory objectives have been removed 
 
Benefit risk-assessment language has been updated to reflect current 
assessments 
 
End of study language edited to reflect current template format 
 
Exclusion criteria 215 added: “Initiation, discontinuation, or change of dosing of 
migraine prophylactic medications within 2 months prior to the start of the 
baseline period, during the baseline period or planned during the study.” 
 
Screen failure and rescreening language updated: a subject may be rescreened 
once if in the opinion of the investigator, the reason for the initial screen failure 
has been resolved or is no longer applicable 
 
Excluded treatments, medical devices, and/or procedures during the study period 
have been updated 
 
Hepatotoxicity sections have been removed per template language regarding it 
as optional 
 
Sampling has been updated for the CGRP biomarker substudy 
 
Editorial and administrative updates have been made throughout 
 
 

SAP_001.pdf: 
Product:  Erenumab 
Protocol Number:  20190006 
Date:  20 April 2023 
Page 1 of 40 
CONFIDENTIAL  
 
 
Statistical Analysis Plan 
Protocol Title:  
Biomarker and Genetic Predictors of Erenumab Treatment 
Response, a Phase 4 Investigational Open-label Study 
(INTERROGATE)  
Short Protocol Title:  
INTERROGATE 
Protocol Number: 
20190006 
NCT Number: 
NCT04265755 
Authors: 
;  
, PhD 
Sponsor:  
Amgen, Inc 
One Amgen Center Drive 
Thousand Oaks, CA, 91320, USA 
SAP Date:  
Document Version 
Date 
Original (v1.0) 
Amendment 1 (v1.1) 
Amendment 1 (v1.2) 
01 October 2020 
28 March 2023 
20 April 2023 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  20 April 2023 
Page 2 of 40 
CONFIDENTIAL  
 
 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
01OCT2020 
Original version 
Amendment 1 (v1.1) 
 
 
 
24MAR2023 
 
Update section 3.2 sample size 
according to protocol amendment 
Sample size updated to 1400. 
 
Update section 4.1: update model 
adjusted variables 
 
Update 5.1 Definition of terms: add 
definition of Migraine classification 
 
Added section 5.4.3 study period 
 
Updated definition of exposed to 
investigational product in section 5.5 
 
Added Dose switch definition in 
section 5.5 
 
Added Duration of IP exposure 
definition in section 5.6 
 
Added description of imputation rules 
for missing IP administration dates of 
the last IP dose in section 8.3 
 
Updated description of 9.5.1 
 
Added ANCOVA methods description 
in section 9.5.2 
 
Added adverse events of interest in 
section 9.6.1 
 
Added section 10 changes from 
protocol-specified analysis. 
 
Added section 13 changes for data 
not covered in this plan. 
 
Amendment 1(v1.2) 
20Apr2023 
 
Update Migraine Pain Intensity to 
Peak Migraine Pain Intensity 
 
Update Monthly Average Migraine 
Pain Intensity to Monthly Average 
Peak Migraine Pain Intensity 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  20 April 2023 
Page 3 of 40 
CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents ................................................................................................... 3 
1. 
Introduction ............................................................................................................. 7 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 7 
2.1 
Objectives and Endpoints ............................................................................ 7 
2.2 
Hypotheses and/or Estimations ................................................................. 10 
3. 
Study Overview .................................................................................................... 10 
3.1 
Study Design ............................................................................................. 10 
3.2 
Sample Size .............................................................................................. 11 
4. 
Covariates and Subgroups ................................................................................... 11 
4.1 
Planned Covariates ................................................................................... 11 
4.2 
Subgroups ................................................................................................. 11 
5. 
Definitions ............................................................................................................. 12 
5.1 
Definition of Terms Included in Study Endpoints ....................................... 12 
5.1.1 
Efficacy Endpoints Based on Daily Data Collection ................... 12 
5.1.2 
Efficacy Endpoints Based on Monthly Collection ....................... 14 
5.1.3 
Safety Endpoints ....................................................................... 14 
5.2 
Study Dates .............................................................................................. 14 
5.3 
Study Points of Reference ......................................................................... 15 
5.4 
Study Time Intervals ................................................................................. 16 
5.4.1 
Monthly Intervals for Efficacy Endpoints Derived From 
Daily Diary Collection ................................................................ 16 
5.4.2 
Analysis Visits for Endpoints Based on Monthly 
Collection .................................................................................. 16 
5.5 
Subject Disposition .................................................................................... 17 
5.6 
Arithmetic Calculations .............................................................................. 18 
5.7 
Disease Characteristics ............................................................................. 19 
6. 
Analysis Sets ........................................................................................................ 19 
6.1 
Full Analysis Set........................................................................................ 19 
6.2 
Safety Analysis Set ................................................................................... 19 
6.3 
Study-specific Analysis Sets...................................................................... 19 
6.3.1 
Observed Data Analysis Set ...................................................... 19 
6.3.2 
Efficacy Analysis Set ................................................................. 20 
7. 
Planned Analyses ................................................................................................. 20 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 20 
7.2 
Primary Analysis ....................................................................................... 20 
8. 
Data Screening and Acceptance ........................................................................... 20 
8.1 
General Principles ..................................................................................... 20 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 20 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  20 April 2023 
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8.3 
Handling of Missing and Incomplete Data ................................................. 20 
8.4 
Detection of Bias ....................................................................................... 22 
8.5 
Outliers ..................................................................................................... 22 
8.6 
Distributional Characteristics ..................................................................... 22 
8.7 
Validation of Statistical Analyses ............................................................... 22 
9. 
Statistical Methods of Analysis.............................................................................. 23 
9.1 
General Considerations ............................................................................. 23 
9.2 
Subject Accountability ............................................................................... 23 
9.3 
Important Protocol Deviations ................................................................... 24 
9.4 
Demographic and Baseline Characteristics ............................................... 24 
9.5 
Efficacy Analyses ...................................................................................... 24 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) .................................. 28 
9.5.2 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 29 
9.6 
Safety Analyses ........................................................................................ 29 
9.6.1 
Adverse Events ......................................................................... 29 
9.6.2 
Exposure to Investigational Product .......................................... 30 
9.6.3 
Exposure to Concomitant Medication ........................................ 30 
9.7 
Other Analyses ......................................................................................... 30 
9.7.1 
Analyses of Biomarker Endpoints .............................................. 30 
10. 
Changes From Protocol-specified Analyses.......................................................... 31 
11. 
Literature Citations / References ........................................................................... 31 
12. 
Prioritization of Analyses....................................................................................... 31 
13. 
Data Not Covered by This Plan............................................................................. 31 
14. 
Appendices ........................................................................................................... 32 
Appendix A.  Reference Values/Toxicity Grades ................................................... 32 
Appendix B.  deCODE Analysis Plan .................................................................... 33 
 
List of Tables 
Table 1. Examples of possible outcomes on migraine-related endpoints. ...................... 13 
Table 2. Calculation for monthly frequency variables within each monthly 
interval .................................................................................................... 14 
Table 3.  Monthly Intervals for Efficacy Endpoints Derived From Daily Data 
Collection ................................................................................................ 17 
Table 4.  MFIQ Analysis Visit Windows ......................................................................... 18 
Table 5 Imputation for Incomplete Start Date of an Adverse Event or 
Concomitant Medication ......................................................................... 22 
Table 6. Primary Efficacy Endpoint Summary Table to be Performed by 
deCODE ................................................................................................. 26 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  20 April 2023 
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Table 7. Exploratory Efficacy Endpoint Summary Table to be Performed by 
deCODE ................................................................................................. 26 
Table 8.  Exploratory Efficacy Endpoint Summary Table to be Performed by 
Amgen .................................................................................................... 27 
 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  20 April 2023 
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List of Abbreviations and Definition of Terms 
Abbreviation or Term 
Definition/Explanation 
AE 
Adverse event 
AHMD 
acute headache medication days 
AMSMD 
acute migraine-specific medication days 
ANCOVA 
Analysis of covariance 
CGRP 
calcitonin gene-related peptide 
CM 
chronic migraine 
CTCAE 
Common Terminology Criteria for Adverse Events 
DARS 
Data Acquisition Requirements Specification 
DMP 
Data Management Plan 
DXDT 
diagnosis date 
EAS 
efficacy analysis set 
eCRF 
eDiary 
electronic case report form 
electronic diary 
EM 
episodic migraine 
EOS 
End of study 
FAS 
full analysis set 
GCP 
GBS 
GSO-DM 
Good Clinical Practice 
Global Biostatistical Science 
Global Study Operations – Data Management 
IP 
Investigational Product 
IPD 
important protocol deviations 
LSM 
Least squares means 
MAF 
MedDRA 
minor allele frequency 
Medical Dictionary for Regulatory Activities 
MFIQ 
Migraine Functional Impact Questionnaire 
MMD 
monthly migraine day 
mPRS 
migraine polygenic risk score 
NCT 
OLTP 
National Clinical Trials 
Open-label Treatment Period 
PRS 
polygenic risk score 
Q4W 
Every 4 weeks 
SAP 
SAE 
statistical analysis plan 
serious adverse events 
SAS 
safety analysis set 
SC 
Subcutaneous 
SNP 
single-nucleotide polymorphism 
TEAE 
treatment-emergent adverse event 
 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  20 April 2023 
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1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the Protocol Amendment 2 for Study 
20190006, Erenumab dated 23 February 2022.  The scope of this plan, includes the 
portion of the final analysis which will be executed by the Amgen Global Biostatistical 
Science department.  The remaining final analysis will be executed by deCODE as 
specified in the deCODE Analysis Plan (Appendix B).   
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
To explore the relationship between 
clinical response to erenumab and genetic 
biomarkers 
 
