Clinical trial NCT03927144
Conditions: Episodic Migraine
Keywords: Erenumab AMG334 Migraine Episodic Headache CGRP
Sponsor: Amgen
Start date: 2019-05-15; Completion date: 2022-09-30
Enrollment: 621 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the sustained long-term benefit between two treatment paradigms of migraine prophylactic agents (erenumab versus a control arm of oral prophylactics) in episodic migraine patients who have previously failed 1 to 2 prophylactic migraine treatments.

Detailed description:

Arms: arm 1: Participants were randomized to receive 70 mg or 140 mg of AMG334 as a subcutaneous injection once per month for 52 weeks in the Core Phase.

Participants were permitted to switch to an approved oral prophylactic based on treatment failure status and at the investigator's and participant's discretion.

Participants who completed visits through Week 52 of the Core Phase were eligible to participate in the 52-week Extension Phase of the study. arm 2: Participants were randomized to receive a standard of care (SOC) locally approved oral prophylactic migraine medication once per day for 52 weeks in the Core Phase, as prescribed per local country labels.

Participants were permitted to switch to a different approved oral prophylactic based on treatment failure status and at the investigator's and participant's discretion.

Participants who completed visits through Week 52 of the Core Phase were eligible to participate in the 52-week Extension Phase of the study.
Interventions: intervention 1: AMG334 intervention 2: Oral Prophylactic
Intervention descriptions: intervention 1: Subcutaneous Injection intervention 2: SOC Oral Tablet/Capsule

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development
AMG334
Clinical Trial Protocol CAMG334A2401 / NCT03927144
A 12-month prospective, randomized, interventional, 
global, multi-center, active-controlled study comparing 
sustained benefit of two treatment paradigms (erenumab 
qm vs. oral prophylactics) in adult episodic migraine 
patients
Document type:
Amended Protocol Version
EUDRACT number:
2018-001228-20
Version number:
02 (Clean)
Clinical Trial Phase:
IV
Release date:
15-Jun-2020
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template version 1.0 dated 01-Dec-2017


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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.................................................................................................................8
Amendment 02 .........................................................................................................................10
Amendment 01 .........................................................................................................................13
Protocol summary..............................................................................................................15
1
Introduction .......................................................................................................................19
1.1
Background............................................................................................................19
1.2
Purpose ..................................................................................................................20
2
Objectives and endpoints...................................................................................................21
3
Study design ......................................................................................................................23
4
Rationale............................................................................................................................26
4.1
Rationale for study design .....................................................................................26
4.2
Rationale for dose/regimen and duration of treatment ..........................................26
4.3
Rationale for choice of control drugs (comparator) ..............................................27
4.4
Purpose and timing of interim analyses/design adaptations..................................28
4.5
Risks and benefits..................................................................................................28
5
Population..........................................................................................................................29
5.1
Inclusion criteria ....................................................................................................29
5.2
Exclusion criteria...................................................................................................30
6
Treatment...........................................................................................................................33
6.1
Study treatment......................................................................................................33
6.1.1
Investigational and control drugs..........................................................33
6.1.2
Additional study treatments ..................................................................33
6.1.3
Treatment arms/group ...........................................................................33
6.1.4
Treatment duration................................................................................34
6.2
Other treatment(s)..................................................................................................34
6.2.1
Concomitant therapy.............................................................................34
6.2.2
Prohibited medication ...........................................................................34
6.2.3
Rescue medication ................................................................................35
6.3
Subject numbering, treatment assignment, randomization....................................35
6.3.1
Subject numbering ................................................................................35
6.3.2
Treatment assignment, randomization ..................................................35


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6.4
Treatment blinding.................................................................................................36
6.5
Dose escalation and dose modification..................................................................36
6.5.1
Dose modifications................................................................................36
6.5.2
Follow-up for toxicities.........................................................................36
6.6
Additional treatment guidance...............................................................................37
6.6.1
Treatment compliance...........................................................................37
6.6.2
Emergency breaking of assigned treatment code..................................37
6.7
Preparation and dispensation.................................................................................37
6.7.1
Handling of study treatment and additional treatment..........................38
6.7.2
Instruction for prescribing and taking study treatment .........................39
7
Informed consent procedures ............................................................................................39
8
Visit schedule and assessments .........................................................................................41
8.1
Screening ...............................................................................................................45
8.1.1
Information to be collected on screening failures.................................45
8.2
Subject demographics/other baseline characteristics.............................................45
8.3
Efficacy..................................................................................................................45
8.3.1
Migraine days........................................................................................46
8.3.2
Appropriateness of efficacy assessments..............................................46
8.4
Safety.....................................................................................................................47
8.4.1
Laboratory evaluations..........................................................................48
8.4.2
Electrocardiogram (ECG) .....................................................................48
8.4.3
Pregnancy..............................................................................................49
8.4.4
Appropriateness of safety measurements..............................................49
8.5
Additional assessments..........................................................................................49
8.5.1
Clinical Outcome Assessments (COAs) ...............................................49
52
53
9
Study discontinuation and completion ..............................................................................53
9.1
Discontinuation......................................................................................................53
9.1.1
Discontinuation of study treatment .......................................................53
9.1.2
Discontinuation of study .......................................................................54
9.1.3
Withdrawal of informed consent...........................................................54
9.1.4
Lost to follow-up...................................................................................55
9.1.5
Early study termination by the sponsor.................................................55
9.2
Study completion and post-study treatment ..........................................................56
10 Safety monitoring and reporting........................................................................................56


