A 12-week Phase 3, Randomized, Double-blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of Once Monthly Subcutaneous Erenumab 70 mg in Adult Chronic Migraine Patients
Phase: PHASE3
Conditions: Migraine
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development 
AMG334 
Clinical Trial Protocol CAMG334A2304 / NCT03867201
A 12-week phase 3, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety of once 
monthly subcutaneous erenumab 70 mg in adult chronic 
migraine patients 
Document type: 
Clinical Trial Protocol (Clean) 
EUDRACT number: 
Not applicable 
Version number: 
02 (Amended protocol) 
Clinical Trial Phase: 
III 
Release date: 
26-Jan-2021
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template version 3.0 (31-Jan-2020) 

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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 9 
Amendment 02 (26-Jan-2021) ........................................................................................... 11 
Amendment 01 (19-Sep-2019) .......................................................................................... 16 
Protocol summary .............................................................................................................. 21 
1 
Introduction ....................................................................................................................... 24 
1.1 
Background ............................................................................................................ 24 
1.2 
Purpose .................................................................................................................. 26 
2 
Objectives and endpoints ................................................................................................... 26 
3 
Study design ...................................................................................................................... 28 
4 
Rationale ............................................................................................................................ 31 
4.1 
Rationale for study design ..................................................................................... 31 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 32 
4.3 
Rationale for choice of control drugs (comparator/placebo)  ................................ 33 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 33 
4.5 
Risks and benefits .................................................................................................. 34 
5 
Study population ................................................................................................................ 36 
5.1 
Inclusion criteria .................................................................................................... 36 
5.2 
Exclusion criteria ................................................................................................... 36 
5.3 
Inclusion/Exclusion criteria for the open-label treatment period .......................... 39 
6 
Treatment ........................................................................................................................... 40 
6.1 
Study treatment ...................................................................................................... 40 
6.1.1 
Investigational and control drugs .......................................................... 40 
6.1.2 
Additional study treatments .................................................................. 40 
6.1.3 
Treatment arms/group ........................................................................... 40 
6.1.4 
Treatment duration ................................................................................ 41 
6.2 
Other treatment(s) .................................................................................................. 41 
6.2.1 
Concomitant therapy ............................................................................. 41 
6.2.2 
Prohibited medication ........................................................................... 41 
6.2.3 
Rescue medication ................................................................................ 42 
6.3 
Subject numbering, treatment assignment, randomization .................................... 43 
6.3.1 
Subject numbering ................................................................................ 43 
6.3.2 
Treatment assignment, randomization .................................................. 43 

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6.4 
Treatment blinding ................................................................................................ 43 
6.5 
Dose escalation and dose modification.................................................................. 44 
6.5.1 
Dose modifications ................................................................................ 44 
6.5.2 
Follow-up for toxicities ......................................................................... 44 
6.6 
Additional treatment guidance ............................................................................... 45 
6.6.1 
Treatment compliance ........................................................................... 45 
6.6.2 
Emergency breaking of assigned treatment code .................................. 46 
6.7 
Preparation and dispensation ................................................................................. 46 
6.7.1 
Handling of study treatment and additional treatment .......................... 46 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 47 
7 
Informed consent procedures ............................................................................................ 48 
8 
Visit schedule and assessments ......................................................................................... 49 
8.1 
Screening ............................................................................................................... 55 
8.1.1 
Information to be collected on screening failures ................................. 55 
8.2 
Subject demographics/other baseline characteristics............................................. 56 
8.3 
Efficacy .................................................................................................................. 56 
8.3.1 
Migraine Days ....................................................................................... 56 
8.3.2 
Appropriateness of efficacy assessments .............................................. 57 
8.4 
Safety ..................................................................................................................... 57 
8.4.1 
Laboratory evaluations .......................................................................... 58 
8.4.2 
Electrocardiogram (ECG) ..................................................................... 59 
8.4.3 
Pregnancy and assessments of fertility ................................................. 60 
8.4.4 
Prospective suicidality assessment ........................................................ 60 
8.4.5 
Appropriateness of safety measurements .............................................. 61 
8.5 
Additional assessments .......................................................................................... 61 
8.5.1 
Clinical Outcome Assessments (COAs) ............................................... 61 
8.5.2 
Patient Reported Outcomes (PROs) ...................................................... 62 
 
 63 
 
 64 
8.5.5 
AMG 334 Antibody testing ................................................................... 65 
9 
Study discontinuation and completion .............................................................................. 65 
9.1 
Discontinuation ...................................................................................................... 65 
9.1.1 
Discontinuation of study treatment ....................................................... 65 
9.1.2 
Withdrawal of informed consent ........................................................... 66 
9.1.3 
Lost to follow-up ................................................................................... 67 
9.1.4 
Early study termination by the sponsor ................................................. 67 
9.2 
Study completion and post-study treatment .......................................................... 67 

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10 Safety monitoring and reporting ........................................................................................ 68 
10.1 
Definition of adverse events and reporting requirements ...................................... 68 
10.1.1 
Adverse events ...................................................................................... 68 
10.1.2 
Serious adverse events .......................................................................... 69 
10.1.3 
SAE reporting........................................................................................ 70 
10.1.4 
Pregnancy reporting .............................................................................. 71 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 71 
10.2 
Additional Safety Monitoring ................................................................................ 72 
10.2.1 
Liver safety monitoring ......................................................................... 72 
10.2.2 
Prospective suicidality assessment ........................................................ 73 
10.2.3 
Data Monitoring Committee ................................................................. 74 
10.2.4 
Steering Committee ............................................................................... 74 
10.2.5 
Adjudication committee ........................................................................ 74 
11 Data Collection and Database management ...................................................................... 74 
11.1 
Data collection ....................................................................................................... 74 
11.2 
Database management and quality control ............................................................ 75 
11.3 
Site monitoring ...................................................................................................... 75 
12 Data analysis and statistical methods ................................................................................ 76 
12.1 
Analysis sets .......................................................................................................... 76 
12.2 
Subject demographics and other baseline characteristics ...................................... 77 
12.3 
Treatments ............................................................................................................. 77 
12.4 
Analysis of the primary endpoint(s) ...................................................................... 77 
12.4.1 
Definition of primary endpoint(s) ......................................................... 77 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 77 
12.4.3 
Handling of missing values/censoring/discontinuations ....................... 78 
12.4.4 
Sensitivity and Supportive analyses ...................................................... 78 
12.5 
Analysis of secondary endpoints ........................................................................... 78 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................... 78 
12.5.2 
Safety endpoints .................................................................................... 78 
 
 79 
 
 79 
12.7 
Interim analyses ..................................................................................................... 81 
12.8 
Sample size calculation.......................................................................................... 81 
12.8.1 
Primary endpoint(s) ............................................................................... 81 
13 Ethical considerations and administrative procedures ...................................................... 82 
13.1 
Regulatory and ethical compliance ........................................................................ 82 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 82 

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13.3 
Publication of study protocol and results............................................................... 82 
13.4 
Quality Control and Quality Assurance ................................................................. 83 
14 Protocol adherence ............................................................................................................ 83 
14.1 
Protocol Amendments ........................................................................................... 83 
15 References ......................................................................................................................... 85 
16 Appendices ........................................................................................................................ 87 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs ......................... 87 
16.2 
Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements ......................................................................................................... 88 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 26 
Table 6-1 
Investigational and control drug ............................................................ 40 
Table 6-2 
Blinding levels ...................................................................................... 44 
Table 8-1 
Assessment Schedule ............................................................................ 50 
Table 8-2 
Safety Assessments ............................................................................... 57 
Table 8-3 
Laboratory Assessments ........................................................................ 59 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 72 
Table 16-1 
Clinically notable laboratory values...................................................... 87 
Table 16-2 
Liver Event and Laboratory Trigger Definitions .................................. 88 
Table 16-3 
Follow Up Requirements for Liver Events and Laboratory Triggers ... 88 
List of figures 
Figure 3-1 
Study design .......................................................................................... 30 
 

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List of abbreviations 
ACE/ARB Angiotensin-Converting Enzyme inhibitor/Angiotensin-Receptor Blocker 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical classification system 
BDI-II 
Beck Depression Inventory II 
BMI 
body mass index 
BOCF 
Baseline observation carried forward 
BUN 
blood urea nitrogen 
CDE 
Centre Drug Evaluation 
CFR 
Code of Federal Regulation 
 
 
 
 
 
 
CGRP 
Calcitonin Gene-related Peptide 
CM 
Chronic Migraine 
CO 
Country Organization 
COVID-
19 
Corona virus Disease 2019 
CMH 
Cochran-Mantel-Haenszel 
CMV 
Cytomegalovirus 
COA 
Clinical Outcome Assessments 
CPK 
Creatine Phosphokinase 
CRA 
Clinical Research Associate 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTT 
Clinical Trial Team 
DILI 
Drug-Induced Liver Injury 
DMC 
Data Monitoring Committee 
EBV 
Epstein-Barr virus 
EC 
Ethics committee 
ECG 
Electrocardiogram 
eC-SSRS 
Electronic Columbia Suicide Severity Rating Scale 
EDC 
Electronic Data Capture 
eDiary 
Electronic Diary 
eGFR 
estimated Glomerular Filtration Rate 
ELISA 
Enzyme-linked immunosorbent assay 
EM 
Episodic Migraine 

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EMA 
European Medicines Agency 
eSource 
Electronic Source 
EU 
European Union 
FAS 
Full Analysis Set 
FUP 
Follow-Up 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
HA 
Health Authorities 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HDL 
high density lipoprotein 
 
 
HIV 
human immunodeficiency virus 
HSV 
Herpes Simplex Virus 
IA 
Interim Analysis 
IB 
Investigator's Brochure 
ICH 
International Council for Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
ICHD 
Headache Classification Committee of the International Headache Society 
IEC 
Independent Ethics Committee 
IHS 
International Headache Society 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IPD 
Important Protocol Deviation 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD 
Intra-uterine device 
IUS 
Intra-uterine system 
LDL 
low density lipoprotein 
LFT 
Liver function test 
LPLV 
Last Patient Last Visit 
LLOQ 
lower limit of quantification 
LSM 
Least square means 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical dictionary for regulatory activities 
MI 
Multiple Imputation 
MIDAS 
Migraine Disability Assessment 
MMD 
Monthly migraine days 
MNAR 
Missing not at random 
MO 
Medication Overuse 

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NSAID 
Nonsteroidal Anti-Inflammatory Drugs 
OAS 
Open-Label treatment Analysis Set 
PD 
pharmacodynamic(s) 
PFS 
Pre-filled syringe 
PK 
pharmacokinetic(s) 
PRN 
Pro re nata (Latin=as required) 
PRO 
Patient Reported Outcomes 
PT 
Preferred Term 
q.m. 
every month, here refers to an every 4 weeks. 
QMS 
Quality Management System 
QTcF 
QT corrected (Fridericia QT formula) 
RBC 
red blood cell(s) 
RDW 
Red cell distribution width 
s.c. 
Subcutaneous 
SAE 
serious adverse event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SNRI 
Serotonin and Norepinephrine Reuptake Inhibitor 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SC 
Steering Committee 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TBIL 
Total Bilirubin 
TEAE 
Treatment-Emergent Adverse Event 
TIA 
Transient ischemic attack 
ULN 
upper limit of normal 
USA 
United States of America 
WBC 
white blood cell(s) 
WHO 
World Health Organization 

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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Cohort 
A specific group of subjects fulfilling certain criteria 
Control drug 
A study drug (active or placebo) used as a comparator to reduce assessment 
bias, preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug 
Dosage 
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day) 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study data 
using data collection systems, such as Web-based applications, interactive 
voice response systems and clinical laboratory interfaces. EDC includes the 
use of electronic Case Report Forms (CRFs) which are used to capture data 
transcribed from paper source forms used at the point of care 
Enrollment 
Point/time of subject entry into the study at which informed consent must be 
obtained 
Healthy volunteer 
A person with no known significant health problems who volunteers to be a 
study participant  
Investigational 
drug/treatment 
The drug whose properties are being tested in the study 
Medication 
number 
A unique identifier on the label of medication kits 
Mis-randomized 
subjects 
Mis-randomized subjects are those who were not qualified for randomization 
and who did not take study treatment, but have been inadvertently randomized 
into the study 
Part 
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single dose part 
and a multiple dose part, or a part in subjects with established disease and in 
those with newly-diagnosed disease 
Patient 
An individual with the condition of interest for the study 
Period 
The subdivisions of the trial design (e.g. Screening, Double-Blind Treatment, 
Open-Label Treatment, Follow-up) which are described in the Protocol. 
Periods define the study phases and will be used in clinical trial database 
setup and eventually in analysis 
Personal Data 
Subject information collected by the Investigator that is transferred to Novartis 
for the purpose of the clinical trial. This data includes subject identifier 
information, study information and biological samples. 
Premature subject 
withdrawal 
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned. 
Randomization 
number 
A unique identifier assigned to each randomized subject 
Screen Failure 
A subject who did not meet one or more criteria that were required for 
participation in the study 
Source 
Data/Document 
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource 
Study completion 
Point/time at which the subject came in for a final evaluation visit or when 
study drug was discontinued whichever is later. 

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Study drug 
discontinuation 
Point/time when subject permanently stops taking study drug for any reason; 
may or may not also be the point/time of premature subject withdrawal. 
Study treatment 
Any single drug or combination of drugs or intervention administered to the 
subject as part of the required study procedures 
Study treatment 
discontinuation 
When the subject permanently stops taking study treatment prior to the defined 
study treatment completion date 
Subject 
A trial participant (can be a healthy volunteer or a patient) 
Subject number 
A unique number assigned to each subject upon signing the informed consent. 
This number is the definitive, unique identifier for the subject and should be 
used to identify the subject throughout the study for all data collected, sample 
labels, etc. 
Variable 
A measured value or assessed response that is determined from specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study 
Withdrawal of 
study consent 
Withdrawal of consent from the study occurs only when a subject does not 
want to participate in the study any longer and does not allow any further 
collection of personal data  

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Amendment 02 (26-Jan-2021) 
Amendment rationale 
Details for potential trial conduct changes due to the COVID-19 pandemic have been 
incorporated in this protocol amendment. No additional risk for COVID-19 pandemic has been 
identified, and therefore the benefit risk is unchanged.  
In addition, clarification that DMC will conduct regular unblinded reviews of cumulative safety 
data has been added.  
 Duration of post-trial access (PTA) in Korea has been updated to June 2021 instead of ‘launch 
in the country’, as sponsor no longer plans to launch erenumab in Korea. Other CGRP 
treatments are expected to be available in Korea in June 2021. 
Furthermore, a mistake regarding the urine pregnancy test has been corrected in the assessment 
schedule and relevant protocol sections.  

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Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
List of Abbreviations 
Section updated to add one abbreviation and correct the definition of another one. 
Section 1.2 Purpose 
Section updated to reflect that in Korea post-trial access will no longer be provided until ‘launch 
in the country’, but until June 2021. 
Section 3 Study design 
Section updated to reflect that in Korea post-trial access will no longer be provided until ‘launch 
in the country’, but until June 2021. Section updated with a guidance for COVID-19. 
Figure 3-1 Study design 
Section updated to reflect that in Korea post-trial access will no longer be provided until ‘launch 
in the country’, but until June 2021. 
Section 4.1 Rationale for study design 
Section updated to reflect that in Korea post-trial access will no longer be provided until ‘launch 
in the country’, but until June 2021. 
Section 4.3 Rationale for choice of control drugs (comparator/placebo) 
Title updated as per Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020. 
Section 4.5 Risks and benefits 
Details from recent studies and from approval of erenumab in several countries have been added. 
Section 5 Study Population 
Title updated as per Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020. 
Section 5.2 Exclusion Criteria 
Section updated to correct a typo. 
Section 6.1.4 Treatment duration 
Section updated to reflect that in Korea post-trial access will no longer be provided until ‘launch 
in the country’, but until June 2021. 
Section 6.2.1 Concomitant therapy 
New prohibited medications have been added. 
Section 6.2.2 Prohibited medication 
New prohibited medications have been added. 
Section 6.2.3 Rescue medication 
This section has been updated for clarification. 