Achievement of at least a 50% reduction 
from baseline in mean monthly migraine 
days (MMD) over months 4, 5, and 6 in 
relation to each individual genome-wide 
significant single-nucleotide polymorphism 
(SNP) contributing to the migraine 
polygenic risk score (mPRS) 
            
Objectives 
Endpoints 
Exploratory 
 
To describe the relationship between 
monthly AMSM use and mPRS in 
erenumab-treated subjects 
 
Change from baseline in monthly AMSMD 
over months 4, 5, and 6, in relation to 
mPRS 
 
To describe the relationship between 
baseline calcitonin gene-related peptide 
(CGRP) levels and clinical response with 
erenumab treatment as assessed by MMD 
in erenumab-treated subjects 
 
Change from baseline in MMD over 
months 4, 5, and 6 in relation to baseline 
CGRP level 
 
Achievement of at least a 50% reduction 
from baseline in mean MMD over months 
4, 5, and 6 in relation to baseline CGRP 
level 
 
Achievement of at least a 75% reduction 
from baseline in mean MMD over months 
4, 5, and 6, in relation to baseline CGRP 
level 
 
To describe the relationship between 
baseline CGRP levels and clinical 
response with erenumab treatment as 
assessed by monthly acute migraine-
specific medication days (AMSMD) in 
erenumab-treated subjects 
 
Change from baseline in monthly AMSMD 
over months 4, 5, and 6, in relation to 
baseline CGRP level 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  20 April 2023 
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Objectives 
Endpoints 
Exploratory (Continued) 
 
To describe the relationship between 
mPRS and baseline CGRP 
 
mPRS in relation to baseline CGRP level 
 
To describe the relationship between 
baseline CGRP levels and migraine 
disease characteristics 
 
Baseline CGRP level in relation to 
baseline MMD 
 
Baseline CGRP level in relation to 
baseline AMSMD 
 
Baseline CGRP level in relation to 
baseline AHMD 
 
Baseline CGRP level in relation to each 
MFIQ individual domain score (physical 
function, usual activities, social function, 
and emotional function) and overall impact 
usual activities global item score at 
baseline 
 
Baseline CGRP in relation to presence of 
aura during baseline 
 
Baseline CGRP in relation to baseline 
mean migraine severity 
 
To describe the relationship between 
mPRS and migraine disease 
characteristics 
 
mPRS in relation to baseline MMD 
 
mPRS in relation to baseline AMSMD 
 
mPRS in relation to baseline acute 
headache medication days (AHMD) 
 
mPRS in relation to Migraine Functional 
Impact Questionnaire (MFIQ) individual 
domain scores (physical function, usual 
activities, social function, and emotional 
function) and overall impact usual 
activities global item score at baseline 
 
mPRS in relation to presence of aura 
during baseline 
 
mPRS in relation to baseline mean 
migraine severity  


Product:  Erenumab 
Protocol Number:  20190006 
Date:  20 April 2023 
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Objectives 
Endpoints 
Exploratory (Continued) 
 
To evaluate the effect of erenumab as 
assessed by change in MMD in 
erenumab-treated subjects 
 
Change from baseline in mean MMD over 
months 4, 5, and 6 
 
Change from baseline in MMD at 
assessment timepoints 
 
Achievement of at least a 50% reduction 
from baseline in mean MMD over months 
4, 5, and 6 
 
Achievement of at least a 50% reduction 
from baseline in MMD at assessment 
timepoints 
 
Achievement of at least a 75% reduction 
from baseline in mean MMD over months 
4, 5, and 6 
 
Achievement of at least a 75% reduction 
from baseline in mean MMD at 
assessment timepoints 
 
To evaluate the effect of erenumab as 
assessed by change in monthly AMSMD 
in erenumab-treated subjects 
 
Change from baseline in mean monthly 
AMSMD over months 4, 5, and 6 
 
Change from baseline in monthly AMSMD 
at assessment timepoints 
 
To evaluate the effect of erenumab as 
assessed by change in monthly AHMD in 
erenumab-treated subjects 
 
Change from baseline in mean monthly 
AHMD over months 4, 5, and 6  
 
Change from baseline in monthly AHMD 
at assessment timepoints 
 
To evaluate the effect of erenumab on 
functional impact as assessed by the 
change from baseline MFIQ score in 
erenumab-treated subjects 
 
Change from baseline in MFIQ individual 
domain scores (physical function, usual 
activities, social function, and emotional 
function) and overall impact usual 
activities global item score at month 6 
 
To describe the relationship between 
change from baseline in MFIQ score and 
mPRS in erenumab-treated subjects 
 
Change from baseline in MFIQ individual 
domain scores (physical function, usual 
activities, social function and emotional 
function) and overall impact usual 
activities global item score at month 6, in 
relation to mPRS 
 
 
 
 
 
 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  20 April 2023 
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2.2 
Hypotheses and/or Estimations 
No formal hypothesis testing will be performed.  All analyses will be descriptive in nature.  
3. 
Study Overview 
3.1 
Study Design 
This is a phase 4 open-label study that will enroll subjects with episodic migraine (EM) 
or chronic migraine (CM) without a predetermined allocation ratio.  The study will 
comprise the following periods: 
 
A screening period of up to 3 weeks (21 days) for the assessment eligibility criteria. 
The screening visit may be performed on the same day as the baseline visit  
 
A baseline period of 4 weeks (28 up to 35 days) to collect data on migraine 
headaches and acute headache medication use using electronic diary (eDiary) and 
to assess compliance in eDiary usage at day 1 visit     
 
A 24-week open-label treatment period 
Subjects will be screened at the screening visit, and if eligible, subjects may enter the 
baseline period at the same visit as screening or may begin baseline procedures 
up to 3 weeks after the screening visit. At completion of the baseline period, those 
who meet the eligibility criteria and demonstrate  75% compliance with eDiary use 
will be enrolled and will enter the open-label treatment period to receive erenumab either 
70 mg or 140 mg subcutaneously (SC) every 4 weeks (Q4W) at the discretion of the 
investigator.


Product:  Erenumab 
Protocol Number:  20190006 
Date:  20 April 2023 
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3.2 
Sample Size 
The primary objective is the identification of genome-wide significant SNPs contributing 
to the mPRS that are significantly associated with clinical response to erenumab 
treatment (based on achievement of at least a 50% reduction from baseline in mean 
MMD over months 4, 5, and 6).  Based on erenumab pivotal EM and CM studies, the 
 50% response rate with respect to MMD reduction is expected to be approximately 
50% after 24 weeks of erenumab treatment.  It is hypothesized that the mPRS SNPs 
with genome-wide significance (p  5 x 10-8) have an additive effect on clinical response, 
ie, for each of these mPRS SNPs, each additional copy of the allele (with 0 as the 
reference) is associated with increased clinical response and will result in an odds ratio 
of 1.8 or higher (allelic odds ratio).  Given the currently known 123 migraine SNPs 
with genome-wide significance and a minor allele frequency (MAF) of at least 0.1, a 
study of 1400 subjects with 10% dropouts (resulting an effective sample size of 1260 at 
week 24) is at least 90% powered to identify five of the genome-wide significant 
migraine SNPs that are statistically significantly associated with clinical response. This 
is based on a two-sided power analysis, with Bonferroni adjustment, 
bootstrapping the data from the pivotal EM Study 20120296 (Mikol et al, 2020), 
using a logistic regression model to predict clinical response with each SNP, and 
adjusting for sex, age, BMI and principal components.   
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
All models will be adjusted for age and sex. In addition, all model-adjusted analyses 
of efficacy endpoints assessing change from baseline will include the corresponding 
baseline value for the endpoint being analyzed. All models that compare baseline 
measurements only will be adjusted for country. However, country will not be 
included as a covariate in any deCODE performed analyses since all deCODE 
analyses will be performed separately by country (Denmark/Iceland) and 
subsequently combined in a meta-analysis. Due to the high correlation between 
baseline dose and country, models assessing change from baseline will instead 
be adjusted for baseline dose (70mg/140mg) and dose switch only.  
Principal components of genotype data will be adjusted for population stratification in 
mPRS related analysis. Calculation of principal components data will be described in 
the analysis plan developed by deCODE.  