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10.1
Definition of adverse events and reporting requirements......................................56
10.1.1
Adverse events ......................................................................................56
10.1.2
Serious adverse events ..........................................................................58
10.1.3
SAE reporting........................................................................................58
10.1.4
Pregnancy reporting ..............................................................................59
10.1.5
Reporting of study treatment errors including misuse/abuse................59
10.2
Additional Safety Monitoring................................................................................60
10.2.1
Liver safety monitoring.........................................................................60
10.2.2
Prospective suicidality assessment........................................................61
11 Data Collection and Database management......................................................................61
11.1
Data collection.......................................................................................................61
11.2
Database management and quality control............................................................62
11.3
Site monitoring ......................................................................................................62
12 Data analysis and statistical methods ................................................................................63
12.1
Analysis sets ..........................................................................................................63
12.2
Subject demographics and other baseline characteristics......................................63
12.3
Treatments .............................................................................................................63
12.4
Analysis of the primary endpoint(s) ......................................................................64
12.4.1
Definition of primary endpoint(s).........................................................64
12.4.2
Statistical model, hypothesis, and method of analysis..........................64
12.4.3
Handling of missing values/censoring/discontinuations.......................64
12.4.4
Sensitivity and Supportive analyses......................................................64
12.5
Analysis of secondary endpoints ...........................................................................65
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................65
12.5.2
Safety endpoints....................................................................................65
12.5.3
Pharmacokinetics ..................................................................................66
12.5.4
DNA......................................................................................................66
12.5.5
Biomarkers............................................................................................66
12.5.6
PK/PD relationships..............................................................................66
66
67
12.7
Interim analyses.....................................................................................................67
12.8
Sample size calculation..........................................................................................67
12.8.1
Primary endpoint(s)...............................................................................67
13 Ethical considerations and administrative procedures ......................................................67
13.1
Regulatory and ethical compliance........................................................................67


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13.2
Responsibilities of the investigator and IRB/IEC..................................................67
13.3
Publication of study protocol and results...............................................................68
13.4
Quality Control and Quality Assurance.................................................................68
14 Protocol adherence ............................................................................................................68
14.1
Protocol Amendments ...........................................................................................69
15 References .........................................................................................................................70
16 Appendices ........................................................................................................................72
16.1
Appendix 1: Clinically notable laboratory values and vital signs .........................72
16.2
Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.........................................................................................................73
List of tables
Table 1-1
Protocol Summary.................................................................................15
Table 2-1
Objectives and related endpoints ..........................................................21
Table 4-1
Rationale for study design.....................................................................26
Table 6-1
Investigational and control drug............................................................33
Table 6-2
Prohibited medication ...........................................................................35
Table 8-1
Assessment Schedule – Core Phase......................................................42
Table 8-2
Assessment Schedule – Extension Phase..............................................44
Table 8-3
Safety Assessments ...............................................................................47
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................60
Table 16-1
Clinically Notable Laboratory Values ..................................................72
Table 16-2
Liver Event and Laboratory Trigger Definitions ..................................73
Table 16-3
Follow Up Requirements for Liver Events and Laboratory Triggers...74
List of figures
Figure 3-1
Study Design Schematic .......................................................................25