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Section 6.6.1 Treatment compliance 
Section updated with a guidance for COVID-19. 
Section 6.7.2 Instruction for prescribing and taking study treatment 
Section updated with a guidance for COVID-19. 
Section 7 Informed consent procedures 
Section updated with a guidance for COVID-19. 
Section 8 Visit schedule and assessments 
Included a guidance section for COVID-19 related to alternatives for conducting study visits 
with options to use phone calls, virtual visits etc. for patients affected by the pandemic. 
Table 8-1 Assessment schedule 
Updated to clarify that urine pregnancy test results are only collected in source documents and 
not in the clinical database. 
Section 8.3 Efficacy 
Section updated with a guidance for COVID-19 that PRO scales may still be collected using 
the eDiary for subjects impacted due to the pandemic. 
Section 8.4 Safety 
Section updated with a guidance for COVID-19 for subjects impacted due the pandemic. 
Table 8-2 Safety Assessments 
Section updated with a guidance for COVID-19 for subjects impacted due the pandemic. 
Section 8.4.1 Laboratory evaluations 
Introduced guidance for COVID-19 to indicate that collection of laboratory samples may need 
to be modified for subjects impacted due to the pandemic. Section also updated to indicate 
which urine pregnancy test are to be used (central lab or local lab tests).  
Section 8.4.2 Electrocardiogram (ECG) 
Section updated with a guidance for COVID-19 for subjects impacted due the pandemic. 
Section 8.4.3 Pregnancy and assessments of fertility 
Section updated with a guidance for COVID-19 for subjects impacted due the pandemic. 
Section 8.4.4 Prospective suicidality assessment 
Section updated with a guidance for COVID-19 for subjects impacted due the pandemic. 
Section 8.5.1 Clinical Outcome Assessments (COAs) 
Section updated with a guidance for COVID-19 for subjects impacted due the pandemic. 
 
 
 

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Table updated to remove mention of the Complete Liver CRF which is not used on the study. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol can be considered non-substantial. However, 
due to local regulations in some countries the changes can be considered substantial and require 
IRB/IEC approval prior to implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.  

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Section 6.2.1 Concomitant therapy 
This section has been updated regarding the recording of the Concomitant Therapies during the 
open-label treatment period. 
Section 6.2.2 Prohibited medication 
This section has been updated regarding the exclusion of the Prohibited medication during the 
open-label treatment period. 
Section 6.2.3 Rescue medication 
This section has been updated regarding the recording of the Rescue medication in the eDiary. 
Section 6.4 Treatment blinding 
Information has been added regarding the unblinding circumstances and the randomization 
information availability. 
Section 6.6.1 Treatment compliance 
Information on open-label treatment period has been added. 
Section 6.7 Preparation and dispensation 
Information on open-label treatment period has been added. 
Section 6.7.1.1 Handling of study treatment 
Removal of the return of unused study treatment by the subjects. 
Section 6.7.2 Instruction for prescribing and taking study treatment 
Information on open-label treatment period study treatment has been added. 
Section 7 Informed consent procedures 
Removal of sentence related to pregnant female partner of male subject. 
Table 8-1 Assessment Schedule 
Table updated to incorporate the open-label treatment period assessments. 
Section 8.3.1 Migraine Days 
Clarifications added to the definition of Migraine Day. 
Section 8.3.2 Appropriateness of efficacy assessments 
Replaced benefit with clinically meaningful response 
Table 8-2 Safety Assessments 
Section updated to specify to which visits Vital Signs assessments are applicable. 
Section 8.4.1 Laboratory evaluations 
Information added regarding the urine pregnancy tests to be performed locally during the open-
label treatment period. 
Section 8.4.3 Pregnancy and assessments of fertility 

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Information on open-label treatment period pregnancy tests has been added. 
Section 8.4.4 Prospective suicidality assessment 
Section updated to specify that this assessment is not applicable during the open-label treatment 
period. 
Section 8.5.1 Clinical Outcome Assessments (COAs) 
Information related to the COAs has been updated. 
Section 8.5.2 Patient Reported Outcomes (PROs) 
Section updated to specify that those assessments are not applicable during the open-label 
treatment period. 
 
 
 
 
 
 
 
 
Section 9.1.1 Discontinuation of study treatment 
Information on open-label treatment period has been added. 
Section 9.2 Study completion and post-study treatment 
Information on open-label treatment period has been added. 
Section 10.1.1 Adverse events 
Update of the CTCAE version to be used 
Section 10.1.4 Pregnancy reporting 
Removal of sentence related to pregnant female partner of male subject. 
Section 10.2.2 Prospective suicidality assessment 
Section updated to specify that this assessment is not applicable during the open-label treatment 
period. 
Section 10.2.4 Steering Committee 
This section has been updated as there will be a Steering committee for this study. 
Section 12 Data analysis and statistical methods 
Information on open-label treatment period analysis has been added. 
Section 12.1 Analysis sets 

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Information on open-label treatment period analysis has been added. 
Section 12.2 Subject demographics and other baseline characteristics 
This section has been updated. 
Section 12.3 Treatments 
Information on open-label treatment period analysis has been added.  
Section 12.4 Analysis of the primary endpoint(s) 
This section has been updated regarding the primary endpoint analysis. 
Section 12.4.3 Handling of missing values/censoring/discontinuations 
Missing at random assumption has been removed.  
Section 12.4.4 Sensitivity and Supportive analyses 
Missing at random assumption has been removed. 
 
  
 
  
Section 12.7 Interim Analyses 
This section has been updated regarding the unblinded interim analyses. 
Section 15 References 
New Reference added 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol are substantial and require IRB/IEC approval 
prior to implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.  

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Protocol summary 
Protocol 
number 
CAMG334A2304 
Full Title 
A 12-week phase 3, randomized, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of once monthly subcutaneous erenumab 70 mg 
in adult chronic migraine patients 
Brief title 
Study of efficacy and safety of erenumab in adult subjects with chronic migraine 
Sponsor and 
Clinical Phase 
Novartis 
Phase III 
Investigation 
type 
Biological 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of this study is to obtain data from regions not adequately 
represented in the global chronic migraine (CM) pivotal Study 2012095, and to 
support registration of 70 mg erenumab in China. It has a similar design to the 
global pivotal study.  
Primary 
Objective(s)  
The primary objective of this study is to evaluate the effect of erenumab 
compared to placebo by measuring the change in monthly migraine days (MMD) 
from baseline to the last 4 weeks of the 12-week treatment period. 
Secondary 
Objectives 
Objective 1: To evaluate the effect of erenumab compared to placebo on change 
in migraine-related disability and productivity as measured by the modified 
Migraine Disability Assessment (mMIDAS) from baseline to the last 4 weeks of 
the 12-week treatment period 
Objective 2: To evaluate the effect of erenumab compared to placebo on the 
proportion of subjects with at least 50% reduction in monthly migraine days from 
baseline to the last 4 weeks of the 12-week treatment period 
Objective 3: To evaluate the effect of erenumab compared to placebo on the 
change in monthly acute headache medication days from baseline to the last 4 
weeks of the 12-week treatment period 
Objective 4: To evaluate the safety and tolerability of erenumab, including 
adverse events (AEs), clinical laboratory values, vital signs, and anti-AMG 334 
antibodies 
Study design 
This study uses a single-cohort, 2-treatment arms, randomized (1:1 (70 mg: 
placebo)), double-blind study design in adult subjects with chronic migraine. A 
screening period of 2 weeks will be used to assess initial eligibility, followed by a 
4-week baseline period to assess diary compliance and headache frequency. 
Eligible patients will then be randomized to either erenumab 70 mg or placebo 
for 12 weeks, followed by an open-label treatment period to last until launch of 
erenumab in the country or until June 2021 in Korea. A safety follow-up visit will 
occur 12 weeks after the last treatment for subjects who discontinue the double-
blind treatment or who complete the double-blind treatment period without 
continuing in the open-label treatment period.  
An unblinded interim analysis (IA) will be conducted after 70% (385) of subjects 
have completed the double-blind treatment period (including early withdrawals), 
to determine whether the study will stop early or continue to the final primary 
analysis (full sample size). The recruitment continues until the read-out of the 
unblinded interim analysis.  

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Study 
Population 
The study population will consist of male and female subjects, ages 18 to 65, 
with a documented history of chronic migraine as outlined in the inclusion 
criteria. Approximately 550 subjects will be randomized in China and other Asian 
countries/regions (approximately 350 Chinese subjects for final analysis or 
around 250 for the unblinded interim analysis). Assuming a 30% screening 
failure rate, approximately 790 subjects are anticipated to be screened. 
Key Inclusion 
criteria 
• 
Adults ≥ 18 to ≤ 65 years of age upon entry into screening 
• 
History of at least 5 attacks of migraine (with or without aura) based on 
medical records and/or patient self-report 
• 
History of ≥ 15 headache days per month of which ≥ 8 headache days were 
assessed by the subject as migraine days per month in each of the 3 months 
prior to screening 
• 
≥ 15 headache days of which ≥ 8 headache days meet criteria as migraine 
days during the baseline period based on the electronic Diary (eDiary) 
calculation (Refer to Section 8.3.1 for definition of migraine day) 
• 
Demonstrated at least 80% compliance with the eDiary during the baseline 
period based on the eDiary calculation 
• 
History of migraine (with or without aura) for ≥ 12 months prior to screening 
according to the IHS Classification based on medical records and/or patient 
self-report 
Key Exclusion 
criteria 
• 
Older than 50 years of age at migraine onset 
• 
Taken an opioid and/or opioid-containing analgesic for any indication during 
more than 4 days within one month prior to the start of the baseline period or 
during the baseline period 
• 
Taken a butalbital-containing analgesic for any indication during more than 2 
days within one month prior to the start of the baseline period or during the 
baseline period 
• 
Prior migraine prophylaxis treatments failure in more than 3 out of the 
following medication categories:  
• 
Category 1: Divalproex sodium, sodium valproate 
• 
Category 2: Topiramate 
• 
Category 3: Beta blockers (for example: atenolol, bisoprolol, metoprolol, 
nadolol, nebivolol, pindolol, propranolol, timolol) 
• 
Category 4: Tricyclic antidepressants (for example: amitriptyline, 
nortriptyline, protriptyline) 
• 
Category 5: Flunarizine, verapamil, cinnarizine 
• 
Category 6: Serotonin-norepinephrine reuptake inhibitors (for example: 
venlafaxine, desvenlafaxine, duloxetine, milnacipran) 
• 
Category 7: Botulinum toxin 
• 
Category 8: lisinopril, candesartan 
• 
Category 9: Pregabalin, gabapentin 
• 
Category 10: Zonisamide 
• 
Category 11: Memantine 
• 
Category 12: Pizotifen 
• 
Use of a prohibited medication for migraine prophylaxis within 5 half-lives, or 
a device or procedure for migraine prophylaxis within one month prior to the 
start of the baseline period or throughout the study (Refer to Section 6.2.2 
for the list of these excluded therapies) 

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1 
Introduction 
1.1 
Background 
Migraine is a common worldwide occurring neurological disorder throughout all regions and 
ethnicities with a high global prevalence, significant socio-economic burden and substantial 
impairment and disability of affected patients. It has a global prevalence of 11% in adults 
(Stovner et al 2007). The first headache epidemiological survey across the China mainland 
showed that the estimated 1-year prevalence of migraine is 9.3% (Yu et al 2012). It is mainly 
characterized by recurrent headache lasting 4-72 hours but is usually accompanied by other 
neurological disturbances, nausea, vomiting and other nonspecific symptoms. The patient 
burden and disability as well as the societal impact increase with higher attack frequency, which 
is why the spectrum of migraine disorders is typically described according to frequency of 
migraine days per month. “Episodic migraine” (EM) is characterized by migraine with fewer 
than 15 headache days per months, while “Chronic migraine” (CM) is defined as 15 or more 
headache days per months, at least 8 out of which have to be typical migraine days. According 
to World Health Organization (WHO), CM is one of the most disabling disorders as it imposes 
a substantial effect on day-to-day functioning. Compared with individuals with EM, those with 
CM are much more likely to be unemployed, be divorced, and have psychological comorbidities, 
suggestive of the burden of the disease on the individual, their families, and society 
(Buse et al 2013). Based on the high frequency of migraine and effect on quality of life, patients 
with CM are good candidates for preventive therapy. In general, EM and CM patients share 
many common features in terms of the clinical presentation, which include the headache pain 
features and associated symptoms. The distinction between EM and CM is somewhat arbitrary 
and numerous lines of evidence support that they are a continuum of the same disorder.  
Migraineurs are currently being treated for migraine prophylaxis by a variety of drug classes, 
many of them being used off-label and often based on insufficient or limited evidence. In 
particular in CM, despite its enormous burden, there are few well-controlled studies for 
migraine prophylaxis with quality evidence available, only for onabotulinum toxin A and 
topiramate. Other therapies such as β blockers or amitriptypine are frequently used, despite a 
lack of evidence in patients with CM. Oral preventive therapies available at present, including 
topiramate, β blockers, and amitriptyline are often not fully efficacious or are poorly tolerated, 
which can lead to low adherence rates. Botulinum toxin (Botox®) is approved in many countries 
for CM use, but not for EM. In China, there is only 1 drug, flunarizine, approved for migraine 
prophylaxis. 
Nontraditional therapies such as herbal medicines, supplements, acupuncture and other 
therapies also have some role in migraine prophylaxis. While the evidence supporting their use 
is minimal and often controversial (Gooriah et al 2015), they are very common in the Asian 
region, and becoming more widespread and increasingly introduced into mainstream Western 
healthcare. 
Based on emerging evidence, Calcitonin Gene-related Peptide (CGRP) is a neuropeptide that 
prominently contributes to migraine pathophysiology. The potential mechanisms of action of 
CGRP receptor antagonists involve components of the trigeminal‑vascular system and include 
normalization of CGRP-induced vasodilation, reduction of CGRP-induced neurogenic 
inflammation, and inhibition of pain transmission at the trigeminal ganglion and trigeminal 

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nucleus (Wang et al 1995, Zimmermann et al 1996, Durham 2006). CGRP is an attractive 
target for the development of a migraine-specific prophylactic therapy with the aim of 
minimizing migraine days and improving patient quality of life in this common and often 
disabling disorder. 
Erenumab (AMG 334) is a fully human monoclonal antibody targeting the CGRP receptor 
under development for migraine prophylaxis in adults. To date studies have been, or are 
currently being, conducted in North America, Europe, Japan and some other Asian 
countries/regions. Erenumab is already approved in United States of America (USA), European 
Union (EU) and other countries for the preventive treatments of migraine in adults. As of 31 
January 2019, approximately 4613 patients with migraine have taken this medicine in clinical 
studies to date including over 200 patients who had >4 years of maximum treatment duration. 
The confirmed good safety and tolerability of erenumab does not suggest increased risks for 
patients with longer exposure. 
Results from the erenumab Phase 2 study (Study 20120178) in patients with episodic migraine 
demonstrated that the 70 mg dose resulted in statistically significant and clinically meaningful 
reductions in monthly migraine days at Week 12 compared with placebo. The 70 mg dose 
produced statistically significant improvements in multiple secondary and exploratory outcome 
measures, including the 50% responder rate, monthly headache days, and monthly migraine-
specific medication treatment days. Exposure-response pharmacokinetic (PK) analyses over a 
large range of PK exposures indicated that 70 mg was the lowest dose resulting in efficacious 
concentrations and potentially higher efficacy could be achieved with 140 mg. Based on this 
results, a higher dose of 140 mg was incorporated into the following pivotal studies. Results 
from the erenumab Phase 2 study (Study 20120295) in patients with chronic migraine also 
showed a positive outcome. Patients randomized to the 70 mg and 140 mg dose groups 
experienced a mean 6.6-day reduction from baseline in monthly migraine days during Weeks 
9-12 in both groups. The results were statistically significant compared with 4.2 days observed 
in the placebo group. The 50% responder rate was 39.9% and 41.2% with 70 mg and 140 mg 
erenumab respectively compared to 23.5% with placebo. Both doses were also effective across 
various other endpoints including frequency-related outcomes and functional improvement 
measured by established Patient Reported Outcome (PRO) scales (Tepper et al 2017). 
The results from two completed Phase 3 studies (Studies 20120296, 70 and 140 mg, and 
20120297, 70 mg) in patients with episodic migraine, also showed positive outcomes for 
erenumab. In Study 20120297, patients randomized to the 70 mg dose group experienced a 2.9-
day reduction from baseline in monthly migraine days compared with 1.8 days observed in the 
placebo group with the difference being statistically significant (Dodick et al 2018). In study 
20120296, patients randomized to the 70 and 140 mg dose groups experienced mean 3.2 and 
3.7-day reductions from baseline, respectively compared with a 1.8 days observed in the 
placebo group over weeks 13-24 (Goadsby et al 2017). Results for both of these studies were 
statistically significant. Fifty percent responder rates were significantly increased with 
erenumab compared to placebo in both of the Phase 3 episodic migraine studies. Treatment 
effects observed with 140 mg in Study 20120296 showed consistently higher values across 
different parameters and subgroups compared to placebo than the 70 mg group, suggesting 
additional efficacy in global patients with episodic migraine. 