Product:  Erenumab 
Protocol Number:  20190006 
Date:  20 April 2023 
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4.2 
Subgroups 
The primary endpoint will be summarized in the subgroups defined by the following:  
 
sex (female/male) 
 
presence of aura during baseline period (yes/no) 
 
menstrual-related migraine at screening (yes/no) 
 
country (Denmark/Iceland) 
 
migraine classification at screening (EM/CM) 
 
prior migraine preventive treatment failure (yes/no) 
The subgroups will be re-examined for appropriateness and may be re-categorized (due 
to small sample size, for example, if there are < 10% of subjects within a subgroup). 
5. 
Definitions 
5.1 
Definition of Terms Included in Study Endpoints 
5.1.1 
Efficacy Endpoints Based on Daily Data Collection 
Subjects’ daily headache information will be collected through the following 
questions. The most severe case will be used in the analysis when there are 
duplicates in the following daily questions. Examples of possible outcomes on 
migraine-related endpoints are summarized in Table 1:   
Table 1. Examples of possible outcomes on migraine-related endpoints. 
  
Scenario 
1 
Scenario 
2 
Scenario 
3 
Scenario 
4 
Scenario 
5 
Daily eDiary questions  
Migraine (Y/N) 
Y 
Y 
Y 
N 
N 
     If Y, Peak pain intensity (1 to 
10) 
1 
10 
7 
 NA 
NA 
Acute medication for migraine  
    (Y/N) 
Y 
Y 
N 
Y 
Y 
     If Y, Triptan (Y/N) 
Y 
N 
NA 
Y 
N 
Aura (Y/N) 
Y 
N 
Y 
Y 
N 
Outcomes on migraine-related endpoints 
Migraine day 
Yes 
Yes 
Yes 
No 
No 
Acute headache medication day 
Yes 
Yes 
No 
Yes 
Yes 
Acute migraine-specific medication 
day 
Yes 
No 
No 
Yes 
No 
Migraine Day 
A calendar day (00:00 to 23:59) in which the subject reports any migraine headache or 
takes any triptan-based acute migraine-specific medication.  


Product:  Erenumab 
Protocol Number:  20190006 
Date:  20 April 2023 
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Peak Migraine Pain Intensity 
Worst or peak pain intensity collected on a migraine headache which ranges from 1 to 
10 with a higher score indicating more severe pain (10-point numerical rating scale).   
Acute Headache Medication Day 
A calendar day (00:00 to 23:59) in which the subject takes any acute headache 
medication (AHM)  
Acute Migraine-specific Medication Day 
A calendar day (00:00 to 23:59) in which the subject takes triptan 
Diary Day  
A calendar day (00:00 to 23:59) with complete migraine headache, aura, and acute 
migraine headache medication data recorded in the eDiary device. 
Migraine Classification 
In subgroup analysis, we will define EM as subjects with < 15 headache days per 
month at baseline and CM as subjects with ≥ 15 headache days per month at 
baseline to ensure all subjects belong to either subgroup. 
Monthly Frequency Variable in Days 
Number of days of interest during each monthly interval as defined in Table 2. Monthly 
frequency variables include 
 
Monthly migraine days (MMD) 
 
Monthly acute migraine-specific medication days  
 
Monthly acute headache medication days 
The following proration rule will be applied to all monthly frequency variables for each 
monthly interval.   
Table 2. Calculation for monthly frequency variables within each monthly interval 
Within Each Monthly 
Interval 
Monthly Frequency Variable 
≥ 14 diary days 
Prorate to 28-day equivalent without rounding 
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑓𝑟𝑒𝑞𝑢𝑒𝑛𝑐𝑦 𝑑𝑎𝑦𝑠 𝑤𝑖𝑡ℎ𝑖𝑛 𝑒𝑎𝑐ℎ 𝑚𝑜𝑛𝑡ℎ𝑙𝑦 𝑖𝑛𝑡𝑒𝑟𝑣𝑎𝑙
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝒅𝒊𝒂𝒓𝒚 𝑑𝑎𝑦𝑠 𝑤𝑖𝑡ℎ𝑖𝑛 𝑒𝑎𝑐ℎ 𝑚𝑜𝑛𝑡ℎ𝑙𝑦 𝑖𝑛𝑡𝑒𝑟𝑣𝑎𝑙
 𝑥 28 
< 14 diary days 
Set to missing 


Product:  Erenumab 
Protocol Number:  20190006 
Date:  20 April 2023 
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Monthly Average Peak Migraine Pain Intensity 
Peak pain intensity will be collected for days with migraine headache reported. 
Monthly average peak migraine pain intensity is defined as the sum of the reported 
peak pain intensity scores during a monthly interval as defined in Table 3 divided by the 
total number of reported peak pain intensity scores. If there is no migraine headache 
observed during the monthly interval, then the monthly average peak migraine pain 
intensity will be set to 0. If less than 14 days of eDiary data in each monthly interval are 
recorded, then the monthly average peak migraine pain intensity will be set to missing.   


Product:  Erenumab 
Protocol Number:  20190006 
Date:  20 April 2023 
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5.1.2 
Efficacy Endpoints Based on Monthly Collection 
Migraine Functional Impact Questionnaire (MFIQ) 
The MFIQ version 2.0 is a self-administered 26-item instrument measuring the impact of 
migraine on broader functioning including 4 domains: Impact on Physical Functioning 
(5 items), Impact on Usual Activities (10 items), Impact on Social Functioning (5 items), 
and Impact on Emotional Functioning (5 items). In addition, there is 1 stand-alone global 
item assessing the overall impact on usual activities.  Subjects respond to items using a 
5-point scale assigned scores from 1 to 5, with 5 representing the greatest burden.  
Each domain score will be calculated as the sum of the item responses, and the sum will 
be rescaled to a 0 to 100 scale, with higher scores representing greater burden.  The 
recall period is the past 7 days.  
5.1.3 
Safety Endpoints 
Treatment-emergent Adverse Event (TEAE) 
An event categorized as “Adverse Event” on the Events eCRF starting on or after first 
dose of investigational product, as determined by “Did event start before first dose of 
investigational product” equal to “No” or missing, and up to the End of Study date. 
Serious Treatment-emergent Adverse Event 
A treatment-emergent adverse event with the indicator flag “Serious” equal to “Yes” on 
the Events eCRF. 
Treatment-emergent Adverse Device Effect 
A treatment-emergent adverse event with the indicator flag “Is there a reasonable 
possibility that the event may have been caused by the investigational device” equal to 
“Yes” on the Events eCRF. 
5.2 
Study Dates 
Informed Consent Date 
The date on which subject signs the informed consent form. 
eDiary Device Assignment Date  
The date on which an eDiary device is assigned to a subject for the first time after 
completion of initial screening.  