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List of abbreviations
γ-GT
Gamma-glutamyl transferase
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
b.i.d.
twice a day
BMI
Body Mass Index
BUN
blood urea nitrogen
C-SSRS
Columbia Suicide Severity Rating Scale
CD-ROM
compact disc – read only memory
CDS
Core Data Sheet (for marketed drugs)
CFR
Code of Federal Regulation
CK
creatinine kinase
CO2
carbon dioxide
COAR
Clinical Operations, Analytics & Regions
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CTC
Common Toxicity Criteria
CTRD
Clinical Trial Results Database
CV
coefficient of variation
DMC
Data Monitoring Committee
EC
Ethics committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
ELISA
Enzyme-linked immunosorbent assay
eSAE
Electronic Serious Adverse Event
FDA
Food and Drug Administration
GCP
Good Clinical Practice
h
hour
HIV
human immunodeficiency virus
i.v.
intravenous
ICH
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology


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LDH
lactate dehydrogenase
LFT
Liver function test
LLN
lower limit of normal
LLQ
lower limit of quantification
MABEL
minimum anticipated biological effect level
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
ml
milliliter(s)
MRSD
maximum recommended starting dose
NCDS
Novartis Clinical Data Standards
NOVDD
Novartis Data Dictionary
o.d.
once a day
p.o.
oral
PA
posteroanterior
PD
pharmacodynamic(s)
PIP
pediatric investigation plan
PK
pharmacokinetic(s)
PTA
Post-trial access
RBC
red blood cell(s)
RDC
Remote Data Capture
REB
Research Ethics Board
s.c.
subcutaneous
SAE
serious adverse event
sCR
serum creatinine
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SoC
Standard of Care
SOM
Site Operations Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin
ULN
upper limit of normal
ULQ
upper limit of quantification
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 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.
Control drug
Any drug (an active drug or an inactive drug, such as a placebo) which is 
used as a comparator to the investigational drug being tested in the trial
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)
Enrollment
Point/time of subject entry into the study; the point at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described in the 
protocol).
Enrollment
Point/time of subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is associated 
with a purpose (e.g. screening, randomization, treatment), which applies 
across all arms of a study.
Healthy volunteer
A person with no known significant health problems who volunteers to be a 
study participant 
Investigational drug
The study drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and is 
synonymous with “investigational new drug” or “test substance”
Investigational drug
The study drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product”.
Investigational 
treatment
All investigational drug(s) whose properties are being tested in the study as 
well as their associated treatment controls. This includes any placebos, any 
active controls, as well as approved drugs used outside of their 
indication/approved dosage or tested in a fixed combination. Investigational 
treatment generally does not include other treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used within approved indication/dosage.
Medication number
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an IRT system.
Medication pack 
number
A unique identifier on the label of each drug package in studies that dispense 
study treatment using an IRT system
Non-investigational 
medicinal Product 
(NIMP)
Products which are not the object of investigation (e.g. any background 
therapy administered to each of the clinical trial subjects, regardless of 
randomization group, rescue medication, active drug run-ins etc.)
Part
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a 
single dose part and a multiple dose part, or a part in patients with 
established disease and in those with newly-diagnosed disease.
Patient
An individual with the condition of interest
Period
A minor subdivision of the study timeline; divides phases into smaller 
functional segments such as screening, baseline, titration, washout, etc.
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 


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study drug administration is discontinued and no further assessments are 
planned.
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment
Screen Failure
A subject who is screened but is not treated or randomized
Stage
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
Study completion
Point/time at which the subject came in for a final evaluation visit or when 
study drug was discontinued whichever is later.
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 
drug/treatment
Any drug (or combination of drugs) administered to the subject as part of the 
required study procedures; includes investigational drug, active drug run-ins 
or background therapy.
Study treatment
Any drug administered to the study participants as part of the required study 
procedures; includes investigational drug (s), control(s) or non-investigational 
medicinal product(s)
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
An individual who has consented to participate in this study. The term 
Subject may be used to describe either 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.
Subject number
A number assigned to each subject who enrolls in the study. When combined 
with the center number, a unique identifier is created for each subject in the 
study.
Treatment number
A unique identifier assigned in non-randomized studies to each dosed 
subject, corresponding to a specific treatment arm 
Variable
Information used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints.
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study
Withdrawal of 
consent (WoC)
Withdrawal of consent from the study is defined as when a subject does not 
want to participate in the study any longer, and does not want any further 
visits or assessments, and does not want any further study related contact, 
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Amendment 02
Amendment rationale 
The purpose of this amendment is to provide Post-Trial Access (PTA) to erenumab for eligible 
patients completing visits through week 52 of the Core Phase.  Patient eligibility will be 
determined by the investigators opinion as follows: 1) patients treated with erenumab must have
benefited from erenumab treatment and 2) patients on Standard of Care (SoC) oral prophylactic 
must be in need of a treatment switch.  PTA to erenumab will be provided for up to 52 weeks
(based on continued benefit of erenumab treatment) in all eligible patients.
The PTA-Open-Label Treatment Period (Extension Phase) will evaluate further long-term 
safety and clinical benefit of erenumab. 
 