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Apart from the global clinical program focused on Caucasian population, a Phase 1 study in 
Japanese subjects (Study 20120130) and a Phase 2 study (Study 20120309) in Japanese subjects 
with EM were conducted to support the registration in Japan. The PK of erenumab at 70 mg 
was similar and there is no ethnic difference between healthy Japanese and Caucasian subjects. 
Study 20120309 is a Phase 2, multicenter, randomized, double-blind, placebo‑controlled, 
parallel-group study. A total of 475 subjects were randomized 2:1:2:2 to receive placebo, 
erenumab 28 mg, 70 mg, or 140 mg during the 24-week double-blind treatment phase. While 
the results were significant for all 3 doses evaluated, the efficacy on the primary and secondary 
endpoints for the 28 mg dose were almost 50% lesser in magnitude than the 70 mg dose. 
Comparable efficacy was seen between 70 mg and 140 mg doses. Besides, the safety profile 
was similar to placebo and also comparable between Japanese and Caucasian subjects. A multi-
regional, three arms (placebo, 70 mg and 140 mg groups), double-blinded, Phase 3 study (Study 
CAMG334A2302) in the EM population, primarily in Asia is currently ongoing. The purpose 
of this study is to obtain data from regions not adequately represented in the global pivotal trials, 
and to support registration in countries or regions requiring local data for regulatory approval 
(India, Korea, and Taiwan).  
The safety and tolerability profile of erenumab was similar to placebo in both treatment groups 
for all studies. No adverse event (AE) occurred with an incidence of > 6%; the most commonly 
reported adverse events included injection site pain, infection of the upper respiratory tract and 
nausea. Based on a pooled analysis across four placebo-controlled trials, the identified adverse 
drug reactions include injection site reactions, constipation, muscle spasm and pruritus. 
In view of limited information on ethnic subgroups, especially Chinese, this trial will provide 
additional information about erenumab safety and efficacy in CM in a mainly Chinese 
population and provide local data for regulatory submission.  
1.2 
Purpose 
The purpose of this study is to obtain data from regions not adequately represented in the global 
Chronic Migraine (CM) pivotal study (Study 20120295), and to support registration of 70 mg 
erenumab in China. It has a similar design to the global pivotal study in CM (Tepper et al 2017), 
with the exception of the open-label treatment period.  
The purpose of the open-label treatment period is to provide continued drug access to patients 
who completed the double-blind treatment period, until erenumab is launched in the country or 
until June 2021 in Korea. 
 
  
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To evaluate the effect of erenumab 
compared to placebo on the change from 
baseline in monthly migraine days, in 
subjects with chronic migraine 
• 
Change from baseline in monthly migraine 
days during the last 4 weeks of the 12-week 
treatment period  

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Objective(s) 
Endpoint(s) 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To evaluate the effect of erenumab 
compared to placebo on change from 
baseline in migraine-related disability and 
productivity as measured by the modified 
Migraine Disability Assessment (mMIDAS) 
• 
Change from baseline in migraine-related 
disability and productivity as measured by the 
mMIDAS during the last 4 weeks of the 12-
week treatment period 
• 
To evaluate the effect of erenumab 
compared to placebo on the proportion of 
subjects with at least 50% reduction from 
baseline in monthly migraine days 
• 
Achievement of at least a 50% reduction from 
baseline in monthly migraine days during the 
last 4 weeks of the 12-week treatment period 
• 
To evaluate the effect of erenumab 
compared to placebo on the change from 
baseline in monthly acute headache 
medication days 
• 
Change from baseline in monthly acute 
headache medication days during the last 4 
weeks of the 12-week treatment period 
• 
To evaluate the safety and tolerability of 
erenumab 
• 
Adverse events, clinical laboratory values, 
vital signs, and anti-AMG 334 antibodies 

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3 
Study design 
This study uses a single-cohort, 2-treatment arm, randomized (1:1 (70 mg: placebo)), 
double-blind study design in adult subjects with chronic migraine (see  Figure 3-1), followed 
by an open-label treatment period.  
Subjects with co-existing Medication Overuse (MO) of triptans, ergot-derivatives, analgesics 
and combination drug use will be allowed in the trial. 
MO will be considered present if any of the following criteria are met during baseline period. 
• ≥ 15 days of simple analgesics 
• ≥ 10 days of triptans 
• ≥ 10 days of ergots 
• ≥ 10 days of combination therapy intake of any combination of ergots, triptans, 
combination-analgesic medications or simple analgesics 
The following periods are included in the study design, with study visits at 4-week intervals 
after completion of screening: 
• Screening (up to 2 weeks): to assess initial eligibility  

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• Baseline (4 weeks) diary compliance and headache frequency will be assessed for a final 
eligibility assessment prior to randomization and dosing. The maximum duration for the 
baseline period is 35 days. During the COVID-19 pandemic that limits or prevents on-site 
study visits, the duration of the baseline visit can be extended up to 50 days. 
• Eligible subjects will be randomized 1:1 to once monthly erenumab 70 mg and placebo 
within each of the 4 strata below: 
• prior prophylactic migraine treatment failure and MO 
• prior prophylactic migraine treatment failure and non-MO 
• non-prior prophylactic migraine treatment failure and MO 
• non-prior prophylactic migraine treatment failure and non-MO 
• Double-blind treatment (12 weeks): Eligible subjects will be randomized to one of two 
treatment arms. At the end of this period (Week 12), the final assessment to address the 
efficacy-related objectives will occur.  
• Post double-blind treatment follow-up (12 weeks): for subjects discontinuing treatment 
during the double-blind treatment period and willing to return for the subsequent scheduled 
follow-up (FUP) visits, until the Week 12 follow-up visit. 
• Safety follow-up (8 weeks):  in subjects completing the double-blind treatment period, but 
not entering into the open-label treatment period, a safety follow-up visit will occur 8 weeks 
after the Week 12 visit (Week 20). Subjects who discontinue study drug during the double-
blind treatment period and who do not remain in the study to follow the assessment schedule 
until the Week 12 FUP visit, will have the safety follow-up visit 12 weeks after the last dose. 
For subjects discontinuing double-blind treatment and remaining in the study to follow the 
assessment schedule until the Week 12 FUP visit, the Safety Follow-Up visit should occur 
on Week 20 even if the last dose was taken at Day 1. The Safety Follow-Up visit is not 
required in subjects who discontinue or complete the open-label treatment period.  
• Open-label treatment (until launch of erenumab in the country or until June 2021 in 
Korea): all subjects completing the double-blind treatment period on study drug are invited 
to participate. Eligible subjects who consented to participate in this open-label treatment 
period will receive erenumab until it is launched in the country, or until June 2021 in Korea, 
in order to ensure continued drug access.  
Should a treatment gap exist between the two treatment periods due to a delay of HA/EC 
approvals or other administrative/logistical reasons, the subject may enter the open-label 
treatment period at a later time provided he or she still meets the eligibility criteria. During 
this treatment gap, the subject is allowed to use standard of care. 
See the assessment schedule in  Table 8-1. 
Two interim analyses (IA) are planned for this study: 
• A blinded IA, after approximately 50% (275) of subjects have completed the 
double-blind treatment period (including early withdrawals), will be conducted to re-
estimate the sample size by providing information on the variance for this trial relative 
to the planned assumptions to account for potential higher variability in general Asian 
population.  

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• An unblinded IA will be conducted after 70% (385, if no increase of sample size is 
needed following the blinded IA) of subjects have completed the double-blind treatment 
period (including early withdrawals), to determine whether the study will stop early or 
continue to the final primary analysis (full sample size). Study recruitment will continue 
until unblinded IA read-out.  
If it is decided to stop early due to success (positive IA read-out), all subjects ongoing 
in the double-blind treatment period at the time of the IA read-out will be scheduled for 
an End of Treatment visit: they will then either enter into the open-label treatment period 
or enter into the safety follow-up Period (in case the subject does not want to continue 
in the open-label treatment period).  
In case of a negative interim analysis (70%) which is meeting the futility boundary, or 
in case of a negative primary analysis at the full sample size (100%), the open-label 
treatment period will be cancelled. All subjects ongoing in the double-blind treatment 
period at that time will be scheduled for an End of Treatment visit followed by a safety 
follow-up visit. All subjects ongoing in the open-label treatment period will be 
scheduled for an End of Treatment Open-Label visit. 
If it is decided to continue until final analysis, the recruitment will continue to full 
sample size. 
In case of exceptionally fast recruitment the unblinded IA might be cancelled and the 
full sample size will be analyzed. 
Two clinical study reports (CSR) are planned for this study:  
• An interim CSR will be prepared for the primary analysis, when the last patient completed 
the double-blind treatment period (including early withdrawals).  This might either be after 
approximately 70% of subjects completed the double-blind treatment period, or when 100% 
of subjects completed the double-blind treatment period. The CSR will include efficacy and 
safety data, as well as safety follow-up visit data up to this point. This CSR will be prepared 
for regulatory submission in China. 
• A final CSR will be prepared when all subjects have completed their respective last visit 
(LPLV). In this CSR, all available data not captured in the interim CSR will be included. 
In case of a negative primary analysis only one CSR will be developed, including all available 
double-blind, safety follow-up and open-label treatment data.  
If the marketing application of erenumab, for the indication in this study, is rejected in a 
participating country, the subjects in that country will be discontinued from the open-label 
treatment period. End of Trial will occur when the last subject completes the last visit (Last 
patient Last Visit (LPLV)) of the trial.  
Figure 3-1 
Study design 
 

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4 
Rationale 
4.1 
Rationale for study design 
The subject population will be described in more detail in the Section 5 below. 
A parallel-group, placebo-controlled design is a standard way of assessing efficacy and safety 
of new migraine prophylactic agents. This study design has been chosen in line with erenumab 
Phase 3 study designs, which were developed in accordance with the guidelines of the 
International Headache Society (IHS) for controlled trials of preventive treatment of chronic 
migraine in adults(Tassorelli et al 2018) and the IHS guidelines for Controlled Trials of Drugs 
in Migraine (Tfelt-Hansen et al 2012). The key design features were also aligned with China 
Centre Drug Evaluation (CDE) on 5-Sep-2018. 
The open-label treatment period is a mechanism to provide post-trial access of erenumab until 
launch, or until June 2021 in Korea, to subjects who completed the double-blind treatment 
period. 
Given that the enrolled chronic migraine subjects have a particular unmet need as they may 
have failed multiple treatments, and the available treatment choices for migraine prevention are 
limited after the completion of the double-blind treatment period, it is assumed that many of 
them will need to be treated for a longer period of time. Besides, subjects in the placebo group 
will get drug access during the open-label treatment period. 
The confirmed good safety and tolerability of erenumab does not suggest increased risks for 
patients with longer exposure up to 64 weeks (Tepper et al 2017). Interim analysis from an 
ongoing five-year open-label extension study (Study 20120178), after all patients completed 
three years in the open-label treatment period, showed that 61.3% of the patients still remained 
in the study, which demonstrated adherence is favorable with erenumab and may result in 
positive long-term outcomes (Ashina et al 2019).  
Therefore, in order to collect additional 
 data in this 
population of Chinese and Asian patients this open-label treatment period has been added.   

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4.2 
Rationale for dose/regimen and duration of treatment 
Dose-finding Phase 2 results for erenumab in EM subjects (Study 20120178) are available for 
the doses of 7 mg and 21 mg (both of which have proven to be ineffective compared to placebo) 
and 70 mg. The dose of 70 mg was established as the effective dose. It has shown a statistically 
significant and clinically relevant reduction in the primary endpoint of monthly migraine days. 
The PK of erenumab at 70 mg SC were similar for healthy Japanese and white subjects (ratio 
of geometric means [i.e, Japanese/white] for Cmax, AUClast, and AUCinf = 1.02, 1.12, and 
1.12, respectively). Data from PK exposure-response modelling in global population indicated 
that additional efficacy might be achieved with a higher dose of 140 mg erenumab. The safety 
profile of erenumab has been investigated up to 280 mg in healthy volunteers in Phase 1 without 
a difference in safety profile. Based on these considerations, an additional dose of 140 mg s.c. 
q.m. has been included in global pivotal programs. The two main studies that inform the dosing 
in the current proposed study in CM population are Study 20120295 and Study 20120309. 
One global pivotal study, Study 20120295, was conducted in the CM population (mostly 
Caucasian subjects). Subjects randomly assigned to either the erenumab 70 mg or erenumab 
140 mg group experienced a mean 6.6 days reduction from baseline in monthly migraine days 
(2.4 days more than subjects receiving placebo). While there was no apparent difference 
between erenumab doses in primary endpoint, point estimates numerically favored 140 mg over 
70 mg at Week 4 and Week 8 for MMD reduction as well as at all timepoints (i.e. weeks 4, 8, 
and 12) for all 3 secondary endpoints and multiple exploratory endpoints. 
A Phase 2 study, Study 20120309, was conducted in Japan in the EM population. While the 
results were significant for all three doses evaluated (28 mg, 70 mg and 140 mg), the efficacy 
on the primary endpoint for the 28 mg dose was almost 50% lesser in magnitude than the 70 
mg dose. Therefore, the 28 mg dose is not considered a clinically relevant dose given the similar 
safety profile between three doses. Comparable efficacy was seen between 70 mg and 140 mg 
doses in primary endpoint and all secondary endpoints, whereas maximal efficacy was observed 
with the 140 mg dose in the global Study 20120296. This study showed comparable exposure-
response characteristics between the overall global and the Japanese population. The clinically 
relevant dose of 70 mg is consistent with the overall higher exposure associated with lower 
body mass index BMI/body weight in Japanese population, which likely led to the lack of 
incremental efficacy benefits in Study 20120309 between the 140 and 70 mg dose that were 
observed in the overall global population. This difference does not reflect any meaningful 
differences in ethnic sensitivity. 
Similar BMI/body weight was observed between Chinese and Japanese based on prior study 
results in the same subject population. Since the body-weight was the only important covariate 
identified with the population PK modeling, we do not expect that other demographic/ethnic 
factors might be associated with a relevant difference between global and Japanese and/or 
Chinese population. Consequently, the 70 mg is likely also the appropriate efficacious dose in 
Chinese population. Although this study was conducted in the EM population, numerous lines 
of evidence that support they are a continuum of the same disorder (Section 1.1). 
The combination of Study 20120295 and Study 20120309 are therefore considered most 
informative for the dose selection and support the selection of the 70 mg dose in this study. 