Product:  Erenumab 
Protocol Number:  20190006 
Date:  20 April 2023 
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First Dose Date 
First Dose Date is the date on which a subject is administered the first dose of IP 
following completion of the Baseline period as recorded on the IP Administration eCRF.  
Last Dose Date 
Last Dose Date is the date on which a subject is administered the last dose of IP during 
the study, where receiving IP is defined as above.  
End of Study (EOS) Date 
End of study (EOS) date is defined as the last date on which the subject participates in 
the study as recorded on the End of Study eCRF. 
5.3 
Study Points of Reference 
Baseline Assessment  
Baseline assessment for the endpoint of the interest is defined as the last non-missing 
measurement taken or the monthly interval assessed (for endpoints derived from daily 
eDiary collection) before the first dose of investigational product.  In cases where 
baseline measurements are taken on the same day as IP, it will be assumed that these 
measurements are taken prior to IP being administered. 
Study Day 1 
Study Day 1 is defined as the first IP dose date. 
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 study day prior to Study Day 1 is -1. 
5.4 
Study Time Intervals 
5.4.1 
Monthly Intervals for Efficacy Endpoints Derived From Daily Diary 
Collection 
The (4-week) monthly intervals for efficacy endpoints derived from daily eDiary collection 
will be determined based on each subject’s monthly IP dosing dates.  When an IP is 


Product:  Erenumab 
Protocol Number:  20190006 
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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.   
Applicable efficacy endpoints utilizing the monthly intervals in Table 3 include:  
 
Monthly migraine days (MMD) 
 
Monthly acute migraine-specific medication days 
 
Monthly acute headache medication days 
 
Monthly average migraine pain severity 
Table 3.  Monthly Intervals for Efficacy Endpoints Derived From Daily Data 
Collection 
Study 
Period 
Assessment 
Timepoint 
Monthly Interval 
Start Date (Day) a 
End Date (Day) b 
Baseline 
Period 
Baseline 
Device assignment date  
Day prior to study day 1 
Open-label 
Treatment 
Period 
 
Week 4 (Month 1) 
Study Day 1  
Week 4 dose date – 1 
Week 8 (Month 2) 
Week 4 dose date  
Week 8 dose date – 1 
Week 12 (Month 3) 
Week 8 dose date  
Week 12 dose date – 1 
Week 16 (Month 4) 
Week 12 dose date  
Week 16 dose date – 1 
Week 20 (Month 5) 
Week 16 dose date  
Week 20 dose date – 1 
Week 24 (Month 6) 
Week 20 dose date  
Week 20 dose date + 27 
a Start Date (Day) = End date (day) of previous monthly interval + 1 if IP dose is not received 
b End Date (Day) = Start date (day) of current monthly interval + 27 if IP dose is not received 
5.4.2 
Analysis Visits for Endpoints Based on Monthly Collection 
Since the actual visit for a subject may not exactly coincide with their targeted visit date, 
the actual visit date is mapped to the analysis visit as in Table 4. Any data occurred after 
EOS date will not be included in the analysis. 
For by-visit summaries, if more than one visit with non-missing measurement (including 
the unscheduled visits, ie, CPEVENT = ‘UNSCHED’) fall within the same visit window, 
the following rules will be applied according to the order described below for selecting 
one visit per visit window for summary:  
1. Scheduled visit will be used regardless of the distance from the target day.  
Unscheduled visit will only be used when there is no measurement from 
scheduled visit in the visit window.   
2. The visit closest to the target day among the same type of visits (scheduled vs. 
unscheduled) will be considered for analysis.   
3. If two assessment dates are equidistant from the target date, the latter visit will 
be considered for analysis.   


Product:  Erenumab 
Protocol Number:  20190006 
Date:  20 April 2023 
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 Table 4.  MFIQ Analysis Visit Windows 
Study Period 
Analysis Visit 
Target Day 
Visit Window (Study Day) 
 Baseline 
Period  
Day 1 (Baseline) 
1 
Last measurement ≤ Day 1 
Open-label  
Treatment  
Period 
Week 24 (Month 6) 
169 
156 to 183 
5.4.3 
Study Period 
Baseline period is defined in Table 3 and Table 4 respectively. The efficacy and 
safety analyses will be summarized for the OLTP. The analysis window will be 
defined with the starting time point given by study day 1 after the 1st IP dose and 
end time point given by EOS date. 
5.5 
Subject Disposition 
Exposed to Investigational Product 
Subjects are defined as exposed if they receive at least one dose of investigational 
product. Subjects will be defined as having received IP if the observed data 
indicates they have received IP (IP date is non-missing) on a specific date, even if 
the IP quantity field is missing (IPQTY = NULL). 
Completing the Investigational Product 
Subjects are defined as completing investigational product if they complete IP at week 
20. It will be derived from the End of IP eCRF with “Completed” as the primary 
reason for ending IP. 
Completing Study 
Subjects are defined as completing study if they complete the entire 24 weeks of study 
evaluation.  It will be derived from the End of Study eCRF with “Completed” as the 
primary reason for ending study. 
On-study 
Subjects are considered on-study if they are enrolled and have not yet completed their 
EOS visit. 
Dose Switch 
Per protocol, dose switch is permitted at the discretion of the investigator at week 
12. However, subjects could switch dose before or after week 12 if needed (e.g., 
adverse event). We define dose switch as an indicator variable indicating is a 
subject’s dosage changed from their baseline dose at any time during the study. 


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5.6 
Arithmetic Calculations 
Migraine Disease Duration 
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. 
Age at Onset of Migraine 
Age at onset of migraine is defined as Age – duration of migraine. 
Duration of IP Exposure 
If subject switches dose, 
 
Duration before the First Switch = Minimum (Last Initial Dose Date + 27, 
First Switch Dose Date – 1) – First Dose Date + 1 
 
Duration on or after the First Switch = Minimum (Last Dose Date + 27, EOS 
Date) – First Switch Dose Date + 1 
Otherwise, 
 
Duration = Minimum (Last Dose Date + 27, EOS Date) – First Dose Date + 1 
Change From Baseline 
Post-baseline monthly value – Baseline, as defined in Section  5.4.   
If the baseline or post-baseline 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:  
(Post-baseline – Baseline) * 100 / Baseline  
If the baseline value is 0 and the post-baseline value is also 0, the percent change from 
baseline is set to 0.  If the baseline value is 0 and the post-baseline value is non-zero, 
then the percent change from baseline is set to missing. 
Mean Monthly Change From Baseline Over Multiple Months 


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Arithmetic Mean monthly change from baseline is the arithmetic mean of the observed 
monthly change from baseline values for the months with non-missing change from 
baseline values.  
Subject Incidence 
The subject incidence for a given event in a given period is defined as the number of 
subjects with at least one reported occurrence of the event divided by the number of 
subjects who enter that period (ie, number of at-risk subjects).  For subjects with multiple 
occurrences of the same event, the event will only be counted once per subject. 
5.7 
Disease Characteristics 
Treatment Failure of Prior Migraine Preventive Medications 
Treatment failure of prior migraine preventive medications is determined by “Reason for 
Stopping” as “Lack of efficacy” or “Adverse reaction” on the Prior Migraine Prophylactic 
Medication eCRF. 
Menstrual-related migraine 
If a female patient responds yes to the question “Does the subject report migraine 
attacks that occurred on day 1 +/- 2 of menstruation (ie Days -2 to +3, day 1 = start of 
menstruation) in at least two out of the last three menstrual cycles prior to screening?” in 
the Headache and Migraine Frequency History eCRF then the patient will be considered 
in the subgroup menstrual-related migraine. 
6. 
Analysis Sets 
6.1 
Full Analysis Set 
The full analysis set (FAS) consists of all subjects who enroll in the study.  Analysis of 
disposition, demographic and baseline characteristics, and important protocol deviations 
(IPD) will utilize the FAS. 
6.2 
Safety Analysis Set 
The safety analysis set (SAS) will consist of a subset of subjects in FAS who receive at 
least 1 dose of investigational product.  Analysis for safety endpoints and summary of 
investigational product administration will utilize the SAS. 
6.3 
Study-specific Analysis Sets 
6.3.1 
Observed Data Analysis Set 
The observed data analysis set consists of a subset of subjects in FAS who receive at 
least 1 dose of investigational product and have an observed value for the endpoint of 
interest and pass the quality control procedures of genetic analysis.  Primary analysis of 


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the efficacy endpoints related to the genetic biomarkers will utilize the observed data 
analysis set. Details of this analysis set is mentioned in the analysis plan developed by 
deCODE. 
6.3.2 
Efficacy Analysis Set 
The efficacy analysis set (EAS) consists of a subset of subjects in FAS who receive at 
least 1 dose of investigational product.  Primary analysis of the exploratory efficacy 
endpoints will utilize observed data for subjects in the EAS. 
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
Not applicable. 
7.2 
Primary Analysis 
The primary analysis (or final analysis, as this study has only 1 milestone analysis) will 
be performed after all subjects have completed their week-24 or end-of-study visit.  The 
data will be cleaned, and the database will be locked for the primary analysis.   
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 RAVE database, data outside of RAVE database (eDiary data and 
biomarkers). The database will be subjected to edit check outlined in the Data 
Management Plan (DMP). Additional details for data outside of RAVE will be provided 
in the DMP and Data Acquisition Requirements Specification (DARS). 
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 because of a subject’s early withdrawal from the study, a missed visit, or 
inability to evaluate an endpoint at a time point.  For this study, efficacy endpoints will be 
collected via eDiary and subjects could miss entering several days of data in each 
monthly interval.  The general procedures outlined below describe how missing data will 
be handled. 
For the eDiary data, if at least 14 days of eDiary are collected in the monthly interval, 
then the monthly frequency measurements (eg, migraine days or acute migraine-specific 