During the Extension Phase patients will be administered study drug at the study site at quarterly 
study visits.  Between the quarterly visits patients will have study drug injections every 28 days 
either 1) administered by the site staff at brief injection visits at site or 2) self-administered at 
home with documented on-site training for correct injection procedure.
In addition, details for potential trial conduct changes due to the COVID-19 pandemic have 
been incorporated in this protocol amendment. Updates have been made to the relevant protocol 
sections.
Changes to the protocol

Protocol Summary

Updated to add details for revised study design, removed Follow-up visit, clarified 
Exclusion criteria language for prohibited medications 
 

Section 3.0 Study design

Added Core Phase text, removed Follow-Up visit, provided details for PTA-
Extension Phase with updated Figure 3-1 and added details for CSR requirements.

Section 4.1 Rationale for study design

Added rationale for PTA-Open-Label Treatment Period

Section 4.3 Rationale for choice of control drugs (comparator)

Deleted table describing SoC oral prophylactic migraine drugs available.

Section 4.5 Risks and benefits

Added Investigators Brochure as a reference for risks and benefits

Section 5.2 Exclusion criteria

Revised Exclusion Criteria 5 and 8 for clarity, removed text with reference to during 
treatment period throughout section as this is not an exclusion criteria and updated 
Exclusion Criteria 18 for clarity.

Section 6.1 Study treatment


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
Revised Core Phase and added Extension Phase drug details in Table 6-1, and added 
details for Extension Phase and Section 6.1.3 and Section 6.1.4 updated for clarity.

Section 6.2.2 Prohibited medication and Section 6.2.3 Rescue medication

Updated prohibited medication section for clarity and added details for rescue 
medication collection in eCRF pages.

Section 6.3.2 Treatment assignment, randomization

Updated details for Core Phase randomization and added Extension Phase details.

Section 6.6.1 Treatment Compliance

Added details for Core and Extension Phase

Section 6.7 Preparation and dispensation

Added guidance section for COVID-19 related to delivery of study drug and self-
administration of study drug for patients affected by the pandemic.

Section 6.7.1.1 Handling of study treatment

Added details for self-administration of study drug.

Section 6.7.2 Instruction for prescribing and taking study treatment

Added details for self-administration of study drug and provided clarity for dosing 
windows.

Section 7 Informed consent procedures

Updated to add guidance for COVID-19 for signing of general informed consent 
documents and added details for patients that had self-administration of study drug 
and the requirements to sign an ICF to document the process.

Section 8 Visit schedule and assessments

Added details for Extension Phase in text, updated Core Phase text and assessment 
Table 8-2 for Extension Phase assessments. Revised guidelines for dosing windows 
for clarity and 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. 

Section 8-3 Efficacy

Added guidance for COVID-19 that PRO scales may still be collected by using the 
eDiary for patients impacted due to the pandemic
 

Section 8.4 Safety

Included guidance for COVID-19 indicating that regular phone or virtual calls would 
occur to monitor the safety of patients impacted due to the pandemic and updated 
schedule for physical exam.

Section 8.4.1 Laboratory evaluations

Introduced guidance for COVID-19 to indicate that collection of laboratory samples 
may need to be modified for patients impacted due to the pandemic.

Section 8.4.3 Pregnancy


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
Introduced guidance for COVID-19 to indicate that urine pregnancy tests may be used 
at home instead of conducted in the clinic when serum or urine pregnancy tests were 
scheduled for patients impacted due to the pandemic.
 

Section 9.1

Introduced additional reasons for discontinuation of study treatment during the
Extension Phase and added a section to provide clarity for what occurs during the 
Core Phase when a patient discontinues the study.

Section 9.2 Study completion and post-study treatment

Provided details for Extension Phase

Section 12 Data analysis and statistical methods

Provided details that Core and Extension phase data would be analyzed separately.

Section 12.1 Analysis sets

Introduced an analysis set for the Extension Phase.

Section 12.5.2 Safety endpoints

Provided details that safety data collected during Extension Phase would be analyzed 
separately and deleted summary of AEs of special interest since analysis is not 
conducted.

Section 13.3 Publication of study protocol and results

Introduced details for clinical study reports.

Section 16.2 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements

Provided guidance in footnote to Table 16-2 for collection of INR if patients have a 
liver event.
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. 