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The 12-weeks double-blind study duration is endorsed by IHS guidelines as a sufficient duration 
to assess efficacy in prophylactic migraine treatment clinical trials. A longer double-blind trial 
duration is not considered feasible due to the prolonged placebo exposure. 
Subjects will receive either erenumab 70 mg q.m. s.c. or matching placebo for 12 weeks in the 
double-blind treatment period, followed by erenumab 70 mg q.m. s.c. in the open-label 
treatment period. 
4.3 
Rationale for choice of control drugs (comparator/placebo)  
The choice of a specific therapy for a migraine headache prophylactic often takes into account 
individual circumstances, comorbidities and patient preferences. The preventive treatment 
choices are similar between other countries and China. Patients are currently being treated by a 
variety of drug classes that were originally developed for other indications, but were repurposed 
for migraine prophylaxis. Some drugs have been formally approved for migraine prophylaxis 
in many countries. The most common approved drugs are propranolol, metoprolol, topiramate 
and flunarizine. For CM patients, the therapeutic options are even more limited, with only 
onabotulinum toxin (Botox®) being specifically approved in United States, several EU countries 
and Canada. In China, only one drug, flunarizine, is approved for migraine prophylaxis. 
However, there is no solid evidence and adequate and well-controlled trial conducted 
worldwide with flunarizine for migraine prophylaxis. Other drugs, while not formally approved, 
are considered acceptable alternatives and are recommended within national treatment 
guidelines. Examples with evidence for migraine headache prophylaxis include other drug 
classes such as antidepressants (mainly amitriptyline and venlafaxine), Angiotensin-Converting 
Enzyme inhibitor/Angiotensin-Receptor Blocker (ACE/ARBs) (mainly candesartan and 
lisinopril) and valproate/divalproex. All of those drugs are occasionally used as migraine 
prophylactics, but the use is off-label and rests on the individual clinical responsibility of the 
prescribing physician after an adequate individual benefit-risk assessment. 
All of these therapies, regardless if approved or off-label, are commonly associated either with 
variable migraine efficacy and/or substantial tolerability issues that often lead to treatment 
discontinuation. The standard of care also varies significantly across different geographies and 
treatment decisions, particularly in patients that have already failed the standard first line 
therapies are often made on a case-by-case basis without general consensus on treatment 
guidelines. Because of the variability of standard of care across different geographies and the 
potential for functional unblinding due to typical adverse events with any active comparator, 
placebo was selected as the comparator. The short duration (12 weeks) of placebo treatment, in 
conjunction with the allowed use of acute migraine treatment, justifies the use of placebo in this 
study as also suggested in the IHS guidelines (Tfelt-Hansen et al 2012, Tassorelli et al 2018). 
All patients continue to receive best supportive care in form of acute abortive medications and 
other non-pharmacological interventions as appropriate. 
4.4 
Purpose and timing of interim analyses/design adaptations 
A blinded interim analysis, after approximately 50% (275) of subjects have completed the 
treatment period (including early withdrawals), will be conducted to re-estimate the sample size 
by providing information on the variance for this trial relative to the planned assumptions to 
account for potential higher variability in general Asian population. 

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An unblinded interim analysis will be implemented when 70% (385) of subjects have completed 
the treatment period (including early withdrawals). An independent Data Monitoring 
Committee (DMC) will conduct this interim analysis. 
The main purpose of this unblinded interim analysis is to determine whether the trial will stop 
early due to success, or will continue to the final analysis with the planned full sample size 
(100%), based on the result of the primary efficacy assessment. This interim analysis will focus 
on the primary efficacy endpoint, but the DMC recommendation on whether to stop the trial or 
not will be based on the evaluation of totality of efficacy and safety data at the time of interim 
cut-off. The study team will not be unblinded unless the study is stopped early for success. 
Refer to Section 12.7 for more information regarding this unblinded IA. 
4.5 
Risks and benefits 
Key risks and benefits are briefly summarized below. For further information, please refer to 
the current Investigator Brochure (IB). 
The safety of erenumab in migraine prophylaxis was assessed from integrated safety analyses 
of 4817 subjects with migraine who received at least one dose of erenumab (dose level at 7, 21, 
70, or 140 mg), representing 4418.3 subject-years of exposure as of data cut-off date 16 May 
2019 as per Investigator’s Brochure edition 11.1. Overall, the safety and tolerability profile of 
erenumab was similar between the 140 mg and 70 mg doses and also comparable to placebo. 
For adverse drug reactions refer to Section 7 (Summary and Data and Guidance for the 
Investigator) of the IB. 
Overall, to date, there is no evidence from nonclinical and clinical data of risk of cardiovascular 
effects. On the theoretical basis of the mechanism of action of erenumab, CGRP receptor 
blockade may reduce compensatory vasodilation, particularly under ischemic conditions. To 
determine the potential impact of erenumab on total exercise time, time to exercise-induced 
angina, and ST depression during a Treadmill Test in subjects with stable angina, a double-
blind, placebo-controlled study conducted and demonstrated that erenumab does not impact 
exercise tolerance or interfere with homeostatic vasodilatory mechanisms in subjects with 
chronic myocardial ischemia. However, in this planned study, cardiovascular effects continue 
to be monitored, and subjects with major cardiovascular disease within 12 months prior to 
screening will be excluded from participation. 
All biologicals, including fully human proteins, have the potential to induce immunogenicity 
leading to the development of specific anti-drug antibodies. Overall, erenumab treatment is 
associated with a low incidence of immunogenicity. While the number of anti-AMG 334 
antibody-positive subjects is limited, impact analyses suggest that despite a modest reduction 
in exposure among anti-AMG 334 antibody-positive subjects, there was no impact of anti‑AMG 
334 antibody development on efficacy or safety. Subjects in clinical studies will continue to be 
monitored for the development of anti‑erenumab antibodies and associated clinical sequelae. 
Plasma levels of CGRP increase with advancement of pregnancy up to the time of delivery, 
followed by a sharp decline at term and postpartum in rats and humans. Endogenous CGRP 
may play an important role in maintaining normal fetoplacental development, fetal survival, 
and vascular adaptation during pregnancy. Women who are breastfeeding, pregnant, or 
planning to become pregnant are excluded from study participation, as well as subjects who are 

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unwilling to comply with the protocol-specified contraception requirements. All women of 
child bearing potential will be screened for pregnancy at each study visit. 
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study, and agree that in order 
to participate in the study they must adhere to the contraception requirements outlined in the 
exclusion criteria. If there is any question that the subject will not reliably comply, they should 
not be entered or continue in the study. 
The need for a regular safety data monitoring committee for this study was assessed and deemed 
not necessary because the safety profile of erenumab has already been well-characterized from 
4 double-blind, placebo-controlled trials in over 2500 subjects. The risk to subjects in this trial 
will be minimized by compliance with the eligibility criteria, close clinical monitoring, and use 
of rescue medications. 
Three pivotal/key Phase 2/3 studies (Goadsby et al 2017, Tepper et al 2017, Dodick et al 2018), 
including 1 study in CM (study 20120295), have been completed with erenumab, which have 
established 70 mg and/or 140 mg as being effective and safe in subjects with EM or CM, with 
a favorable benefit/risk profile. Positive treatment effects in general were observed in a robust 
way across typical migraine endpoints such as change in mean monthly migraine days, > 50% 
(and higher) responder rates, change in migraine-specific medication use and functional 
improvement by established PRO scales. Results were in general highly statistically significant 
and clinically meaningful. Retention rates observed in clinical trials were very high (~95% with 
active treatment after 3 months and ~90% after 6 months with only minimal discontinuations 
attributed to adverse events). This feature is important, as discontinuation rates are high for 
other current migraine prophylaxis treatments, with the main drivers of discontinuation being 
either lack of efficacy or tolerability issues (Blumenfeld et al 2013). As such, there is a high 
unmet need for a therapy that is well-tolerated, has sustained response rates and excellent 
compliance. 
Besides, a one-year open-label extension to Study 20120295 in CM subjects was completed to 
evaluate the long-term efficacy, safety and tolerability of erenumab. Based on results for all 
dose groups, a long-term persistence of efficacy was observed that the mean (95% CI) change 
from baseline in MMDs was -8.36 (-8.92, -7.80) days at week 24 and ‑9.29 (‑9.96, ‑8.62) days 
at week 52. From the safety aspect, the AE profile with longer exposure up to 1 year were 
similar to  the AE profile in placebo-controlled phase and no additional signals of concern were 
identified with long-term treatment in global studies. 
As of July 2018, two open-label extension studies of erenumab in patients with chronic and 
episodic migraine were reported (1 and 3 years extension respectively), confirming sustained 
efficacy and a favorable safety and tolerability profile (Tepper et al 2017, Ashina et al 2019) 
(Study 20120295 and Study 20120178). Additionally, erenumab has been approved for 
migraine prophylaxis in adults in the United States of America (USA), the European Union 
(EU) as well as in other countries since 2018. 
Overall, given the characteristics of erenumab and the large experience in clinical trials, the 
overall benefit-risk assessment is supportive. 

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5 
Study population 
The study population will consist of male and female subjects, ages 18 to 65, with a documented 
history of chronic migraine as outlined in the inclusion criteria. 
The goal is to randomize approximately 550 subjects in China and other Asian countries/regions. 
Approximately 350 Chinese subjects will be recruited, or around 250 subjects for the unblinded 
IA 
(when 
70% 
of 
subjects 
completed 
the 
treatment 
period 
(including 
early 
withdrawals)). Assuming a 30% screening failure rate, approximately 790 subjects will be 
screened. 
5.1 
Inclusion criteria 
Subjects eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study. 
2. Adults ≥ 18 to ≤ 65 years of age upon entry into screening 
3. History of at least 5 attacks of migraine without aura and/or migraine with visual, sensory, 
speech and/or language, retinal or brainstem aura according to the IHS Classification 
ICHD-3 (Headache Classification Committee of the International Headache Society, 
3rd edition 2018) based on medical records and/or patient self-report. 
4. History of ≥ 15 headache days per month of which ≥ 8 headache days were assessed by 
the subject as migraine days per month in each of the 3 months prior to screening 
5. ≥ 15 headache days of which ≥ 8 headache days meet criteria as migraine days during the 
baseline period based on the eDiary calculation (the detailed definition of migraine day 
can be found in Section 8.3.1) 
6. Demonstrated at least 80% compliance with the eDiary (e.g. must complete eDiary items 
on at least 23 out of 28 days during the baseline period) based on the eDiary calculation 
7. History of migraine (with or without aura) for ≥ 12 months prior to screening according to 
the IHS Classification (Tassorelli et al 2018) based on medical records and/or patient self-
report 
5.2 
Exclusion criteria 
Subjects meeting any of the following criteria are not eligible for inclusion in this study. 
1. Older than 50 years of age at migraine onset 
2. History of cluster headache or hemiplegic migraine headache 
3. Chronic migraine with continuous pain, in which the subject does not experience any pain 
free periods (of any duration) during the 1 month prior to screening 
4. Unable to differentiate migraine from other headaches 
5. Taken an opioid and/or opioid-containing analgesic for any indication during more than 
4 days within one month prior to the start of the baseline period or during the 
baseline period 
6. Taken a butalbital-containing analgesic for any indication during more than 2 days within 
one month prior to the start of the baseline period or during the baseline period 
7. Prior migraine prophylaxis treatments failure in more than 3 out of the following 
medication categories: 

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• Category 1: Divalproex sodium, sodium valproate 
• Category 2: Topiramate 
• Category 3: Beta blockers (for example: atenolol, bisoprolol, metoprolol, nadolol, 
nebivolol, pindolol, propranolol, timolol) 
• Category 4: Tricyclic antidepressants (for example: amitriptyline, nortriptyline, 
protriptyline) 
• Category 5: Flunarizine, verapamil, cinnarizine 
• Category 6: Serotonin-norepinephrine reuptake inhibitors (for example: venlafaxine, 
desvenlafaxine, duloxetine, milnacipran) 
• Category 7: Botulinum toxin 
• Category 8: Lisinopril, candesartan 
• Category 9: Pregabalin, gabapentin 
• Category 10: Zonisamide 
• Category 11: Memantine 
• Category 12: Pizotifen 
Prior migraine prophylaxis treatments failure is defined as efficacy failure or tolerability 
failure. 
• Efficacy failure is defined as "no meaningful reduction in headache frequency after 
administration of the respective medication for at least 6 weeks at generally accepted 
therapeutic dose(s) based on the investigator’s assessment within the last 5 years prior 
to screening." 
• Tolerability failure is defined as "documented discontinuation due to adverse events 
of the respective medication at any previous time." 
8. Use of a prohibited medication for migraine prophylaxis within 5 half-lives, or a device 
or procedure for migraine prophylaxis (e.g. transcranial magnetic stimulation, greater 
occipital nerve block, invasive or non-invasive neuromodulation) within one month prior 
to the start of the baseline period or throughout the study (Refer to Section 6.2.2 for the 
list of these excluded medications, devices and procedures for migraine prophylaxis) 
Note: use of other non-pharmacological treatments and traditional techniques such as 
acupuncture, traditional and herbal medicine, etc. is in general allowed if the dose/regimen 
is stable for at least 1 month prior to the start of the baseline phase and also stable 
throughout the study. 
9. Prior Botulinum toxin A treatment in the head/neck region within 4 months prior to the 
start of the baseline period or during the baseline period 
10. Active chronic pain syndromes (such as fibromyalgia and chronic pelvic pain) 
11. History of major psychiatric disorder (such as schizophrenia or other psychotic disorders, 
bipolar disorder, obsessive-compulsive disorder, post-traumatic stress disorder), or current 
evidence of depression based on a Beck Depression Inventory (BDI)-II total score > 24 at 
Screening. Subjects with anxiety disorder and/or major depressive disorder are permitted 
in the study if they are considered by the investigator to be stable and are taking no more 
than one medication for each disorder. Subjects must have been on a stable dose within 
the 3 months prior to the start of the baseline period. 

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12. History of seizure disorder or other significant neurological conditions other than 
migraine. (note: A single childhood febrile seizure is not exclusionary) 
13. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless 
of whether there is evidence of local recurrence or metastases. 
14. History or evidence of any other unstable or clinically significant medical condition, that 
in the opinion of the investigator, would pose a risk to subject safety or interfere with the 
study evaluation, procedures or completion 
15. Human immunodeficiency virus (HIV) infection by history 
16. Evidence of pre-existing liver condition as defined as any of the following: 
• Total bilirubin (TBIL) ≥ 2.0 × upper limit of normal (ULN) or alanine transaminase 
(ALT) or aspartate aminotransferase (AST) ≥ 3.0 x ULN, as assessed by the central 
laboratory at initial screening 
• Known history of acute/active hepatitis B virus (HBV) or hepatitis C virus (HCV) 
within 3 months prior to screening according to local clinical practice 
17. Myocardial infarction (MI), stroke, transient ischemic attach (TIA), unstable angina, or 
coronary artery bypass surgery or other revascularization procedure within 12 months 
prior to screening 
18. Subject has any clinically significant vital sign, laboratory, or electrocardiogram (ECG) 
abnormality during screening that, in the opinion of the investigator, could pose a risk to 
subject safety or interfere with the study evaluation 
19. Score “yes” on item 4 or item 5 of the Suicidal Ideation section of the Columbia Suicide 
Severity Rating Scale (C-SSRS), if this ideation occurred in the past 6 months, or “yes” on 
any item of the Suicidal Behavior section, except for the “Non-Suicidal Self-Injurious 
Behavior” (item also included in the Suicidal Behavior section), if this behavior occurred 
in the past 2 years. 
20. Evidence of drug or alcohol abuse or dependence within 12 months prior to screening, 
based on medical records, patient self-report, or positive urine drug test performed during 
screening (with the exception of prescribed medications such as opioids or barbiturates) 
21. Pregnant or nursing (lactating) women 
22. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using basic methods of contraception during dosing of 
investigational drug. Basic contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 m prior to screening). For female subjects on the study, 
the vasectomized male partner should be the sole partner for that subject 

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• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps).  
• Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that have comparable efficacy 
(failure rate < 1%), for example hormone vaginal ring or transdermal hormone 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS) 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking investigational drug.  
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she considered 
not of child bearing potential. 
If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the informed consent form.  
23. Use of other investigational drugs within 5 half-lives of enrollment, or until the expected 
pharmacodynamics (PD) effect has returned to baseline, whichever is longer. 
24. History of hypersensitivity to any of the study treatments or its excipients or to drugs of 
similar chemical classes 
25. Any prior exposure to investigational or marketed products targeting the CGRP pathway, 
including previous erenumab studies 
26. Unlikely to be able to complete all protocol required study visits or procedures, and/or to 
comply with all required study procedures to the best of the subject’s and investigator’s 
knowledge. No additional exclusions may be applied by the investigator, in order to 
ensure that the study population will be representative of all eligible patients 
5.3 
Inclusion/Exclusion criteria for the open-label treatment period 
Inclusion criteria 
Subjects eligible for inclusion in the open-label treatment period must meet the following 
additional criteria: 
8. Completed the double-blind treatment period on study drug and did not meet any of the 
discontinuation criteria 
9. Signed informed consent covering the open-label treatment period 
Exclusion criteria 
Subjects meeting any of the following criteria are not eligible for the open-label treatment 
period: 
27. Local access to launched erenumab 