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medications days [AMSMD]) will be prorated based on the number of days with available 
The analysis of all efficacy and safety endpoints will be performed by using observed 
data only. Missing efficacy assessments (eg, MMD, MFIQ etc.) will not be imputed. 
Missing safety endpoints will not be imputed.  Missing or incomplete dates will be listed 
as reported, except for incomplete start date of an adverse event or concomitant 
medication (Table 5). 
Table 5 Imputation for Incomplete Start Date of an Adverse Event or Concomitant 
Medication 
Missing 
Imputation 
Exception on Adverse Event Start Date 
Day 
01 
Default to study day 1 if an adverse event started 
the same year and month as study day 1 and the 
flag indicates that the adverse event started on or 
after the first dose of investigational product on the 
Events eCRF 
Day/Month 
01 Jan 
Default to study day 1 if an adverse event started 
the same year as study day 1 and the flag 
indicates that the adverse event started on or after 
the first dose of investigational product on the 
Events eCRF 
Day/Month/Year 
None 
— 
eCRF = electronic case report form 
Imputation Rules for Missing IP administration Dates of the last IP dose 
If the date of last exposure treatment weeks is partial or entirely missing but 
receiving IP is confirmed, impute the date by the study Day 1 + last exposure 
treatment weeks * 7 days. Ensure the imputed last exposure to treatment date is 
on or before the end of study date.  
Imputation of missing genotype data 
The details for the imputation of genotype data will be described in the deCODE 
Analysis Plan (Appendix B). 
8.4 
Detection of Bias 
The factors that may bias the results of the study include: 


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 important protocol deviations likely to impact the analysis and interpretation of the 
efficacy endpoints  
 investigational product dosing non-compliance  
 the timing of and reasons for early withdrawal from treatment and from study  
The incidence of these factors may be assessed. Important protocol deviations will be 
tabulated and/or listed.   
The reasons for early withdrawal from treatment and from study will be tabulated and/or 
listed. 
8.5 
Outliers 
Histograms will be examined to identify outliers in any of the continuous variables used 
in the analyses. Unexpected and/or unexplained values in categorical data will be 
identified by utilizing frequency tables.  
Outliers due to data entry errors will be corrected by the study team before final 
database lock.  The validity of any questionable values or outliers will be confirmed. 
Outliers or any questionable values with confirmed validity will be included in the 
analyses presented in this statistical analysis plan unless there is sufficient justification 
to exclude them. However, ad-hoc sensitivity analyses may be conducted to evaluate 
the influence of extreme values in the data. 
8.6 
Distributional Characteristics 
Continuous endpoints of change from baseline value will be analyzed under normality 
assumption. Transformations may be used if necessary. For example, baseline 
CGRP levels will be log-transformed before analysis if high skewness is present. 
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.   
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later. 


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9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Summary statistics will be tabulated at each assessment time point, as applicable.  For 
continuous endpoints, the descriptive statistics include the following:  number of 
observations, means, medians, standard deviations, standard errors, first and third 
quartiles, minimums and maximums, and 2-sided 95% CIs of the means (CIs will be 
provided for efficacy endpoints only).  For categorical endpoints, the summaries will 
contain the number and percentage of subjects in each category. 
The primary (or final) analysis for the study will be performed on a locked database after 
all subjects have completed the study or discontinued from the study. 
Weighted Bonferroni adjustment will be used to maintain a family-wise error rate of 0.05 
(2-sided) for primary endpoint. Analyses involving endpoints related to genetic features 
will be performed by deCODE. 
Summary of efficacy endpoints by treatment group will be based on treatment 
received on study day 1. Dose switching between 70 mg and 140 mg erenumab are 
permitted at the week 12 visit per investigator’s discretion. 
9.2 
Subject Accountability 
The disposition of all enrolled subjects will be tabulated by treatment dose group 
received on study day 1. The summary will include the number of subjects who are 
enrolled, the number and percent of subjects who received/never received the IP, who 
completed IP, discontinued IP and reasons for discontinuing, who completed the study, 
and who withdrew prematurely from the study before completion of the 24-week 
treatment period and their reasons for withdrawal. 
Key study dates for the first subject enrolled, last subject enrolled, last subject's end of 
investigational product, last subject's end of study will be presented. 
The number and percent of subjects enrolled will be tabulated by study site.  
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to database lock.  These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the course of the study.  Eligibility deviations are defined 
in the protocol. 


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9.4 
Demographic and Baseline Characteristics 
Subject demographic and baseline characteristics will be summarized using descriptive 
statistics by country and overall study population using FAS.  If multiple races have been 
reported for a subject, the subject will be categorized as multiple races. 
The following demographic and baseline characteristics will be summarized:  
 
Age 
 
Sex 
 
Ethnicity 
 
Race 
 
Targeted neurological disease diagnosis at baseline 
 
Disease duration of migraine 
 
Age at onset of migraine 
 
Monthly migraine days during baseline period 
 
Acute headache medication days (AHMD) during baseline 
 
Acute headache medication used during baseline 
 
MFIQ domain scores of function (physical, usual activities, social, and emotional) 
and overall impact on usual activities global item score at baseline 
 
Female subjects of child bearing potential and those with menstrual related 
migraine (yes/no)  
 
Plasma CGRP levels during baseline 
 
Migraine classification at screening (EM/CM) 
 
Aura (yes/no) during baseline 
 
Prior migraine preventive treatment use 
 
Triptan medication used during baseline 
 
Triptan medication days during baseline  
9.5 
Efficacy Analyses 
Detailed analysis methods and covariates included in the models are summarized in the 
table below. 
Table 6. Analysis of Primary Efficacy Endpoint to be Performed by deCODE 
Endpoint 
Primary Summary and Analysis Method 
Achievement of at least a 50% 
reduction from baseline in mean 
monthly migraine days (MMD) over 
months 4, 5, and 6 in relation to 
each individual genome-wide 
significant single-nucleotide 
polymorphism (SNP) contributing to 
This analysis is planned to be performed by deCODE 
and details of the analysis are described in deCODE 
Analysis Plan (Appendix B).  


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Endpoint 
Primary Summary and Analysis Method 
the migraine polygenic risk score 
(mPRS) 
Table 7. Analysis of Exploratory Efficacy Endpoint to be Performed by deCODE 
Endpoint 
Primary Summary and Analysis Method 
Change from baseline in monthly 
AMSMD over months 4, 5, and 6, in 
relation to mPRS 
This analysis is planned to be performed by 
deCODE and details of the analysis are described 
in deCODE Analysis Plan (Appendix B).  
mPRS in relation to baseline CGRP 
level 
mPRS in relation to baseline MMD 
mPRS in relation to baseline 
AMSMD 
mPRS in relation to baseline acute 
headache medication days (AHMD) 
mPRS in relation to Migraine 
Functional Impact Questionnaire 
(MFIQ) individual domain scores 
(physical function, usual activities, 
social function, and emotional 
function) and overall impact usual 
activities global item score at 
baseline 
mPRS in relation to presence of aura 
during baseline 
mPRS in relation to baseline mean 
migraine severity 
Change from baseline in MFIQ 
individual domain scores (physical 
function, usual activities, social 
function and emotional function) and 
overall impact usual activities global 
item score at month 6, in relation to 
mPRS 
Published migraine SNPs in relation 
to baseline CGRP 
 
 
Table 8.  Analysis of Exploratory Efficacy Endpoints to be Performed by Amgen 
Endpoint 
Primary Summary and Analysis Method 
Change from baseline in MMD over 
months 4, 5, and 6 in relation to 
baseline CGRP level 
 
1. Summary statistics by visit using observed data at 
each visit, and the calculated mean monthly 
migraine days over month 4, 5 and 6. 
2. Estimated slope for baseline CGRP, associated 
95% CI and nominal p-value from a linear 


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Endpoint 
Primary Summary and Analysis Method 
regression model including baseline CGRP, age, 
sex, dose switch (yes/no), baseline dose (full 
sample analysis only), and baseline MMD value 
as covariate using observed data. Dose switch 
was excluded for 140 mg treatment group. 
3. Spearman correlation between baseline non-
transformed CGRP and Change from baseline 
in MMD over months 4, 5, and 6. 
4. A scatterplot with loess will developed for 
CGRP level with change from baseline in 
monthly MMD over months 4, 5, and 6.  
 