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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.
Amendment 01
Amendment Rationale
The purpose of this global amendment is to update the protocol language to reflect feedback 
received from Health Authorities on contraception/pregnancy language and on standard of care 
practices globally from participating investigators. Additionally, text was added to clarify 
protocol text language, typographical errors, and grammatical errors.  
Changes to the protocol

Protocol Summary

The Protocol Summary was updated to reflect the updates made in the protocol 
below.
 

Section 3 Study design

Clarified discrepancy on study completion and the Follow-up Visit that it should 
occur 16 weeks after the Week 52 visit

Section 5.1 Inclusion Criteria

Inclusion criterion 6 updated to align with exclusion criterion 4

Section 5.2 Exclusion Criteria

Exclusion criterion 4 was updated to reflect guidance documents and investigator 
practice for prior treatment failures.  

Exclusion criterion 20 has been updated to include language related to highly 
effective methods of contraception.

Section 6.1.1 Investigational and Control Drugs

Capsule was added as a possible formulation for oral prophylactics.

Section 6.1.3 Treatment arms/groups

The stratification cap was re-iterated to provide better clarity.

Section 6.2.2 Prohibited Medication

Text table was updated to align with exclusion criterion 22

Section 6.5 Dose escalation and dose modification

Added statement clarifying source documentation of dose changes

Section 6.6.1 Treatment compliance


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
Clarified that documentation to be captured only in the source documents and drug 
accountability log for standard of care

Table 8-1 Assessment Schedule

Updated table to reflect amended protocol text

Section 8.3.1 Migraine days

Added text on additional data points captured in the eDiary related to vertigo and 
menses

Table 8-3 Safety Assessments

Clarified that height and weight will only be captured at full physical exams
 

Section 10.1.1 Adverse Events

Clarified that adverse event collection should only begin at Treatment/Day 1 visit

Section 12.4 Analysis of the primary endpoint(s)

Clarified that the analysis is comparing to oral prophylactics

Section 12.5 Analysis for the secondary endpoints

Updated language to reflect updates to objectives and endpoints

Section 12.8 Sample size calculation

Clarified that the analysis is comparing to oral prophylactics


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Protocol summary
Table 1-1
Protocol Summary
Protocol 
number
AMG334A2401
Full Title
A 12-month prospective, randomized, interventional, global, multi-center, active-
controlled study comparing sustained benefit of two treatment paradigms 
(erenumab qm vs. oral prophylactics) in adult episodic migraine patients
Brief title
Study of sustained benefit of erenumab in adult episodic migraine patients
Sponsor and 
Clinical Phase
Novartis & Amgen
Phase IV
Investigation 
type
Biological
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to compare the sustained long-term benefit between 
two treatment paradigms of migraine prophylactic agents (erenumab versus a 
control arm of oral prophylactics) in episodic migraine patients who have 
previously failed 1 to 2 prophylactic migraine treatments. Data from this study, in 
addition to the data generated thus far in the clinical program, will provide 
important data for clinicians treating migraine patients, particularly for patients 
who have previously failed existing preventative treatments, as there are limited 
treatment options. Subsequently it will determine if early use of erenumab during 
a treatment algorithm is associated with a favorable long-term sustained benefit.
The PTA-Open-Label Treatment Period will provide additional information for 
longer term safety and will provide an assessment of effectiveness.
Primary 
Objective(s) 
The primary objective is to demonstrate the superiority of subcutaneous 
erenumab compared to oral prophylactic(s) on sustained benefit defined as % 
subjects completing one-year on the randomized treatment and achieving at 
least a 50% reduction from baseline in monthly migraine days at month 12.
Secondary 
Objectives
Objective 1: To evaluate the effect of erenumab compared to oral prophylactic(s) 
on overall subject retention defined as % subjects completing treatment period at 
Month 12 on initially assigned treatment
Objective 2: To evaluate the effect of erenumab compared to oral prophylactic(s) 
on the change from baseline in monthly migraine days during the treatment period
Objective 3: To evaluate the effect of erenumab compared to oral prophylactic(s) 
on the subject's assessment of the change in clinical status since the start of 
treatment as measured by the Patients' Global Impression of Change (PGIC) Scale
Study design
This study uses a single-cohort, 2-treatment arm (erenumab versus SoC oral 
prophylactic treatment), parallel-group randomized (2:1 [erenumab (70 mg or 140
mg): SoC oral prophylactic]), open-label design in adult patients with episodic 
migraine who have previously failed 1 or 2 prophylactic migraine treatments. The 
following periods are included in the study design, with study visits at 4-week 
intervals after completion of screening:

Screening Period (0-2 weeks) – Required for all subjects to assess initial 
eligibility and to obtain informed consent


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
Baseline Period (4 weeks) – All subjects successfully completing the 
Screening Period will be invited to participate. Eligibility for randomization will 
be assessed based on migraine frequency and diary compliance during this 
period. Randomization will be stratified by prior prophylactic migraine 
medication treatment failure (due to insufficient efficacy or poor tolerability) 
reported during Screening/Baseline Period: 1 treatment failure (TF1) vs 2 
treatment failures (TF2). A cap of 30% randomized subjects to the TF2 strata 
will be implemented. The stratification and 30% cap will be implemented 
within IRT.