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28. Subject developed, during the double-blind treatment period, any contra-indication as per 
the Investigator's Brochure (IB) Edition 9.1 Appendix A section 4.3, or any unstable or 
clinically significant medical condition, laboratory or ECG abnormality that in the opinion 
of the investigator would pose a risk to subject safety. Note: Any ECG abnormality noted 
by the central reader must be evaluated by the investigator and discussed with the sponsor 
as deemed necessary to determine if the ECG finding is representative of an unstable or 
clinically significant medical condition 
6 
Treatment 
6.1 
Study treatment 
6.1.1 
Investigational and control drugs 
Novartis will supply the investigational product listed below in Table 6-1. 
Table 6-1 
Investigational and control drug 
Investigational/ 
Control Drug 
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor 
(global or local) 
AMG334 
70 mg/1 mL 
Solution for injection 
Subcutaneous 
Use 
Double Blind 
supply; pre-filled 
syringe 
Sponsor global 
Matching 
placebo 1 mL  
Solution for injection 
Subcutaneous 
Use 
Double Blind 
supply; pre-filled 
syringe 
Sponsor global 
AMG334 
70 mg/1 mL 
Solution for injection 
Subcutaneous 
Use 
Open Label 
supply; pre-filled 
syringe 
Sponsor global 
The matching placebo to AMG334 70 mg/1 mL pre-filled syringe will have the same 
appearance as the investigational drug. Each syringe will be packaged individually in 
double‑blinded fashion for the double-blind treatment period. The study treatments will be 
labeled as AMG334 70 mg/1 mL/Placebo. 
For the open-label treatment period each pre-filled syringe will be packaged individually in 
open-label fashion. This open-label study treatment will be labeled as AMG334 70 mg. 
6.1.2 
Additional study treatments 
No additional treatment beyond investigational drug and control drug are included in this 
trial. Rescue medication is allowed as outlined in Section 6.2.3. 
6.1.3 
Treatment arms/group 
Subjects will be assigned to either erenumab 70 mg, or placebo at the Randomization Visit 
(Visit Day 1), in a 1:1 ratio, stratified by prior prophylactic migraine medication treatment 
failure and medication overuse status. 

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Study medication will be provided as follows: 
• Placebo: One pre-filled 1 mL syringes (PFS) containing placebo identical in appearance to 
erenumab 
• AMG334 70 mg: One PFS containing 70 mg/1 mL of erenumab 
6.1.4 
Treatment duration 
The planned duration of double-blind treatment is 12 weeks. Subjects who complete the double-
blind treatment period may be eligible to participate in the open-label treatment period until the 
drug is launched in the country or until June 2021 in Korea. 
Subjects may be discontinued from treatment earlier due to unacceptable toxicity, disease 
progression and/or treatment is discontinued at the discretion of the investigator or the subject. 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject was enrolled into the study must be recorded 
in the appropriate Case Report Form (CRF) or eDiary for the double-blind treatment period and 
in the CRF only for the open-label treatment period.  
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a subject or allowing a new medication to be started. If the subject is already 
enrolled, contact Novartis to determine if the subject should continue participation in the study. 
Use of concomitant therapies for indications other than migraine prevention is allowed 
throughout the course of the study. Medications with possible migraine prophylactic effects (the 
list of relevant medications can be found in Section 6.2.2) for indications other than migraine 
prevention (e.g. beta blockers used for anti-hypertension, SNRIs used for major depressive 
disorder) are permitted in the study if they are considered by the investigator to be stable and 
are taking no more than 1 medication for each indication. Subjects must have been on a stable 
dose within the 3 months prior to the start of the baseline period. The dose level must be stable 
throughout the study. 
Use of other non-pharmacological treatments and traditional techniques such as acupuncture, 
traditional and herbal medicine, etc. is in general allowed if the dose/regimen is stable for at 
least 1 month prior to the start of the baseline period and also stable throughout the study (with 
the exception of Cao Wu Jia Su Pian, Du Liang Ruan Jiao Nang that shall not be administered 
at least 2 weeks prior to the start of the baseline period and throughout the study). 
6.2.2 
Prohibited medication 
1. The following medications used for migraine prophylaxis are excluded within 5 half-
lives prior to the start of the baseline period and throughout the study, including the open-
label treatment period:  
• Antiepileptics (e.g. divalproex sodium, sodium valproate, topiramate, carbamazepine, 
gabapentin, pregabalin, zonisamide) 

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• Beta blockers (e.g. atenolol, bisoprolol, metoprolol, nadolol, nebivolol, pindolol, 
propranolol, timolol) 
• Tricyclic antidepressants (e.g. amitriptyline, nortriptyline, protriptyline) 
• Serotonin-norepinephrine reuptake inhibitors (e.g. venlafaxine, desvenlafaxine, 
duloxetine, milnacipran) 
• Calcium channel blockers (e.g. flunarizine, verapamil, cinnarizine) 
• Others: Lisinopril, candesartan, cyproheptadine, pizotifen, memantine, butterbur, 
feverfew, magnesium (> 600 mg/day), riboflavin (> 100 mg/day) 
• Cao Wu Jia Su Pian, Du Liang Ruan Jiao Nang 
2. Botulinum toxin A (in the head and/or neck region) is excluded within 4 months prior to 
the start of the baseline period and throughout the study. 
3. Ergotamine-derivatives, steroids and triptans used for migraine prophylaxis are excluded 
within 2 months prior to the start of the baseline period and throughout the study. 
4. Devices and procedures used for migraine prophylaxis (e.g. nerve stimulators, transcranial 
magnetic stimulation, greater occipital nerve block, invasive or non-invasive 
neuromodulation, pulsed radiofrequency) are excluded within 1 month prior to the start of 
the baseline period and throughout the study.  
5. Investigational medications, devices, and procedures, unless specifically allowed as per 
above, are excluded throughout the study. 
6.2.3 
Rescue medication 
Subjects can continue to use “best supportive care” as rescue medication. This can include both 
pharmacologic interventions (i.e., abortive treatments for acute attacks) and non-pharmacologic 
interventions (e.g. biofeedback, psychotherapy, acupuncture or other locally accepted and 
endorsed interventions for migraine). Traditional medications (e.g. herbal medicines) are 
allowed as determined by the investigator, as long as the regimen is not likely to interfere with 
headache assessments. Chronically administered “best supportive care” is recommended to be 
in a stable regimen for at least 1 month prior to the start of baseline period. 
During or before the screening period, the subject and investigator are to agree on the 
medications for the acute treatment of headache pain and the appropriate dose(s) that the subject 
may take on an as-needed basis (Pro re nata, PRN) throughout the study. Medications for acute 
treatment of headache pain include: simple analgesics, combination analgesics, triptans, ergot-
derivatives. Opioid-containing and butalbital-containing analgesics are not allowed during the 
study. To avoid confounding the study results, new acute medications for treatment of headache 
pain should not be introduced after the start of baseline visit (in double blind treatment period) 
and addition of daily medication that fall into the categories of simple analgesics, combination 
analgesics, triptans, and ergot-derivatives should be avoided, even if the medication is used for 
indications other than headache. 
Site staff will pre-specify the name, dose strength, and route of administration of the subject’s 
acute headache (rescue) medications in the subject’s eDiary (double-blind treatment period 
only). If the subject takes an acute headache medication during aura or to treat a migraine or 
non-migraine headache, they will select one of the pre-specified medications (or “other” 
medication) and enter the date of administration, the number of times the medication was taken 

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on that date and number of units taken. Use of rescue medication must be recorded in the eDiary 
during the double-blind treatment period only. Relevant non-drug therapies as part of “best 
supportive care” use should also be recorded in appropriate CRF.  
6.3 
Subject numbering, treatment assignment, randomization 
6.3.1 
Subject numbering 
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential subject 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the subject is assigned to the next sequential Subject 
No. available. 
6.3.2 
Treatment assignment, randomization 
At Day 1, all eligible subjects will be randomized via Interactive Response Technology (IRT) 
to one of the treatment arms. The investigator or his/her delegate will contact the IRT after 
confirming that the subject fulfills all the inclusion/exclusion criteria. The IRT will assign a 
randomization number to the subject, which will be used to link the subject to a treatment arm 
and will specify a unique medication number for the first package of study drug to be dispensed 
to the subject. The randomization number will not be communicated to the caller. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of subject numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 
Global Clinical Supplies using a validated system that automates the random assignment of 
medication numbers to packs containing the investigational drug(s). 
Randomization will be stratified by prior prophylactic migraine treatment failure (Yes vs. No) 
and presence of medication overuse (Yes vs. No) during baseline according to the planned 
randomization ratio within each stratum. The randomization scheme for subjects will be 
reviewed and approved by a member of the Randomization Group. 
6.4 
Treatment blinding 
Subjects, investigator staff, persons performing the assessments, and clinical trial team (CTT) 
will remain blind to the identity of the treatment from the time of randomization using the 
following methods:  
1. Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible by anyone else involved in the study with the following exceptions:  
• PK/anti-AMG 334 antibody analysts who will keep PK/anti-AMG 334 antibody 
results confidential until data base lock 

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• DMC members and unblinded statisticians and programmers in charge of the outputs 
of unblinded IA (including statisticians from external vendors involved in data 
analyses) 
 
2. The identity of the treatments will be concealed by the use of study treatment that are all 
identical in packaging, labeling, schedule of administration, appearance, taste and odor. 
Unblinding will occur in the case of subject emergencies (see Section 6.6.2) and at the 
conclusion of the primary analysis. Randomization information will be available to the 
investigator when the clinical study report for the primary analysis has been finalized. 
Table 6-2 
Blinding levels 
Role 
Time or Event 
Treatment 
allocation & 
dosing 
Safety event (single 
subject unblinded) 
Interim Analysis & 
dose escalation 
Subjects/Patients 
B 
UI 
B 
Site staff 
B 
UI 
B 
Independent committees used for 
assessing interim results 
UI 
UI 
UI 
Statistician/statistical 
programmer/data analysts 
B 
B 
B 
B Remains blinded 
UI Allowed to be unblinded on individual patient level 
6.5 
Dose escalation and dose modification 
6.5.1 
Dose modifications 
The starting dose for erenumab is 70 mg/1 mL and matching placebo is 1 mL. Subjects will 
keep this dose throughout the study. Study treatment dose adjustments are not permitted. For 
subjects who are unable to tolerate the protocol-specified dosing scheme, dose interruptions of 
study treatment are permitted in order to keep the subject on study drug. These changes must 
be recorded on the appropriate CRF. 
6.5.2 
Follow-up for toxicities 
6.5.2.1 
Follow up on potential drug-induced liver injury cases 
Subjects with transaminase increase combined with TBIL increase may be indicative of 
potential DILI and should be considered as clinically important events. 
The threshold for potential drug-induced liver injury (DILI) may depend on the subject’s 
baseline AST/ALT and TBIL value; subjects meeting any of the following criteria will require 
further follow-up as outlined below: 
• For subjects with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN 
• For subjects with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2.0 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2.0 
x baseline AND > 2.0 x ULN] 

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Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as alkaline phosphatase (ALP) elevation > 2.0 x ULN with R value < 2 in subjects without bone 
metastasis, or elevation of ALP liver fraction in subjects with bone metastasis. 
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R > 2 and < 5) liver injury. 
In the absence of cholestasis, these subjects should be immediately discontinued from study 
treatment, and repeat Liver Function Test (LFT) testing as soon as possible, preferably within 
48 hours from the awareness of the abnormal results. The evaluation should include laboratory 
tests, detailed history, physical assessment and the possibility of liver metastasis or new liver 
lesions, obstructions/compressions, etc. 
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, Gamma-glutamyl transferase (GGT), prothrombin time (PT)/ 
International Normalized Ratio (INR), and alkaline phosphatase. 
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, and history of any pre-existing 
liver conditions or risk factors, should be collected. 
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted. 
4. Obtain PK sample, as close as possible to last dose of, if PK analysis is performed in the 
study. 
5. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant” and thus, meet the definition of Serious Adverse Event (SAE) and should be 
reported as SAE using the term “potential drug-induced liver injury”. All events should be 
followed up with the outcome clearly documented. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
During both the double-blind treatment and the open-label treatment period, the study 
medication is administered by the investigator or designated study staff at each visit. This 
information should be captured in the source documents and the CRF at each visit. All study 
treatment administered must be recorded in the Drug Accountability Log. Information 
regarding treatment during the COVID-19 pandemic can be found in Section 13.2. 
Site staff will review eDiary compliance with the subject at each visit during the double-blind 
treatment period. 

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6.6.2 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a subject, he/she must provide the 
requested subject identifying information and confirm the necessity to break the treatment code 
for the subject. The investigator will then receive details of the investigational drug treatment 
for the specified subject and a fax or email confirming this information. The system will 
automatically inform the Novartis monitor for the site and the study team that the code has been 
broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide: 
• protocol number 
• study drug name 
• subject number 
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time. 
6.7 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section. 
A unique medication number is printed on the study medication label.  
Investigator staff will identify the study medication kits to dispense to the subject by contacting 
the IRT and obtaining the medication number(s). The study medication has a 2-part label (base 
plus tear-off label), immediately before dispensing the medication kit(s) to the subject, site 
personnel will detach the outer part of the label(s) from the packaging and affix it to the source 
document. 
During both the double-blind treatment as well as the open-label treatment period, one 
medication kit will be dispensed per visit by the IRT system. The medication is administered 
by the investigator or designated study staff at each visit. 
6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the Investigator’s Brochure (IB). Clinical supplies are 

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to be dispensed only in accordance with the protocol. Technical complaints are to be reported 
to the respective Novartis Country Organization (CO) Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial.  
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
6.7.1.2 
Handling of additional treatment 
Not applicable. 
6.7.2 
Instruction for prescribing and taking study treatment 
Subcutaneous (s.c.) injections are to be administered in the clinic by qualified staff at drug 
dispensing visit.  
For purposes of study treatment dosing, “q.m.” refers to an every 4 weeks injection regimen. 
The study drug administration date should be in 4-week increments (± 5 days) from the first 
dose of study drug. Any dose administrations that may occur greater than ± 5 days from the 4-
week timepoint (e.g. subject unavailability) should be discussed with the Sponsor prior to 
dosing. The anatomical sites for administration of investigational product are the upper arm, 
upper thigh, or abdomen; the location of the injection sites should be documented in the source 
document. 
One injection will be administered by qualified study staff at each dosing visit during the 12-
week treatment period (i.e. at Day 1 and Weeks 4 and 8). Subjects will be administered one of 
the following, depending on their randomization: 
• 70 mg erenumab: one 70 mg erenumab syringe 
• Placebo: one placebo syringe 
One injection of 70 mg erenumab will be administered by qualified study staff at each visit 
during the open-label treatment period. 
The investigator must promote compliance administering the study treatment exactly as 
prescribed. The investigational product dose is fixed and will not be adjusted for individual 
subjects during the study. There are no temporal restrictions for study drug administration (eg, 
proximity to meals, sleep or activity). 
All kits of study treatment assigned will be recorded in the IRT, both for the double-blind 
treatment and the open-label treatment period. Novartis monitors will reconcile treatment 
assigned vs treatment administered and ensure that the information is congruent during their 
monitoring visits. 