Achievement of at least a 50% 
reduction from baseline in mean 
MMD over months 4, 5, and 6 in 
relation to baseline CGRP level 
1. Summary statistics based on observed data. 
2. Odds ratio estimate for baseline CGRP, associated 
95% CI, and nominal p-value from a logistic 
regression model with baseline CGRP level as 
covariate along with baseline MMD, dose switch 
(yes/no), baseline dose (full sample analysis 
only), age and sex. Dose switch was excluded 
for 140 mg treatment group. 
3. Predicted probabilities of achieving at least a 50% 
reduction in MMD 
Achievement of at least a 75% 
reduction from baseline in mean 
MMD over months 4, 5, and 6, in 
relation to baseline CGRP level 
Same as above. 
Change from baseline in monthly 
AMSMD over months 4, 5, and 6, in 
relation to baseline CGRP level 
1. Estimated slope for baseline CGRP, associated 
95% CI and nominal p-value from a linear 
regression model including baseline CGRP, age, 
sex, dose switch (yes/no), baseline dose (full 
sample analysis only), and baseline AMSMD 
value as covariate using observed data. Dose 
switch was excluded for 140 mg treatment 
group. 
2. Spearman correlation analysis will be applied 
between baseline CGRP and change from baseline 
in monthly AMSMD over months 4, 5, and 6. 
3. A scatterplot with loess will developed for 
CGRP level with change from baseline in 
monthly AMSMD over months 4, 5, and 6. 
Baseline MMD in relation to baseline 
CGRP level 
 
1. Summary statistics using observed data. 
2. Estimated slope for CGRP, associated 95% CI and 
nominal p-value from a linear regression model 
including age, sex, country (full sample analysis 
only), and baseline CGRP as covariate using 
observed data. 
3. Spearman correlation between baseline CGRP 
and baseline MMD. 


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Endpoint 
Primary Summary and Analysis Method 
Baseline AMSMD in relation to 
baseline CGRP level 
 
1. Summary statistics using observed data. 
2. Estimated slope for CGRP, associated 95% CI and 
nominal p-value from a linear regression model 
including age, sex, country (full sample analysis 
only), and baseline CGRP value as covariate using 
observed data. 
3. Spearman correlation between baseline CGRP 
and baseline AMSMD. 
Baseline AHMD in relation to 
baseline CGRP level 
 
1. Summary statistics using observed data. 
2. Estimated slope for CGRP, associated 95% CI and 
nominal p-value from a linear regression model 
including age, sex, country (full sample analysis 
only), and baseline CGRP value as covariate using 
observed data. 
3. Spearman correlation between baseline CGRP 
and baseline AHMD. 
Baseline mean migraine severity in 
relation to baseline CGRP level 
1. Summary statistics using observed data. 
2. Estimated slope for baseline CGRP, associated 
95% CI and nominal p-value from a linear 
regression model including age, sex, country (full 
sample analysis only), and baseline CGRP as 
covariate using observed data. 
3. Spearman correlation between baseline CGRP 
and baseline mean migraine severity. 
Presence of aura during baseline in 
relation to baseline CGRP level 
 
1. Summary statistics using observed data. 
Estimated odds ratio for baseline CGRP, 
associated 95% CI and nominal p-value from a 
logistic regression model including age, sex, 
country (full sample analysis only), and baseline 
CGRP using observed data. 
Each MFIQ individual domain score 
(physical function, usual activities, 
social function, and emotional 
function) and overall impact usual 
activities global item score at 
baseline in relation to baseline 
CGRP level  
1. Summary statistics using observed data. 
2. Estimated slope for baseline CGRP, associated 
95% CI and nominal p-value from a linear 
regression model including age, sex, country (full 
sample analysis only),  and baseline CGRP as 
covariate using observed data. 
3. Spearman correlation between baseline CGRP 
and baseline MFIQ score. 
Change from baseline in MFIQ 
individual domain scores (physical 
function, usual activities, social 
function, and emotional function) and 
overall impact usual activities global 
item score at month 6 
1. Summary statistics using observed data. 
2. Estimated least squares means and associated 
95% CI from an ANCOVA model including age, 
sex, dose switch (yes/no), baseline dose, and 
baseline MFIQ score as covariate using observed 
data.  
 
 
 


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9.5.1 
Analyses of Primary Efficacy Endpoint(s) 
Analyses for the primary endpoint will identify the migraine SNPs significantly 
associated with clinical response of achievement of at least a 50% reduction from 
baseline in mean MMD over months 4, 5, and 6 and will be performed by deCODE. 
Details of this analysis are outlined in deCODE Analysis Plan (Appendix B).  
9.5.2 
Analyses of Exploratory Efficacy Endpoint(s) 
The exploratory endpoints except the endpoints related to genetic biomarkers will utilize 
the EAS. All models described below will include covariates as specified in 
Section 4.1. 
Endpoint 
Primary Summary and Analysis Method 
Change from baseline in mean MMD 
over months 4, 5, and 6 
 
Change from baseline in MMD at 
assessment timepoints 
 
Change from baseline in mean 
monthly AMSMD over months 4, 5, 
and 6 
 
Change from baseline in monthly 
AMSMD at assessment timepoints 
 
Change from baseline in mean 
monthly AMHD over months 4, 5, 
and 6 
 
Change from baseline in monthly 
AHMD at assessment timepoints 
 
 
1. Summary statistics using observed data. 
2. Least squares means and associated 95% CI from 
a generalized linear mixed effect model including 
visit, age, sex, dose switch (yes/no), baseline 
dose (full sample analysis only), and baseline 
value as covariate using observed data for all 
assessment timepoints. Dose switch was 
excluded for 140 mg treatment group. A LSM 
will be presented for change from baseline at each 
assessment timepoints, and a LSM comparing 
change from baseline over months 4, 5, 6 will be 
presented using contrasts.  
Achievement of at least a 50% 
reduction from baseline in mean 
MMD over months 4, 5, and 6 
 
Achievement of at least a 50% 
reduction from baseline in MMD at 
assessment timepoints 
 
Achievement of at least a 75% 
reduction from baseline in mean 
MMD over months 4, 5, and 6 
 
Achievement of at least a 75% 
reduction from baseline in mean 
MMD at assessment timepoints 
1. Summary statistics based on observed data. 


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The continuous exploratory efficacy endpoints at each assessment time point or as the 
mean over months 4, 5, and 6 of the 6-month OLTP will be analyzed using the 
generalized linear mixed effects model that includes visit and baseline values of the 
endpoint, without any imputation for missing data. Least squares means and associated 
95% CI will be reported. 
The continuous exploratory efficacy endpoints involving two cross-sectional measures 
(eg. Change from baseline in MMD at week 12  [endpoint], in relation to change from 
baseline in CGRP level at week 12 [factor]) will be analyzed using a linear regression 
model that includes corresponding baseline values and the variable of interest as 
covariates without any imputation for missing data. Estimated slope for the variable of 
interest, associated 95% CI, and nominal p-value from the same model will be reported. 
The continuous exploratory efficacy endpoints with relation to a factor (eg. baseline 
CGRP) will be analyzed using the generalized linear regression model that includes 
corresponding baseline values and the factor as covariate without any imputation for 
missing data. Estimated slope for the factor, associated 95% CI and nominal p-value 
from the same will be reported. Least square means and 95% CI corresponding to 
selected baseline values of the factor (eg. quintiles) will be reported. 
The continuous exploratory efficacy endpoints involving change from baseline 
MFIQ at week 24 will be analyzed using an ANCOVA model including baseline 
score as covariates without any imputation for missing data. Least squares means 
and associated 95% CI will be reported. 
The dichotomous efficacy endpoints with relation to a factor (eg. baseline CGRP) will be 
analyzed using logistic regression model including the factor of interest as a 
covariate and without any imputation of missing data. Odds ratios with associated 95% 
confidence intervals and p-values will be reported. Otherwise, descriptive statistics using 
observed data will be summarized. 
The analysis of exploratory endpoints with mPRS will be performed by deCODE and 
details of the analysis are outlined in deCODE Analysis Plan (Appendix B). 
9.6 
Safety Analyses 
9.6.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 22.0 or later will be 
used to code all events categorized as adverse events to a system organ class and a 