Open-Label Randomized Treatment Period (52 weeks) – All subjects 
successfully completing the Baseline Period will be invited to participate. 
Eligible subjects will be randomized 2:1 to one of two treatment arms 
[erenumab s.c. q.m. versus SoC oral prophylactic (active comparator)]. Only 
monotherapy will be allowed in both arms and no concomitant use of other 
prophylactics for migraine specifically should be used. At the end of this 
period, the final assessment to address the effect of erenumab compared to 
SoC oral prophylactic cycling on the net benefit and related objectives will 
occur. The last dose for erenumab will occur at Week 48 (monthly dose) and 
the last dose for SoC will occur at Week 52. 

Switching: Treatment (failure) status and decision on whether or not to 
switch to a new treatment will be checked at every visit and will be 
based on investigator and subject discretion (based on 
efficacy/tolerability/satisfaction but not based on pre-specified cutoffs for 
certain parameters). In both arms, switching will be allowed within 
approved prophylactics in the respective country for prophylaxis of 
migraine.

PTA-Open-Label Treatment Period (52 Weeks) – Patients completing visits 
through week 52 of the Core Phase will be eligible to participate.  Patient 
eligibility will be determined by the investigators opinion as follows: 1) 
patients treated with erenumab must have benefited from erenumab 
treatment and 2) patients on Standard of Care (SoC) oral prophylactic must 
be in need of a treatment switch. PTA to erenumab will be provided for up to 
52 weeks (based on continued benefit of erenumab treatment) in all eligible 
patients; this will ensure erenumab access until country-level launch and 
subsequent reimbursement decision in all countries.
Should a treatment gap exist between the Core and Extension Phase due to
a delay of HA/EC approvals or other administrative/logistical reasons, the 
subject may enter the PTA-Open-Label Treatment Period at a later time. 
During this treatment gap the patient would remain in the main study and is 
allowed to be treated with any medication as deemed appropriate by the 
investigator to manage the patient’s migraines. Upon HA and EC approval of 
the PTA-Open-Label Treatment Period, the patient will then be administered 
study drug corresponding to the Week 52 dose and will continue dosing 
every 4 weeks as per protocol.  Patients will be required to follow all protocol 
requirements for treatments allowed and for prohibited medications (Section 
6.2.2).
End of Trial will occur when the last subject completes their last visit (LPLV) of 
the study. A final study report will be prepared and finalized for all data after 
all subjects have completed their respective last visit (LPLV).
Population
The study population will consist of adult male and female subjects with a 
documented history of episodic migraine (4 to 14 baseline migraine days), who 
have failed 1 or 2 previous migraine prophylactic treatments for lack of efficacy or 


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tolerability. The goal is to randomize approximately 600 subjects in approximately 
100 centers worldwide.
Key Inclusion 
criteria

Adults ≥18 of age upon entry into screening.

Documented history of migraine (with or without aura) ≥12 months prior to 
screening.

≥4 and <15 days per month of migraine symptoms (based on ICHD-3 criteria) 
on average across 3 months prior to screening based on retrospective 
reporting.

<15 days per month of headache symptoms (i.e., migraine and non-migraine)

Subjects in need for switching by documented failure of 1 or 2 prophylactic 
therapies in the last 6 months due to either lack of efficacy or poor tolerability 
(see list of prophylactic therapies in Exclusion Criteria 6 and definition for 
lack of efficacy and poor tolerability). For subjects with 1 prior treatment 
failure, the failure should have occurred in the last 6 months. For subjects 
with 2 prior treatment failures, the second treatment failure should have 
occurred in the last 6 months.

During baseline period, confirmed migraine frequency of 4 to 14 migraine 
days and <15 days of headache symptoms.

During baseline period, ≥80% compliance with the headache diary.
Key Exclusion 
criteria

Older than 50 years of age at migraine onset.