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During the COVID-19 pandemic: 
During the COVID-19 pandemic that limits or prevents on-site study visits, delivery of study 
drug directly to a subject’s home is generally permitted in the event the Investigator has decided 
that an on-site visit by the subject is no longer appropriate or possible, and that it is in the interest 
of the subject’s health to administer (e.g., self-injection or study staff administration at subjects’ 
home) the study treatment even without performing an on-site visit. Implementation will need 
to be discussed with Novartis (see section 7 for required training process). The dispatch of study 
drug from the site to the subject’s home remains under the accountability of the investigator. 
Each shipment/provisioning will be for a maximum of 1 month supply. In this case, regular 
phone calls or virtual contacts (at the time of every scheduled visit, or more frequently if needed) 
will occur between the site and the subject for instructional purposes, safety monitoring, and 
discussion of the subject’s health status until the subjects can again visit the site. 
7 
Informed consent procedures 
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-
approved informed consent. 
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the International Council for Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidelines 
and regulatory requirements and is considered appropriate for this study. Any changes to the 
proposed consent form suggested by the investigator must be agreed by Novartis before 
submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an Investigator Notification (IN) 
or an aggregate safety finding. New information might require an update to the informed 
consent and then must be discussed with the subject. 
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements. 

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A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
During the COVID-19 pandemic that may challenge the ability to obtain a standard written 
informed consent due to limits that prevent an on-site visit, the investigator may conduct the 
informed consent discussion remotely (e.g. telephone, videoconference). Guidance issued by 
local regulatory bodies on this aspect prevail and must be implemented and appropriately 
documented (e.g. the presence of an impartial witness, sign/dating separate informed consent 
form by subject and person obtaining informed consent, etc...). 
During the COVID-19 pandemic the investigator should also discuss the home-delivery of 
study drug, and should provide detailed step by step instructions for the proper method for self-
administration of study drug including: 1) the correct handling, 2) self-administration procedure, 
and 3) storage of study drug. This training may be done in person or videoconference or by 
telephone if subject visits to site are not possible. This training process needs to be documented 
in the subject chart with the subject’s verbal/e-mail/ or chat function agreement. Written 
informed consent must be obtained once protocol amendment 2 is approved at the site. 
8 
Visit schedule and assessments 
The Assessment Schedule (Table 8-1) lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the subject’s source documentation. 
Subjects should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation. Subjects who prematurely discontinue the study 
for any reason should be scheduled for a visit as soon as possible, at which time all of the 
assessments listed for the End of Treatment visit will be performed. At this visit, all dispensed 
investigational product should be reconciled, and the adverse event and concomitant 
medications recorded on the CRF. 
If the COVID-19 pandemic limits or prevents on-site study visits, alternative methods of 
providing continuing care may be implemented. Phone calls, virtual contacts (e.g. teleconsult) 
or visits by site staff to the subject’s home depending on local regulations and capabilities, can 
replace on-site study visits, for the duration of the pandemic until it is safe for the subject to 
visit the site again (see Section 8.3 Efficacy, Section 8.4 Safety, Section 8.4.1 Laboratory 
evaluations, Section 8.4.2 Electrocardiogram (ECG), Section 8.4.3 Pregnancy and assessments 
of fertility, Section 8.4.4 Prospective suicidality assessment, 
 
, Section 8.5.5 AMG 334 Antibody testing, Section 
10 Safety monitoring and reporting, Section 10.2.2 Prospective suicidality assessment and 
Section 13.2 Responsibilities of the Investigator and IRB/IEC for further COVID-19 guidance).   
  
 
 

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6 Sites will access the Interactive Response Technology (IRT) System to enter the subject into the initial screening period, to randomize an eligible 
subject into the 
double-blind treatment period, to dispense study treatment during the double-blind and open-label treatment periods, and to register study early 
termination. Subject data will be collected in the IRT System including, but not limited to, reason for screen fail (if applicable).  The IRT system will 
automatically assign study drug when a subject is randomized.  
7 Including prior prophylactic migraine medication 
8 Height collected at Screening visit only. Weight collected at Screening, Baseline, and End Of Treatment (double-blind treatment period) visits. Blood 
pressure, pulse and body temperature collected at every double-blind treatment period visit. 
9 At Day 1 visit sample should be collected prior to dose administration. 
10 Subject brings the eDiary device to each double-blind treatment visit for use at site. 
11 Subjects will record headache and headache medication information daily, using the provided eDiary device, during the double-blind treatment period. 
12 Completed daily via the eDiary device, during the double-blind treatment period. 
13 To be completed during applicable study visits before study drug administration. 
14 Adverse Events will be collected after Informed Consent signature through the end of the Follow-Up Period (12 weeks after the last dose of study drug) 
. 
15 Study drug is administered by study staff, every 4 weeks (± 5 days) during the applicable study visits. One pre-filled syringe will be administered at 
each visit. 

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8.1 
Screening 
The procedures are to be completed during the screening period can be found in  Table 8-1. 
The duration of the screening period is up to 2 weeks. Certain screening procedures may be 
repeated during the original screening period. In case a safety laboratory assessment at 
screening is outside of the range specified in the exclusion criteria, the assessment may be 
repeated once prior to baseline period. If the repeat value remains outside of the specified ranges, 
the subject must be excluded from the study. Novartis may grant an extension to the screening 
period in rare cases where additional time is required to confirm eligibility. 
Investigators may re-screen a subject (screening period only) if the investigator is reasonably 
certain that reasons for screen failure will be resolved prior to or during a repeat screening 
attempt. Re-screening after the subject entered the baseline period is not allowed. Reasons to 
re-screen may include but are not limited to the following: 
• Laboratory value(s) out of range due to sampling error or that might be within range after 
medically-appropriate supplementation. (Note: Before screen failing and then re-screening 
the subject, effort should be made to repeat the laboratory assessment(s) during the 
original screening period.) 
• The subject has a medical condition that can be stabilized or resolved prior to the repeat 
screening attempt; 
or 
• Additional time is required following the subject's last dose of an excluded medication. 
Investigators are encouraged to consult with Novartis prior to re-screening subjects for other 
reasons. 
A subject must provide informed re-consent prior to the initiation of any re-screening 
procedures. A new subject number will be assigned. A subject may be screened up to 2 times 
(i.e. no more than 1 re-screen). 
Near to the end of randomization, sites may be notified when no additional subjects will be 
screened or re-screened. 
8.1.1 
Information to be collected on screening failures 
Subjects who sign an informed consent and subsequently found to be ineligible prior to 
randomization will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate Case Report Form. The demographic information, informed 
consent, and Inclusion/Exclusion pages must also be completed for subjects who are found to 
be ineligible during the Screening visit. No other data will be entered into the clinical database 
for screen failure subjects, unless the subject experienced a serious adverse event during the 
Screening period (see SAE section for reporting details). If the subject fails to be randomized, 
the IRT should be notified within 2 days of the screen fail that the subject was not randomized. 
Subjects who are randomized and fail to start treatment, e.g. subjects randomized in error, will 
be considered an early terminator. The reason for early termination should be recorded on the 
appropriate Case Report Form. 

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8.2 
Subject demographics/other baseline characteristics 
Subject demographic and baseline characteristic data to be collected on all subjects include: age, 
sex, race, ethnicity, relevant medical history/current medical condition present before signing 
informed consent where possible, diagnoses and not symptoms will be recorded. 
Prior headache characteristics and previous headache medication history will be collected as 
part of baseline characteristics. 
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature. 
8.3 
Efficacy 
Efficacy assessments will include: 
• Migraine days 
The timing and frequency of these assessments are outlined in  Table 8-1. Subjects will record 
the efficacy information using the provided eDiary platform. To aid in compliance, it is 
recommended that the information be completed at the same time every day that is convenient 
for the subject. Retroactive completion will be allowed one day prior to the time of completion. 
Any entries > 2 days old will not be allowed and will be considered missing data. 
During the COVID-19 pandemic that limits or prevents on-site study visits, efficacy 
information including PRO scales may still be collected by using the provided eDiary. 
 
8.3.1 
Migraine Days 
A migraine day is defined as any calendar day in which the subject experiences a qualified 
migraine headache (onset, continuation, or recurrence of the migraine headache). A qualified 
migraine headache is defined as a migraine with or without aura, lasting for ≥ 4 continuous 
hours, and meeting at least one of the following criteria: 
1.≥ 2 of the following pain features: 
• Unilateral 
• Throbbing 
• Moderate to severe 
• Exacerbated with exercise/physical activity 
2.≥ 1 of the following associated symptoms: 
• Nausea and/or vomiting 
• Photophobia and phonophobia 
If the subject took ANY acute medication (simple analgesics [NSAIDs, acetaminophen], 
combination analgesics, triptans or ergot-derivative) during aura, or to treat a moderate or 
severe headache on a calendar day, then it will be counted as a migraine day regardless of the 
duration and pain features/associated symptoms. A migraine headache event that is lasting less 
than 24 consecutive hours in duration, regardless whether or not it extends into the prior or next 

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calendar day for less than 4 hours, should be counted as a single migraine day, even if acute 
medication is taken on the prior or next calendar day. Opioid-containing analgesic and 
butalbital-containing analgesics are excluded in allowed acute medication categories.  
8.3.2 
Appropriateness of efficacy assessments 
Monthly migraine days (MMD) is a clinically relevant and commonly accepted primary 
endpoint in accordance with current standards and guidelines (Tassorelli et al 2018, 
Tfelt-Hansen et al 2012) for migraine prophylactic studies. The definition of migraine day 
(Section 8.3.1) in this study is adapted based on the diagnostic criteria of ICHD-3 
(3rd edition 2018) and the clinical practice in China. Acute migraine-specific medication 
(mainly triptan) use is very common in global countries or regions. In global pivotal Study 
20120295 in CM population, 75%-79% patients used acute migraine-specific medication during 
baseline. However, the use of triptan or ergots is extremely low in China 
(Jiang et al 2016). Almost all of migraine patients in China usually use migraine unspecific 
analgesics such as NSAIDs or combination analgesics for the acute treatment of migraine. Due 
to the difference in use pattern of acute migraine-specific medication (mainly triptans) between 
Chinese and the global migraine population, the criteria of migraine day in ICHD-3 makes this 
clinical tool less applicable in our clinical setting, and argues for inclusion of other acute 
migraine-unspecific medications in the definition of migraine day in this study to better 
illustrate Chinese patients characteristics. This definition of migraine day was also aligned with 
China CDE. The monthly migraine days will be calculated using migraine day data collected 
from the eDiary.  
As the mean change in MMD however describes a population-based measure and given the 
natural variability in migraine trials often is associated with small effect sizes, clinically an 
important complementary information is the proportion of patients that achieve a certain 
clinically meaningful response, which is usually described with achieving at least a 50% 
reduction of migraine days compared to the individual baseline (“50% responder rate”). In 
pivotal trials, 50% (or higher) responder rates are usually included as secondary or key 
secondary outcomes.  
8.4 
Safety 
During the COVID-19 pandemic that limits or prevents on-site study visits regular phone or 
virtual calls will occur (at the time of every scheduled visit or more frequently if needed) for 
safety monitoring and discussion of the subject´s health status until the subject can again visit 
the site. 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 
For details on AE collection and reporting, refer to AE section. 
Table 8-2 
Safety Assessments 
Assessment 
Specification 
Physical examination 
A complete physical examination will include the 
examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, 

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Clinically notable laboratory findings are defined in Section 16.1 
During the COVID-19 pandemic that limits or prevents on-site study visits, or if visits by site 
staff to a subject’s home are not feasible, the collection of samples may be modified by Novartis 
and will be communicated to the investigator (e.g., local lab collection of samples).   
 
Table 8-3 
Laboratory Assessments 
Test Category 
Test Name 
Hematology 
Red Blood Cells (RBC), Nucleated RBCs, 
Hemoglobin, Hematocrit, MCV, MCH, MCHC, 
RDW, Reticulocytes, Platelets, White Blood 
Cells (WBCs), WBC differential (Bands/Stabs, 
Neutrophils, Eosinophils, Basophils, 
Lymphocytes, Monocytes, Myeloblasts, 
Promyelocytes, Myelocytes, Metamyelocytes, 
and Atypical Lymphocytes) 
Chemistry 
Sodium, Potassium, Chloride, Bicarbonate, Total 
Protein, Albumin, Calcium, Magnesium, 
Phosphorus, Glucose, BUN/Urea, Bilirubin 
(Direct and Total), Alkaline Phosphatase, ALT 
(SGPT), AST (SGOT), Total Cholesterol, HDL, 
LDL, Triglycerides, CPK, and eGFR. 
Drug Screen 
Urine Drug test for substances of abuse, at 
Screening. It can also be performed during the 
study at the investigator's discretion based on 
clinical suspicion. If a subject has a positive 
urine drug screen during the study (except for 
certain prescribed medications), the investigator 
should consider discontinuation from the 
investigational product. 
Pregnancy testing 
Serum or Urine 
8.4.2 
Electrocardiogram (ECG) 
All ECGs must be recorded as outlined in the central ECG reading manual. The preferred 
sequence of cardiovascular data collection during study visits is ECG collection first, followed 
by vital signs, and blood sampling. The Fridericia QT correction formula (QTcF) as reported 
by the central reader should be used for clinical decisions. 
Single 12 lead ECGs are collected. The original ECGs, printed on non-heat sensitive paper, 
appropriately signed, must be collected and archived at the study site. 
Each ECG tracing must be labeled with study number, subject initials, subject number, date and 
time, and filed in the study site source documents. For any ECGs with subject safety concerns, 
two additional ECGs must be performed to confirm the safety finding and forwarded to the 
central ECG laboratory for assessment. Clinically significant ECG findings at randomization 
(pre-dose) must be discussed with the sponsor before administration of study treatment. 
Clinically significant abnormalities must be recorded on the relevant section of the CRFs as 
appropriate. 

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During COVID-19 pandemic, if a subject cannot visit the site to have ECG recorded, or if 
visits by site staff to a subject’s home are not feasible, the ECG may be performed locally and 
the result reported to the site. If local ECG is an option, each ECG tracing must be recorded as 
outlined in the central ECG reading manual, be labeled with study number, subject initials, 
subject number, date and time, and filed in the study site source documents. A communication 
process should be established with the patient so that the site is informed of the ECG result if 
performed locally. 
If it is not possible to perform ECG locally, ECG must then be performed at the next on-site 
visit.  
8.4.3 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have pregnancy testing.  
Serum pregnancy tests will be performed at Screening and End of Treatment (End of 
Treatment visit/week 12 being the first visit of the open-label treatment period in case the 
subject agrees to participate). 
Urine pregnancy tests will be performed at the remaining double-blind treatment visits, every 
three months during the open-label treatment period and at the End of Treatment Open-Label 
visit. Kits will be provided by the Central Lab only for the double-blind treatment visits 
assessments. 
The specific schedule is outlined in Table 8-1. 
For more details about potential deviation in case of local regulations, please refer to 
Section 5.2 and Exclusion criterion #22. 
During COVID-19 pandemic, if a subject cannot visit the site to have pregnancy tests 
conducted the subject may complete a urine pregnancy test at home and report the result to the 
site. It is important that subjects are instructed to perform the urine pregnancy test first and only 
if the test result is negative proceed with the administration of the study treatment. A 
communication process should be established with the subject so that the site is informed of the 
pregnancy test results. 
8.4.4 
Prospective suicidality assessment 
The C-SSRS is a questionnaire that prospectively assesses Suicidal Ideation and Suicidal 
Behavior. The C-SSRS must be administered at each visit of the double-blind treatment period, 
including unscheduled visits. 
A validated version of the electronic Columbia Suicide Severity Rating Scale eC-SSRS will be 
used to capture self-reported eC-SSRS data via a web-based interactive response system and 
via a phone system (both interchangeable). The eC-SSRS uses a detailed branched logic 
algorithm to perform the eC-SSRS subject interview, evaluating each subject’s suicidality 
ideation and behavior in a consistent manner. At the conclusion of each assessment, a detailed 
eC-SSRS Findings Report will be available on the vendor portal. If the system assesses the 
subject as having positive suicidal signs, the investigator will be immediately notified by either 
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If, at any time after screening and/or baseline, the score is “yes” on item 4 or item 5 of the 
Suicidal Ideation section of the C-SSRS or “yes” on any item of the Suicidal Behavior section, 
the subject must be referred to a mental health care professional for further assessment and/or 
treatment. The decision on whether the study treatment should be discontinued is to be taken 
by the investigator in consultation with the mental health professional to whom the subject is 
referred. 
In addition, all life-threatening events must be reported as SAEs. For example, if a subject 
answers “yes” to one of the questions in the Suicidal Behavior section, an SAE must be reported 
if the event was life-threatening. All events of “Non-Suicidal Self-Injurious Behavior” 
(question also included in the Suicidal Behavior section) should be reported as AEs and 
assigned the appropriate severity grade. 
All SAEs relating to suicidal behavior must be reviewed by the safety physician. 
During the COVID-19 pandemic that limits or prevents on-site study visits, the eC-SSRS may 
still be collected via a web-based interactive response system or via a phone system (both 
interchangeable). In this latter case, the dialing number will be temporarily kept by the vendor. 
8.4.5 
Appropriateness of safety measurements 
The safety assessments have been selected based upon the safety profile of the drug as reported 
in the Investigator Brochure, are standard for this subject population and drug class. 
8.5 
Additional assessments 
8.5.1 
Clinical Outcome Assessments (COAs) 
Clinical Outcome assessments (COAs) will be collected by subjects using a handheld electronic 
diary (eDiary) at various frequencies during the double-blind treatment period. 
The eDiary will collect the following COAs daily, at home: 
• Date and time of start of headache (i.e. migraine or non-migraine headache) 
• Date and time of end of headache 
 
 
• Pain features (e.g. one-sided, throbbing, worsens with exercise/physical activity) 
• Symptoms (e.g. aura, nausea, vomiting, photophobia, phonophobia) 
• Use of acute headache medications (medication name [from pre-entered list], date of 
dosing, number of times taken of each date, number of units taken) 
The eDiary will categorize headache events as migraine days or headache days based on the 
definitions below: 
• Headache Day: Any calendar day in which the subject experiences a qualified migraine or 
a non-migraine headache (initial onset, continuation, or recurrence of the headache lasting 
≥ 4 continuous hours, or a headache of any duration for which acute medication was 
administered for treatment of headache pain). A headache event that is lasting less than 24 
consecutive hours in duration, regardless if it extends into the prior or next calendar day 
for less than 4 hours even if acute medication is taken on the prior or next calendar day, 
should be counted as a single headache day. 