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preferred term. All AEs will be graded using the Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.03. 
The subject incidence of adverse events will be presented for the following groups: 
(1) subjects always receiving 70mg, (2) subjects who switched from 70mg to 
140mg at any time during the study, (3) subjects who switched from 140mg to 
70mg at any time during the study, (4) subjects always receiving 140mg, (5) 
overall – all subjects combined. The subject incidence rates will summarized by 
SOC in alphabetical order and PT in descending order of frequency for all 
treatment-emergent adverse events, serious treatment-emergent adverse events, 
treatment-emergent adverse events leading to withdrawal of investigational product, 
treatment-emergent adverse device effect, treatment-related adverse events, 
treatment-related serious adverse events, and fatal adverse events, 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) 
Summaries of treatment-emergent adverse events and serious treatment-emergent 
adverse events will be tabulated by system organ class, preferred term, and CTCAE 
grade. 
9.6.2 
Exposure to Investigational Product 
The total length of investigational product exposure and exposure by dose level, the 
total dose of investigational product, and the proportion of subjects receiving each dose 
will be summarized using descriptive statistics. 
9.6.3 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving acute headache medication or triptan will 
be summarized for baseline and post-baseline. 


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9.7 
Other Analyses 
9.7.1 
Analyses of Biomarker Endpoints 
Summary statistics will be provided for baseline CGRP Biomarker measurements. 
Endpoints related to baseline CGRP measurements have been described in Section 
9.5.2 and Tables 7 & 8.  
10. 
Changes From Protocol-specified Analyses 
The proteomics analyses performed by deCODE are not specified in the protocol 
but will be performed and included in the final CSR.  
The primary endpoint analyses have evolved based on deCODE’s 
recommendation. We will no longer present summaries for any genetic variant 
that is found to be statistically associated with a 50% reduction in MMD over 
months 4, 5, and 6. Instead, we will only consider associations for a pre-
determined set of genetic variants, where these genetic variants will be selected 
because they have shown genome-wide significant association with migraine in 
previous studies (~135 SNPs total expected). The reasoning for this change is that 
the Bonferroni threshold to determine statistical significance will be stricter if we 
considered all genetic variants (0.05/1,000,000 = 5E-8) than if we only considered a 
subset of genetic variants (using 135 SNPs gives a threshold of 0.05/135 =3.7E-4). 
This will substantially improve power to detect statistical significance for 
individual genetic variants.  
11. 
Literature Citations / References 
Mikol DD, Picard H, Klatt J, Wang A, Peng C, Stefansson K. Migraine Polygenic Risk 
Score Is Associated with Severity of Migraine–Analysis of Genotypic Data from Four 
Placebo-controlled Trials of Erenumab. Neurology. 2020;94 (15 supplements): 1214.  
12. 
Prioritization of Analyses 
Prioritization of analyses has not been identified at this time. 
13. 
Data Not Covered by This Plan 
The Global Biostatistical Science department will not perform any analyses using 
genomics or proteomics data in this study and will not analyze post-baseline 
CGRP data at this time. 
 


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14. 
Appendices 
Appendix A.  Reference Values/Toxicity Grades 
Adverse event severity and laboratory toxicity are graded based on NCI Common 
Toxicity Criteria version 4.03 or higher, which is available at the following:  
https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf 
 
 


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Appendix B.  deCODE Analysis Plan 
 
 


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English: Genetic research methods and data analyses for the Biomarker 
and Genetic Predictors of Erenumab Treatment Response, a Phase 4 
Investigational Open-label Study (INTERROGATE) 
 
Methods and analysis plan: 
Whole genome sequencing, genotyping and imputation.  
DNA samples will be genotyped using Illumina chips and automated allele-calling software. The front 
end of the Illumina LIMS system has been integrated with deCODE‘s blood and DNA sample tracking 
LIMS system. The data output will feed into deCODE‘s genotype QC system. We have confirmed the 
high quality of the data through inheritance checking of large parent-offspring sets. SNPs will be 
excluded if they have (i) yield lower than 95%, (ii) minor allele frequency less than 1% in the population 
or (iii) significant deviation from Hardy-Weinberg equilibrium in the controls (P< 0.001). All samples 
with a call rate below 98% will be excluded from the analysis and SNP imputations. 
Whole-genome sequencing (WGS) may be performed on selected samples using Illumina technology (1) 
if they show evidence of rare variants of interest. The sequencing will be performed using NEBNext 
Ultra™ II DNA Library Preparation and Illumina NovaSeq sequencers.  
Sequence variants discovered by deCODE‘s whole genome sequencing (WGS) project (1) will be 
imputed. The basis for this imputation is the long range phasing of all chip-genotyped individuals as 
performed with methods described previously (2,3). Currently, whole genome sequences have been 
obtained for over 50,000 Icelandic individuals at high coverage of at least 10x (average coverage close to 
30x).  Sequence variants from these individuals have been propagated using our genealogy and high 
density genotype databases throughout Iceland’s entire population resource.  Approx. 36  million variants 
(SNPs and indels) WGS of ~ 50,000 Icelanders are imputed into >155,000 chip-typed individuals and 
their first and second degree relatives (1) according to their long range phasing results by the same model 
as used by IMPUTE (4). For all participants we will impute the SNPs identified and genotyped through 
sequencing, using imputation assisted by long-range haplotype phasing, the genotypes of all the variants 
identified by sequencing will be determined for >155,000 Icelanders who have been genotyped with 
Illumina SNP chips (300K to 2.5 million SNP chips).  The nationwide Icelandic genealogical database 
then allows the propagation of this genotype information into close relatives (for whom we have neither 
SNP chip nor sequence data) of the chip-genotyped individuals (familial imputation). Such imputed 
genotypes will be estimated and used temporarily for association  analysis, but never stored or made 
accisible to the researchers. 
In addition sequence variants will be imputed from the publicly available SNP data of the HapMap (5) 
European CEU sample1 (60 triads) and the 1000 Genomes Project data (6) (179 individuals). 
Approximately 2.5 million SNPs will be imputed based on the HapMap (6) data, and 6.9 million SNPs 
based on the 1000 Genomes Project data.  
Analysis plan: 
Analysis of primary and exploratory objectives will be performed by deCODE. Amgen will provide the 
subject level clinical endpoints and covariates of interest to be analysed in relation to mPRS, sequence 
variants, and proteins. The analysis set for all deCODE performed analyses consists of individuals who 
receive at least one dose of investigational product, have an observed value for the endpoint of interest, 
pass all quality control procedures, and who are determined to be of Icelandic or Danish ancestry based 
on admixture analysis. Age, sex, dose switch (yes/no), and the baseline value of the clinical endpoint of 
interest (when applicable) will be used as covariates in all analyses. Additionally, principal components 
will be included as covariates in all Denmark related genomic analyses to account for population 
structure. Analyses will be run both with and without the dose switch (yes/no) and baseline clinical value 


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covariates to assess model robustness. All described analyses will be run separately in the Iceland and 
Denmark samples, and subsequently combined in a meta-analysis. 
Genomic analyses will focus on a subset of 136 migraine variants found to be associated with migraine in 
previous literature instead of genome-wide analyses (9, 23). The rationale for focusing on this subset of 
migraine variants is to substantially reduce the multiple testing burden, since a Bonferroni genome-wide 
significance threshold = 5E-8 and a Bonferroni corrected threshold for the migraine variant subset = 
0.05/136 = 3.7E-4. 
Primary objective 
To explore the relationship between clinical response to erenumab and genetic/proteomic biomarkers 
 
Endpoint: 
Achievement of at least a 50% reduction from baseline in mean monthly migraine days (MMD) over 
months 4, 5, and 6 in relation to each individual genome-wide significant single-nucleotide polymorphism 
(SNP) contributing to the migraine polygenic risk score (mPRS). 
 