Lack of efficacy or poor tolerability with > 2 treatments from the following 7 
medication categories for prophylactic treatment of migraine after an 
adequate therapeutic trial. These medication categories are:
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: Serotonin-norepinephrine reuptake inhibitors (for example: 
venlafaxine, desvenlafaxine, duloxetine, milnacipran)
Category 6: Flunarizine, verapamil
Category 7: Lisinopril, candesartan
Efficacy failure is defined as no meaningful reduction in headache 
frequency, duration, and/or severity after administration of the 
medication for at least 6 weeks at the generally accepted therapeutic 
dose(s) based on the investigator’s assessment. 
Tolerability failure is defined as documented discontinuation due to adverse 
events of the respective medication during the last 6 months prior to 
screening
The following scenarios do not constitute lack of therapeutic response:

Lack of sustained response to a medication

Patient decision to halt treatment due to improvement 

Used a prohibited medication from the 7 categories of prior prophylactic 
medications within 3 months prior to the start of and during baseline for a 
non-migraine indication if dose is not stable.

Device, or procedure that potentially may interfere with the intensity or 
number of migraine days within 2 months prior to the start of or during 
baseline.


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
Exposure to botulinum toxin in the head and/or neck region within 4 months 
prior to the start of the baseline period, during the baseline period

Taken the following for any indication in any month during the 2 months prior 
to the start of the baseline period: 

Ergotamines or triptans on ≥ 10 days per month, or

Simple analgesics (non-steroidal anti-inflammatory drugs [NSAIDs], 
acetaminophen) on ≥ 15 days per month, or

Opioid- or butalbital-containing analgesics on ≥4 days per month.

Previous exposure to erenumab or exposure to any other prophylactic 
CGRP-targeted therapy.
Study 
treatment

Erenumab (70 mg or 140 mg) in 70 mg/1mL pre-filled syringes

Locally approved oral prophylactics
Efficacy 
assessments

Migraine days

Patient study completion
Key safety 
assessments

Adverse events

Physical examinations

Laboratory evaluations

ECG
Other 
assessments
Patient Reported Outcomes (PROs)

Patients' Global Impression of Change (PGIC)
 
Data analysis
The primary analyses will compare the proportion of subjects who achieve a net 
benefit between erenumab vs oral prophylactics. A Cochran-Mantel-Haenszel 
(CMH) test stratified by number of previous treatment failures (1 vs. 2) will be 
used under a 2-sided significance level of 0.05 to evaluate the association 
between the net benefit rate and the treatment.
The secondary analysis will be handled as such:

Proportion of subjects completing the study at month-12 on the randomized 
treatment 

This variable will be analyze same as that of the primary analysis.

Global satisfaction as measured by PGIC at month 12 as per randomized 
treatment 

Patient will be considered as responder if PGI-I score is 5, 6, or 7. 
Proportion of responders based on PGI-I score at month 12 will be 
analyzed same as that of the primary endpoint.

Cumulative average change from baseline on the monthly migraine days 
during the treatment period (month 1-12) 

The average of monthly migraine days will be obtained cumulatively at 
each month across 12 months. The cumulative average change from 


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baseline on the monthly migraine days will be derived using difference 
between cumulative average at each month and baseline monthly 
migraine days. The change from baseline will be analyzed using a linear 
mixed effects model including treatment group, baseline value, 
stratification factor(s), scheduled visit, and the interaction of treatment 
group with scheduled visit.
Key words
Erenumab, AMG334, migraine, episodic, headache, CGRP
1
Introduction
1.1
Background
Migraine is one of the most common neurological disorders with a high global prevalence, 
significant socio-economic burden and substantial impairment and disability of affected 
patients (2017). It is mainly characterized by recurrent headache lasting 4-72 hours and is 
usually accompanied by other neurological disturbances, nausea, and vomiting. 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 the presence of up to 
14 migraine 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.
Migraine patients are currently being treated prophylactically by a variety of drug classes, many 
of them being used off-label and often based on insufficient or limited evidence. Common 
prophylactic drugs or drug classes used include beta-blockers, anti-epileptic agents (including 
topiramate and valproate), antidepressants (mainly amitriptyline and venlafaxine), certain 
calcium channel blockers (such as flunarizine and verapamil), and certain angiotensin-
converting-enzyme inhibitor/angiotensin II receptor blockers (ACE/ARBs such as lisinopril and 
candesartan). Botulinum toxin (Botox®) is approved in US and the majority of the EU countries 
for CM use, but not for EM.
All of these therapies are commonly associated with either insufficient efficacy and/or 
substantial tolerability issues that often leads to treatment discontinuation in migraine patients. 
For example, in a recent claims database analysis in chronic migraine, persistence of oral 
prophylactics at one year, irrespective of class, was as low as 13-16% (Hepp et al 2016), 
therefore reflecting a high unmet medical need for new therapies. The standard of care also 
varies significantly across different geographies and treatment decisions are often made on a 
case-by-case basis without consensus on treatment guidelines.
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-neurovascular 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 
nucleus (Wang et al 1995, Zimmermann et al 1996, Durham 2006). The CGRP pathway was 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.