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8.5.5 
AMG 334 Antibody testing 
Blood samples for antibody testing are to be collected for the measurement of anti-AMG 334 
binding antibodies. Samples will be collected at the timepoints defined in Table 8-1, prior to 
study drug administration. Samples testing positive for binding antibodies will also be tested 
for neutralizing antibodies and may be further characterized for quantity/titer, isotype, affinity, 
and presence of immune complexes. Additional blood samples may be obtained for further 
evaluation of anti-AMG 334 antibodies during the study. 
Sites will not be notified of positive neutralizing antibody results to the investigational product 
for a subject prior to that subject’s final scheduled study visit and the subjects with a positive 
neutralizing antibody response will continue to be dosed during the course of study. 
During the COVID-19 pandemic that limits or prevents on-site study visits, or if visits by site 
staff to a subject’s home are not feasible, the collection of samples may be modified by Novartis 
and will be communicated to the investigator. 
9 
Study discontinuation and completion 
9.1 
Discontinuation 
9.1.1 
Discontinuation of study treatment 
Discontinuation of study treatment for a subject occurs when study drug is stopped earlier than 
the protocol planned duration, and can be initiated by either the subject or the investigator. 
The investigator must discontinue study treatment for a given subject if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of trial participation. 
Study treatment must be discontinued under the following circumstances: 
• Subject/Guardian decision 
• Pregnancy (See Section 8.4.3) 
• Use of prohibited treatment as per recommendations in Section 6.2.2  
• Any situation in which study participation might result in a safety risk to the subject 
• Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the subject’s overall status, prevents the subject from continuing 
participation in the study 
• Following emergency unblinding (during the double-blind treatment period) 
In addition, study treatment should be discontinued under the following circumstances during 
the open-label treatment period:  
• Upon launch of erenumab in the country or in June 2021 in Korea 
• Subject is no longer clinically benefitting in the opinion of the investigator  
If discontinuation of study treatment occurs during the double-blind or open-label treatment 
period, the subject should NOT be considered withdrawn from the study (unless the subject 
specifically withdrew the consent). The Subject should return to the clinic at the time of the 
next scheduled visit (4-weeks interval), for the 'End of Treatment' or ‘End of Treatment Open-
Label’ visit respectively. Assessments detailed for this visit in Table 8-1 should be completed 

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and recorded in the appropriate CRF. The investigator should make a reasonable effort to 
understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information on the appropriate CRF. 
Subjects who discontinue the study treatment in the double-blind treatment period and are 
willing to return for the subsequent scheduled Follow-Up (FUP) visits should perform the End 
of Treatment assessments at the time of the next scheduled visit (4-weeks interval). The subject 
will then continue the subsequent FUP visits as per Table 8-1, including the Safety Follow-Up 
visit on Week 20.  
All subjects ongoing in the treatment period at the time of a positive IA read-out will be 
scheduled for an End of Treatment visit and then enter directly into the open-label treatment 
period or into the safety Follow-Up Period (in case the subject does not want to continue in the 
open-label treatment period) without performing those FUP visits. 
Subjects who discontinue the study treatment in the double-blind treatment period and are NOT 
willing to return for the subsequent FUP visits should perform the assessments according to the 
End of Treatment visit as soon as possible and the following data should be collected after study 
treatment discontinuation and until the Safety Follow-Up visit (which should occur 12 weeks 
after the last dose): 
• new / concomitant treatments 
• adverse events/Serious Adverse Events 
If the subject who discontinued study treatment in the double-blind treatment period cannot or 
is unwilling to attend the End of Treatment visit or the Safety Follow-Up visit, the site staff 
should maintain telephone contact with the subject, or with a person pre-designated by the 
subject. 
Subjects who discontinue the treatment during the open-label treatment period and performed 
the End Of Treatment visit will not be allowed to re-enter the study. 
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment. 
If study drug discontinuation occurs because the treatment code has been broken, please refer 
to Section 6.6.2. Subjects who are prematurely withdrawn from the study will not be replaced 
by an equal number of newly enrolled subjects. 
9.1.2 
Withdrawal of informed consent 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject: 
• Does not want to participate in the study anymore 
and 
• Does not allow further collection of personal data 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. 

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Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject's samples until their time of withdrawal) according to applicable 
law. 
All biological samples not yet analyzed at the time of withdrawal will no longer be used, unless 
permitted by applicable law. They will be stored according to applicable legal requirements. 
9.1.3 
Lost to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed or until the end of the study. 
9.1.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. 
Reasons for early termination: 
• Unexpected, significant, or unacceptable safety risk to subjects enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
• Discontinuation of study drug development 
In taking the decision to terminate, Novartis will always consider the subject welfare and safety. 
Should early termination be necessary, subjects must be seen as soon as possible for End of 
Treatment Visit and treated as a prematurely withdrawn subject. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate consideration 
is given to the protection of the subject’s interests. The investigator or sponsor depending on 
the local regulation will be responsible for informing IRBs/IECs of the early termination of the 
trial. 
9.2 
Study completion and post-study treatment 
A subject will be considered to have completed the double-blind treatment period when the 
subject has completed Week 12. A subject will be considered to have completed the open-label 
treatment period when the subject remained in the study until erenumab is launched in the 
country or until June 2021 in Korea.  

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A subject will be considered to have completed the study when the subject has completed the 
last visit as per the protocol. The study will be considered completed when the last subject 
completes their last visit planned in the protocol.  
Enrollment will continue at least until the time of the unblinded IA read-out. In case of positive 
read-out, enrollment will stop. Refer to Section 9.1.1 for details on how to handle ongoing 
subjects. In case the study does not stop early, enrollment will continue until the full sample 
size. 
10 
Safety monitoring and reporting 
During the COVID-19 pandemic that limits or prevents on-site study visits, regular phone or 
virtual calls will occur (at the time of every scheduled visit or more frequently if needed) for 
safety monitoring and discussion of the subject’s health status until the subject can again visit 
the site. 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial-related medical 
questions or problems.  
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments. 
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information (as far as possible) 
(if the event is serious refer to Section 10.1.2): 
1. Adverse events will be assessed and graded according to the most current version of the 
Common Terminology Criteria for Adverse Events (CTCAEs)  
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
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3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported. 
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. action taken regarding with study treatment. 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
• Dose not changed 
• Drug interrupted/withdrawn 
6. its outcome (i.e. recovery status or whether it was fatal) 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease. Alert ranges for laboratory and other test abnormalities are included in 
Section 16.1 
10.1.2 Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 

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• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are 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 dependency or abuse (please refer to the ICH-
E2D Guidelines). 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.  
10.1.3 SAE reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until the last study visit must be reported to Novartis safety 
within 24 hours of learning of its occurrence. Any SAEs experienced after the last study visit 
should only be reported to Novartis safety if the investigator suspects a causal relationship to 
study treatment. Detailed instructions regarding the submission process and requirements are 
to be found in the investigator folder provided to each site. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 

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Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to each specific 
component of study treatment, (if study treatment consists of several components) complete the 
SAE Report Form in English, and submit the completed form within 24 hours to Novartis. 
Detailed instructions regarding the submission process and requirements for signature are to be 
found in the investigator folder provided to each site. 
Follow-up information is submitted as instructed in the investigator folder. Each re-occurrence, 
complication, or progression of the original event must be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was broken or not, and 
whether the patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a Novartis Safety associate may 
urgently require further information from the investigator for health authority reporting. 
Novartis may need to issue an Investigator Notification (IN) to inform all investigators involved 
in any study with the same study treatment that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
Note: SAEs must be reported to Novartis within 24 hours of the investigator learning of its 
occurrence/receiving follow-up information. 
10.1.4 
Pregnancy reporting 
Pregnancies 
If a female subject becomes pregnant, the study treatment must be stopped, and the subject must 
be asked to read and sign the pregnancy follow-up consent form to allow the investigator to ask 
about her pregnancy. To ensure subject safety, each pregnancy occurring after signing the 
informed consent must be reported to Novartis within 24 hours of learning of its occurrence. 
The pregnancy should be followed up to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded and reported by the investigator to the Novartis Safety. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment for any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported. 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (European Medicines agency (EMA) definition). 

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Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the Study Treatment CRF irrespective of whether or not associated with an AE/SAE and 
reported to Novartis Safety only if associated with an SAE. Misuse or abuse will be collected 
and reported in the safety database irrespective of it being associated with an AE/SAE within 
24 hours of Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dose 
Administration (DAR) 
CRF (Yes/No) 
Document in AE CRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the, 
respective sections. 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as AE/SAE): 
• Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 
• Liver events, which will require close observation, follow-up monitoring and completion 
of the standard AE CRF pages 
Please refer to Table 16-2 in Section 16.2 for complete definitions of liver laboratory triggers 
and liver events. 
Once a subject is exposed to study treatment, every liver event defined in Table 16-2 should be 
followed up by the investigator or designated personnel at the trial site, as summarized below. 
Additional details on actions required in case of liver events are outlined in Table 16-3. Repeat 
liver chemistry tests (i.e. ALT, AST, TBIL, PT/INR, ALP and GGT) to confirm elevation. 
• These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a 
local laboratory to monitor the safety of the subject. If a liver event is subsequently 

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reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results reported on the unplanned local laboratory CRF (or liver CRF 
page). 
• If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
• Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
section), if appropriate 
• Hospitalization of the subject if appropriate 
• Causality assessment of the liver event 
• Thorough follow-up of the liver event should include  
• These investigations can include based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant 
drug use, exclusion of underlying liver disease 
All follow-up information, and the procedures performed must be recorded as appropriate in 
the AE CRF. 
10.2.2 Prospective suicidality assessment 
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire that prospectively 
assesses suicidal ideation and suicidal behavior. The C-SSRS must be administered at each visit 
of the double-blind treatment period, including unplanned visits. 
A validated version of the eC-SSRS will be used to capture self-reported eC-SSRS data via an 
interactive voice response telephone system (eC-SSRS). The eC-SSRS uses a detailed branched 
logic algorithm to perform the eC-SSRS subject interview, evaluating each subject’s suicidality 
ideation and behavior in a consistent manner. At the conclusion of each assessment, the 
investigator will receive a detailed eC-SSRS Findings Report via e-mail or fax. If the system 
assesses the subject as having positive suicidal signs, the investigator will be immediately 
notified by either fax, email and/or via telephone. 
If, at any time after screening and/or baseline, the score is “yes” on item 4 or item 5 of the 
suicidal ideation section of the eC-SSRS or “yes” on any item of the suicidal behavior section, 
the subject must be referred to a mental health care professional for further assessment and/or 
treatment. The decision on whether the study treatment should be discontinued is to be taken 
by the investigator in consultation with the mental health professional to whom the subject is 
referred. 
In addition, all life-threatening events must be reported as SAEs. For example, if a subject 
answers “yes” to one of the questions in the suicidal behavior section, an SAE must be reported 
if the event was life-threatening. All events of “Non-Suicidal Self-Injurious Behavior” 
(question also included in the suicidal behavior section) should be reported as AEs and assigned 
the appropriate severity grade. 
During the COVID-19 pandemic that limits or prevents on-site study visits, the eC-SSRS may 
still be collected via phone or via the web link.   

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10.2.3 
Data Monitoring Committee 
This study will include a DMC which will function independently of all other individuals 
associated with the conduct of this clinical trial, including the site investigators participating in 
the study. 
The DMC will conduct regular unblinded safety reviews of cumulative safety data.  In addition, 
the DMC will assess efficacy and safety data at the pre-defined unblinded interim analysis 
timepoint (see Section 12.7). 
This unblinded IA will be conducted after 70% (385) of subjects have completed the treatment 
period (including early withdrawals). Although this unblinded IA will focus on the primary 
efficacy endpoint, the secondary efficacy endpoints and safety data will also be assessed. The 
DMC recommendation on whether to stop the trial or not will be based on the evaluation of the 
totality of efficacy and safety data at the interim cut-off. The study team will not be unblinded 
unless the study is stopped early for success. 
Specific details regarding composition, responsibilities, data monitoring and meeting frequency, 
and documentation of DMC reports, minutes, and recommendations will be described in a 
separate charter that is established between the sponsor and the DMC. 
10.2.4 
Steering Committee 
There will be a Steering Committee (SC) for this study. The SC is comprised of a group of 
external subject matter experts who will provide guidance to Novartis on scientific conduct and 
reporting of the study, as well as to serve as the publication committee. The SC membership, 
roles and responsibilities, meeting arrangements and other detailed information will be defined 
in a separate charter that is established between the sponsor and the SC. 
10.2.5 
Adjudication committee 
Not applicable.  
11 
Data Collection and Database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the electronic Case 
Report Forms (CRF). The CRFs have been built using fully validated secure web-enabled 
software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not be given 
access to the Electronic Data Capture (EDC) system until they have been trained. Automatic 
validation programs check for data discrepancies in the CRFs, allow modification and/or 
verification of the entered data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into CRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate 
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site. 