Method: 
Test for association using logistic regression between migraine variants and the mPRS and whether 
individuals treated with erenumab achieve 50% reduction from baseline in MMD over months 4, 5, and 6. 
Individuals who do not achieve at least a 50% reduction are considered controls and those who achieve a 
least a 50% reduction are considered cases.  
Additionally, this analysis will be performed separately in each of the following subgroups: sex 
(female/male), presence of aura during baseline period (yes/no), menstrual-related migraine at screening 
(yes/no), migraine classification at screening (EM/CM), and prior migraine prophylactic treatment failure 
(yes/no). The subgroups will be re-examined for appropriateness and may be re-categorized (due to small 
sample size, for example, if there are < 10% of subjects within a subgroup). 
 
Exploratory objectives 
1. To explore the relationship between effect of erenumab on AMSMD and the mPRS 
Endpoint: Change from baseline in mean monthly AMSMD over months 4, 5, and 6, in relation to the 
mPRS 
Method: 
Test for association between the mPRS and the mean change from baseline in monthly AMSMD over 
months 4, 5, and 6 using linear regression.  
2. To describe the relationship between the mPRS and baseline CGRP 
Endpoint: The mPRS in relation to baseline CGRP level 
Method: 
Test for association between the mPRS and baseline CGRP using linear regression. Association between 
the migraine SNPs and baseline CGRP will also be analyzed. If high skewness is present, baseline CGRP 
will be transformed using a log-transformation and rank-based inverse normal transformation to assess 
model robustness. See Exploratory Objective 1. 
3. To describe the relationship between the mPRS and migraine disease characteristics 
Endpoints:  


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 
mPRS in relation to baseline MMD 
 
mPRS in relation to baseline AMSMD 
 
mPRS in relation to baseline acute headache medication days (AHMD) 
 
mPRS in relation to Migraine Functional Impact Questionnaire (MFIQ) individual domain scores 
(physical function, usual activities, social function, and emotional function) and overall impact 
usual activities global item score at baseline 
 
mPRS in relation to presence of aura during baseline 
 
mPRS in relation to baseline mean migraine severity 
Method: 
Test for association between the mPRS and baseline migraine disease characteristic endpoints using linear 
regression. See Exploratory Objective 1. 
4. To describe the relationship between change from baseline in MFIQ score and mPRS in 
erenumab treated subjects 
Endpoint: Change from baseline in MFIQ individual domain scores (physical function, usual activities, 
social function and emotional function) and overall impact usual activities global item score at month 6, 
in relation to mPRS 
Method: 
Test for association between the mPRS and the specified MFIQ endpoints using linear regression. See 
Exploratory Objective 1. 
Methods: 
Association analysis and meta-analysis.  
Genomic associations will only be assessed for SNPs previously validated as being genome-wide 
associated with migraine. This comprises 136 SNPs to date (9, 23), and this list will be updated with any 
additional migraine SNPs that may be published at the time of analysis. Associations will be assessed 
separately in each sample (Iceland, Denmark) and then combined in a meta-analysis. A Bonferroni 
correction will be used to account for multiple testing. 
Calculation of migraine polygenic risk scores (mPRS)  
Complex traits such as migraine, are affected by many genes and sequence variants, most of which have a 
small effect on disease risk (8,9). Polygenic scores can be constructed for any complex genetic phenotype 
for which a GWAS is available, such as from the large migraine GWAS meta-analyses by Gormley et al. 
including 375,000 individuals (8) and the most recent, even larger (approximately 1 million individuals) 
by Hautakangas et al (9). The migraine polygenic risk score (mPRS) will be calculated using migraine 
GWAS summary statistics from the largest cohorts available to deCODE genetics at the time of analysis 
(excluding data from Denmark and Iceland). The polygenic risk score (mPRS) values can then be 
calculated for the individuals participating in the clinical trial by summing their identified risk alleles, 
which are weighted by effect sizes derived from the GWAS results (8). Linkage disequilibrium will be 
accounted for using the LDPred software package (10). Principal components will be used to account for 
population structure within Denmark. No overlap between training and testing datasets is essential to 
maintain independence of predictions, and the removal of related individuals is also needed, as 
demonstrated and described in detail by Wray et al. (11). 
Effect of sequence variants on levels of plasma proteins and CGRP. 
Proteins (n=~7,000) in plasma samples from the study participants will be measured using SomaLogic® 
(SomaLogic, Inc.) as described elsewhere (16,17). In short, aptamers are modified to recognize specific 


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proteins and an assay quantifies them on a DNA microarray after the protein concentrations are converted 
into DNA aptamer concentrations. We will perform a proteome-wide association study (PWAS) and 
evaluate whether migraine associating sequence variants associate with protein levels, after taking into 
account other pQTLs at the locus that could be driving the signal. Statistical analyses (PWAS) will be 
performed using linear regression of log-transformed protein levels against erenumab-response, SNP 
allele count and mPRS. A Bonferroni correction will be used to account for multiple testing. 
CGRP will be measured by Meso Scale Diagnostics (MSD). Association of baseline CGRP levels with 
migraine SNPs and mPRS will be tested. 
The ethics of extensive genetic testing 
Extensive genetic testing (GWA chip analysis and genome sequencing) is used to assess common 
complex diseases, i.e., migraine in this study, where the individual risk variant is neither sufficient nor 
necessary to cause disease. The research results of the extensive genetic testing are therefore important at 
the group level for scientific purposes, but not valid for making clinical judgments on the individual level 
on the health of the participants. The research participants will, in general, not be informed of the results 
of their genetic makeup apart for incidental findings (see below). 
Incidental findings 
The Infinium® Global Screening Array (GSA) from Illumina® includes a large number of clinically 
relevant variants (derived fromClinVar, CPIC and PharmGKB) and whole genome sequencing using 
the Illumina HiSeqX sequencer together with imputation  may detect most clinically relevant variants. 
Therefore, clinically important variants included on the list of genes defined by the American college of 
Medical Genetics and Genomics (ACMG) that are well studied and would require feed-back to the 
research participants could incidentally appear in the analysis of genetic associations to specific traits 
within this study. Because it is not the purpose of these studies to find these variants, detection of these 
variants will be considered an incidental finding (21). 
In the unlikely event that we find a known disease-specific mutations with high penetrance even though it 
is not part of the specific purpose of the study, we have established an independent committee that will 
advise us on how to confirm that the mutation is indeed present (confirmation analysis by use of a CE 
marked assay, see the recommendations given by the National Scientific Ethics Committee doc. no.: 
228077, November 2016). The committee will include clinical immunologists, bioinformaticians and 
molecular biologists. Elsebet Østergaard, chief physician, professor from the Department of Clinical 
Genetics at Rigshospitalet will also be part of the committee. If technically validated, the committee will 
carefully assess the level of evidence for pathogenicity. This will be done using all available literature and 
exome sequence databases of variants seen in the control population. Such a careful assessment is 
necessary as recent studies have indicated that many variants have erroneously been reported as 
pathogenic in monogenic diseases, caused by biased study designs (22). If a mutation is found within the 
ACMG actionable disorder panel, the participant will be contacted by the research group, provided the 
participant had previously provided consent.  
Contact to the participants with information on incidental findings 
For research participants that have a confirmed clinical relevant genetic variant as an incidental finding, 
the expert committee will appoint a doctor within the specific speciality in the region of the research 
participants to take care of the clinical management. It is arranged that the research participant has an 
appointment at the specialist department before the research participant is contacted by phone by the 
project manager. Only research participants that have agreed to be contacted in case of incidental findings 
will be contacted. The contact by phone will confirm the research participant’s current stance on feedback 
on genetic findings and will inform the research subject about the finding and the immediate handling of 


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this. If the research participant agrees to further clinical treatment for the finding he/she will immediately 
be scheduled for an appointment at the specialist department. At this stage, it will be obvious for the 
research participant that we have a significant genetic finding. However, the research participant will be 
offered time for consideration whether he/she wants to be told what the specific genetic finding is – and 
what it means. If the research participant wants the information – at the same telephone consultation – or 
at a later consultation – the precise information is given, and the further clinical managements will be in 
accordance with the management offered for the specific genetic finding. The research participant will be 
given a phone number on which the project manager can be contacted in case of questions. The research 
participant will also be offered to invite a representative (e.g. a family member or a friend) to participate 
in the consultation at the hospital or at telephone conference. At the consultation at the hospital specialist 
department, the research participant will be given thorough genetic counselling including information 
about the general knowledge about genetic aetiologies in many diseases and the clinical application of 
such findings and ethical and legal aspects will be addressed. The research participant will be told about 
the potential use of genetic findings including the options in relation to work-up of families with inherited 
diseases. The research participant’s rights to know and rights not to know will be discussed. 
 
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