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All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
11.2 
Database management and quality control 
Novartis personnel (or designated Contract Research Organization (CRO)) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated investigator 
site staff are required to respond promptly to queries and to make any necessary changes to the 
data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) terminology. 
Randomization codes and data about all study treatment (s) dispensed to the subject and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis. Any changes to the database after that time can only be made after 
written agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource DDE or 
CRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of subject records, the accuracy 
of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis/CRA organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis clinical teams to assist with trial oversight. 
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 

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12.2 
Subject demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group (choose appropriate term as needed, e.g. for all 
subjects, or by treatment group or dose cohort) for the FAS.  
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class (SOC) and preferred term (PT) by treatment group. 
12.3 
Treatments 
The number of investigational drug injections administered will be summarized and the study 
administration information will be presented in listing for SAF for the double-blind treatment 
period and for OAS for the open-label treatment period. 
In addition, concomitant medications and significant non-drug therapies during the double-
blind treatment period, prior to and after the start of the study treatment, will be listed and 
summarized according to the Anatomical Therapeutic Chemical (ATC) classification system, 
by treatment group for SAF. Prior medications and significant non-drug therapies which were 
used and ended before start of study treatment will be summarized for FAS. The rescue 
medications and prohibited medications will be analyzed similarly.  
12.4 
Analysis of the primary endpoint(s) 
The primary objective of the study is to evaluate the effect of erenumab compared to placebo 
on the reduction of monthly migraine days from baseline. This will be measured by the change 
from baseline in monthly migraine days at the last 4 weeks of the 12-week treatment period. 
Primary endpoints will be analyzed for FAS.  
12.4.1 
Definition of primary endpoint(s) 
The primary efficacy endpoint is the change from baseline in monthly migraine days during the 
last 4 weeks of the 12-week treatment period. The monthly migraine days will be calculated 
using data collected from the eDiary. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The null hypothesis is that there is no difference in the change from baseline in monthly 
migraine days in the last 4 weeks of the 12-week treatment period between erenumab group and 
placebo group versus the alternative hypothesis that there is a difference between the two groups. 
The null hypothesis will be rejected if the observed p-value for the between-group comparison 
is less than the significant level adjusted according to the alpha spending function with the 
O'Brien-Flemming approach. The nominal p-value threshold will be calculated upon the exact 
information collected in the interim analysis, considering the alpha-level spent at interim 
analysis and considering the actual correlation among the test statistics, in order to achieve a 
cumulative type I error smaller than the desired significance level (i.e. smaller than the 5% for 
a two-sided test). The primary efficacy endpoint variable will be analyzed using a generalized 

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linear mixed model with treatment, scheduled visit, treatment by visit interaction, and the 
stratification variables and baseline values as covariates. If applicable, unstructured covariance 
structure is assumed. Least squares means (LSMs) for treatment groups and its associated 95% 
confidence intervals, difference of LSMs compared to placebo group and the associated 95% 
confidence interval of the difference, as well as the nominal two-sided p-values, will be 
tabulated by visit and treatment. 
12.4.3 
Handling of missing values/censoring/discontinuations 
The method of handling missing data for efficacy endpoints will be described for each set of 
endpoints. For the primary analysis, missing data will not be imputed, but various sensitivity 
analyses under missing not at random (MNAR) assumptions will be performed. Missing data 
will not be imputed for safety endpoints. Details of the missing data handling will be specified 
in the Statistical Analysis Plan (SAP). 
12.4.4 
Sensitivity and Supportive analyses 
Multiple imputation (MI) techniques applying MNAR approaches will be used to assess the 
impact of missing values on the interpretation of the results during study. In addition, the 
baseline observations carried forward (BOCF) method will also be used. 
12.5 
Analysis of secondary endpoints 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
The secondary efficacy variables (all during the 12-week treatment period) are: 
• Proportion of subjects who achieve at least a 50% reduction from baseline in monthly 
migraine days during the last 4 weeks of the 12-week treatment period. 
• Change from baseline in monthly acute headache medication days during the last 4 weeks 
of the 12-week treatment period 
• Change from baseline in migraine-related disability and productivity as measured by 
modified MIDAS during the last 4 weeks of the 12-week treatment period 
The above continuous endpoints (i.e. change from baseline) will be analyzed using a 
generalized linear mixed effects model similar to the primary endpoint. The dichotomous 
endpoints will be analyzed by Cochran-Mantel-Haenszel (CMH) test with subjects who are 
missing monthly migraine day data during the last 4 weeks of the treatment period imputed as 
non-responders. Nominal 95% confidence intervals and p-values will be reported. Tests of 
secondary endpoints will be tested at nominal 2-sided significant level 0.05. 
12.5.2 
Safety endpoints 
Safety analyses for the double-blind treatment period and the safety follow-up period will be 
conducted on SAF set. Safety data will be presented by actual treatments. Safety variables for 
the double-blind treatment and safety follow-up period include: 
• Adverse events 
• Clinical laboratory values, vital signs, and ECG 
• Anti-AMG 334 antibodies 

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12.7 
Interim analyses 
To account for potential larger than expected variability during the study, a blinded sample size 
re-estimation is planned after about 50% (275) subjects finish their treatment or early withdraw. 
Only the standard deviation of the primary variable, change from baseline in monthly migraine 
days in the last 4 weeks of the 12-week treatment period based on pooled (blinded) data, will 
be estimated. The sample size will be increased appropriately if the standard deviation is larger 
than expected. The blinded sample size re-estimation will be conducted by study team. 
An unblinded interim analysis for potentially stopping the trial early for efficacy will be 
implemented when approximately 70% (385, if no increase of sample size is needed 
following the blinded IA) of subjects finished the double-blind treatment period or 
discontinued from the study. The significant level will be adjusted using the alpha spending 
function with the O'Brien-Fleming boundary. An observed two-sided p-value ≤ 0.014 will be 
required at 70% information. The adjusted significance level based on the actual information 
included in the interim analysis will be used. If the study proceeds after interim analysis, the 
hypothesis test will be performed at the end of the double-blind treatment period using the 
pre-planned final adjusted significance level. 
This unblinded analysis will be conducted and reviewed by an independent DMC. Interim 
results and unblinded data will not be accessible to Novartis personnel who are managing trial 
operations nor to study investigators and raters. Only DMC members will receive unblinded 
results. Detailed operating procedures will be specified in a DMC charter, which will define 
the composition and responsibilities of the DMC members as well as the detailed procedure 
for handling unblinded data within the DMC and for sharing with Novartis management 
personnel who is not part of the study team. The interim analysis will focus on the primary 
efficacy endpoint, but the DMC recommendation on whether to stop the trial or not will be 
based on the evaluation of totality of efficacy and safety data at interim cut-off. The detailed 
decision algorithms will be described in the DMC charter. 
In case of a positive IA read-out with 70% information, the analysis results will be prepared for 
regulatory submission. Subjects who are ongoing at the cut-off time of the interim analysis will 
not be included in the unblinded interim analysis. Their data and all data collected beyond the 
IA cut-off will be analyzed separately. 
12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
The planned total sample size in this proposed China-centric phase 3 study is 550 subjects. The 
key assumptions in calculating the sample size are based on prior results from erenumab global 
pivotal study. A treatment difference in terms of change from baseline on MMDs during Week 
9-12 (primary endpoint) for erenumab 70 mg vs. placebo is assumed at -2.0 days. The common 
standard deviation of the primary variable is assumed at 6.8. Given a 1:1 randomization ratio 
among erenumab 70 mg and placebo, it requires a total of 550 subjects (including 10% drop out 
rate) to achieve approximate 90% power to demonstrate the treatment difference of erenumab 
70 mg compared with placebo under two-sided 0.05 alpha level. The impact of spending alpha 
at unblinded interim analysis on sample size and power is relatively negligible. Having this 
interim analysis with alpha spending at 0.014 two-sided, at final analysis an observed p-value 

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≤ 0.046 two-sided would be required (given that the interim analysis was performed when 70% 
subject finished treatment or early withdraw). With that said, the overall power will be 
maintained approximately at 90% with planned sample size. 
The sample size for Chinese sub-population will make sure the consistency of treatment effect 
between Chinese and total population. The methods for consistency assessment is proposed as,  
Pr(Dchina / Doverall >0.5) > 95%, 
which means that this China study should have high probability (>95%) to demonstrate 
consistency where the treatment effect (treatment difference of erenumab compared with 
placebo) observed in the Chinese population should be as high as at least 50% of the treatment 
effect observed in the overall study population in the prospective trial, assuming there is no 
difference between the Chinese population assessed in the trial and the overall population. 
To meet the above criteria, approximately 350 (out of 550 for the overall study) 
Chinese subjects will be recruited.  
At the interim analysis, as long as China population takes the majority of the overall population, 
there should have high likelihood to demonstrate the consistency as well.   
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
As mentioned in Section 7, during the COVID-19 pandemic, the training related to the home-
delivery of study drug should be documented in the subject chart. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 

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and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.). 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk-based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal Standard Operating Procedures (SOPs), and are performed according to 
written Novartis processes. 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented. 
14.1 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 

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Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 

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15 
References 
References are available upon request 
Ashina M, Goadsby PJ, Reuter U, et al (2019) Long-term safety and tolerability of erenumab: 
Three-plus year results from a five-year open-label extension study in episodic migraine. 
Cephalalgia 1-10.  
Blumenfeld AM, Bloudek LM, Becker WJ, et al (2013) Patterns of use and reasons for 
discontinuation of prophylactic medications for episodic migraine and chronic migraine: 
results from the second international burden of migraine study (IBMS-II). Headache 644-55. 
Buse DC, Silberstein SD, Manack AN, et al (2013) Psychiatric comorbidities of episodic and 
chronic migraine. J. Neurol. 1960-9. 
Dodick DW, Ashina M, Brandes JL, et al (2018) ARISE: A Phase 3 randomized trial of 
erenumab for episodic migraine. Cephalalgia 1026-1037. 
Durham PL (2006) Calcitonin gene-related peptide (CGRP) and migraine. Headache S3-8. 
Goadsby PJ, Reuter U, Hallström Y, et al (2017) A Controlled Trial of Erenumab for Episodic 
Migraine. N. Engl. J. Med. 2123-2132. 
Gooriah R, Nimeri R, Ahmed F (2015) Evidence-Based Treatments for Adults with Migraine. 
Pain Res Treat 629382. 
Headache Classification Committee of the International Headache Society (IHS) (2018) The 
International Classification of Headache Disorders, 3rd edition. Cephalalgia 1-211. 
Jiang H, Deng Y, Zhang Y, et al (2016) Field testing of the ICHD-3β and expert opinion 
criteria for chronic migraine. J Headache Pain 85. 
Stovner Lj, Hagen K, Jensen R, et al (2007) The global burden of headache: a documentation 
of headache prevalence and disability worldwide. Cephalalgia 193-210. 
Tassorelli C, Diener HC, Dodick DW, et al (2018) Guidelines of the International Headache 
Society for controlled trials of preventive treatment of chronic migraine in adults. Cephalalgia 
Vol. 38(5) 815-832. 
Tepper S, Ashina M, Reuter U, et al (2017) Safety and efficacy of erenumab for preventive 
treatment of chronic migraine: a randomised, double-blind, placebo-controlled Phase 2 trial. 
Lancet Neurol 425-434. 
Tfelt-Hansen P, Pascual J, Ramadan N, et al (2012) Guidelines for controlled trials of drugs in 
migraine: third edition. A guide for investigators. Cephalalgia 6-38. 
Wang X, Yue TL, Barone FC, et al (1995) Discovery of adrenomedullin in rat ischemic cortex 
and evidence for its role in exacerbating focal brain ischemic damage. Proc. Natl. Acad. Sci. 
U.S.A. 11480-4. 
Yu S, Liu R, Zhao G, et al (2012) The prevalence and burden of primary headaches in China: 
a population-based door-to-door survey. Headache 582-91. 

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Zimmermann U, Fischer JA, Frei K, et al (1996) Identification of adrenomedullin receptors in 
cultured rat astrocytes and in neuroblastboma x glioma hybrid cells (NG108-15). Brain Res. 
238-45. 

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16 
Appendices 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs 
Only selected lab parameters which have potential to be sensitive to erenumab exposure are 
listed. 
Table 16-1 
Clinically notable laboratory values 
Laboratory Variable 
Gender (M/F/Both) 
Standard Units 
SI Units 
LIVER FUNCTION AND RELATED VARIABLES 
SGOT (AST) 
F 
>93 U/L 
>93 U/L 
SGOT (AST) 
M 
>111 U/L 
>111 U/L 
SGPT (ALT) 
F 
>90 U/L 
>90 U/L 
SGPT (ALT) 
M 
>123 U/L 
>123 U/L 
Total bilirubin 
Both 
>3.6 mg/dL 
>63 mmol/L 
Alkaline Phosphatase 
F 
>832 U/L 
>832 U/L 
Alkaline Phosphatase 
M 
>1032 U/L 
>1032 U/L 
HEMATOLOGY VARIABLES 
Neutrophils 
Both 
<1.5 x 103/uL 
<1.5 x109/L 

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16.2 
Appendix 2: Liver event and Laboratory trigger Definitions and 
Follow-up Requirements 
Table 16-2 
Liver Event and Laboratory Trigger Definitions 
 
Definition/ threshold 
LIVER LABORATORY TRIGGERS 
• 
3 x ULN < ALT / AST < 5 x ULN 
· 1.5 x ULN < TBIL < 2 x ULN 
LIVER EVENTS 
• 
ALT or AST > 5 × ULN 
 
• 
ALP > 2 × ULN (in the absence of known 
bone pathology) 
 
• 
TBIL > 2 × ULN (in the absence of known 
Gilbert syndrome) 
 
• 
ALT or AST > 3 × ULN and INR > 1.5 
 
• 
Potential Hy’s Law cases (defined as ALT or 
AST > 3 × ULN and TBIL > 2 × ULN [mainly 
conjugated fraction] without notable increase 
in ALP to > 2 × ULN) 
 
• 
Any clinical event of jaundice (or equivalent 
term) 
 
• 
ALT or AST > 3 × ULN accompanied by 
(general) malaise, fatigue, abdominal pain, 
nausea, or vomiting, or rash with 
eosinophilia 
 
• 
Any adverse event potentially indicative of a 
liver toxicity* 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms TBIL: total bilirubin; ULN: upper limit of normal 
Table 16-3 
Follow Up Requirements for Liver Events and Laboratory Triggers  
Criteria 
Actions required 
Follow-up monitoring 
Potential Hy’s Law casea 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize, if clinically 
appropriate 
• 
Establish causality 
ALT, AST, TBIL, Albumin, 
PT/INR, ALP and GGT until 
resolutionc (frequency at 
investigator discretion) 
ALT or AST 
> 8 × ULN 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
ALT, AST, TBIL, Albumin, 
PT/INR, ALP and GGT until 
resolutionc (frequency at 
investigator discretion) 
> 3 × ULN and INR > 1.5 
• 
Discontinue the study 
treatment immediately 
ALT, AST, TBIL, Albumin, 
PT/INR, ALP and GGT until 
resolutionc (frequency at 
investigator discretion) 

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Criteria 
Actions required 
Follow-up monitoring 
• 
Hospitalize, if clinically 
appropriate 
• 
Establish causality 
> 5 to ≤ 8 × ULN 
• 
Repeat LFT within 48 
hours 
• 
If elevation persists, 
continue follow-up 
monitoring 
• 
If elevation persists for 
more than 2 weeks, 
discontinue the study drug 
• 
Establish causality 
ALT, AST, TBIL, Albumin, 
PT/INR, ALP and GGT until 
resolutionc (frequency at 
investigator discretion) 
> 3 × ULN accompanied by 
symptomsb 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Complete liver CRF 
ALT, AST, TBIL, Albumin, 
PT/INR, ALP and GGT until 
resolutionc (frequency at 
investigator discretion) 
> 3 to ≤ 5 × ULN (subject is 
asymptomatic) 
• 
Repeat LFT within the next 
week 
• 
If elevation is confirmed, 
initiate close observation of 
the subject 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks 
ALP (isolated) 
 
 
> 2 × ULN (in the absence of 
known bone pathology) 
• 
Repeat LFT within 48 
hours 
• 
If elevation persists, 
establish causality 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
TBIL (isolated) 
 
 
> 2 × ULN (in the absence of 
known Gilbert syndrome) 
• 
Repeat LFT within 48 
hours 
• 
If elevation persists, 
discontinue the study drug 
immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
ALT, AST, TBIL, Albumin, 
PT/INR, ALP and GGT until 
resolutionc (frequency at 
investigator discretion) 
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin) 
> 1.5 to ≤ 2 × ULN (subject is 
asymptomatic) 
• 
Repeat LFT within the next 
week 
• 
If elevation is confirmed, 
initiate close observation of 
the subject 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
Jaundice 
• 
Discontinue the study 
treatment immediately 
ALT, AST, TBIL, Albumin, 
PT/INR, ALP and GGT until 

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Criteria 
Actions required 
Follow-up monitoring 
• 
Hospitalize the subject 
• 
Establish causality 
resolutionc (frequency at 
investigator discretion) 
Any AE potentially indicative of 
a liver toxicity* 
• 
Consider study treatment 
interruption or 
discontinuation 
• 
Hospitalization if clinically 
appropriate 
• 
Establish causality 
Investigator discretion 
aElevated ALT/AST > 3 × ULN and TBIL > 2 × ULN but without notable increase in ALP to > 2 × 
ULN  
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death.