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Erenumab (AMG334) is a monoclonal antibody targeting the CGRP receptor, that is 
administered once monthly via subcutaneous injection. Erenumab was approved by the FDA 
on 17 May 2018 and EMA on 26 July 2018 for migraine prevention with an approved monthly 
dose of 70 mg or 140 mg. The benefits and safety of Aimovig were studied in four clinical trials 
involving >2600 patients and has been shown to be an effective and well-tolerated treatment 
for 
both 
episodic 
(Goadsby et al 2017, 
Study 
20120296) 
and 
chronic 
migraine 
(Tepper et al 2017, Study 20120295). Results were consistently robust across different studies 
and different subgroups of patients, including patient groups with high unmet need such as those 
who have failed one or more prior prophylactic therapies due to lack of efficacy or poor 
tolerability.
The initial phase 2 dose finding study in episodic migraine (Sun et al 2016, Study 20120178) 
included an ongoing 5-year open-label extension phase. In a pre-specified interim analysis after 
all ongoing patients have completed one year of treatment, sustained efficacy has been shown 
with a long-lasting reduction from baseline of approximately 5 monthly migraine days and with 
65% of patients achieving a 50% responder rate in the last month (Ashina et al 2017). Other 
recently available longer-term data after one year from studies 20120295 and 20120296 have 
also confirmed that the retention remains high (75-80% range at one year) and that the efficacy 
with continued erenumab treatment is sustained over time.
No active comparator studies were conducted in the pivotal program. With all existing standard
of care treatments, no clearly defined, evidence-based and commonly accepted treatment 
algorithms exist. Choice of a treatment is heterogeneous across geographies and highly 
dependent on both individual experience of the treating physician as well as particular patient 
profiles. Due to the low persistence of oral prophylactics, switches between therapies are 
common and usually lead to inadequate longer-term disease control, particularly as many 
therapies require titration.
Given the emerging erenumab clinical profile including the available data in treatment failure 
patients, one key question is if early use of erenumab during a treatment algorithm is associated 
with a favorable long-term sustained benefit and how erenumab compares with oral 
prophylactics over one year in a real world setting.
1.2
Purpose
The purpose of this study is to compare the sustained long-term benefit between two treatment 
paradigms of migraine prophylactic agents (erenumab versus a control arm of oral prophylactics) 
in episodic migraine patients who have previously failed 1 to 2 prophylactic migraine treatments. 
Data from this study, in addition to the data generated thus far in the clinical program, will 
provide important data for clinicians treating migraine patients, particularly for patients who 
have previously failed existing preventative treatments, as there are limited treatment options. 
Subsequently it will determine if early use of erenumab during a treatment algorithm is 
associated with a favorable long-term sustained benefit.


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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 demonstrate the superiority of subcutaneous 
erenumab compared to oral prophylactics on 
sustained benefit defined as % subjects 
completing one-year on the randomized 
treatment and achieving at least a 50% reduction 
from baseline in monthly migraine days at month
12.

Proportion of subjects who complete 
initially assigned treatment and achieve 
at least 50% reduction from baseline in 
monthly migraine days at Month 12
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To evaluate the effect of erenumab compared to 
oral prophylactics on overall subject retention 
defined as % subjects completing treatment 
period at Month 12 on initially assigned treatment

Proportion of subjects completing the 
treatment period at Month 12 on the 
initially assigned treatment

To evaluate the effect of erenumab compared to 
oral prophylactics on the change from baseline in 
monthly migraine days during the treatment 
period

Cumulative average change from 
baseline on the monthly migraine days 
during the treatment period for subjects
on the initially assigned treatment 
(Months 1-12)

To evaluate the effect of erenumab compared to 
oral prophylactics on the subject's assessment of 
the change in clinical status since the start of 
treatment as measured by the Patients' Global 
Impression of Change (PGIC) Scale

Proportion of responders (PGI-I score 
≥5) as measured by PGIC at month 12 
for subjects completing the treatment 
period at Month 12 on initially assigned 
treatment


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3
Study design
This study uses a single-cohort, 2-treatment arm (erenumab versus SoC oral prophylactic 
treatment), parallel-group randomized (2:1 [erenumab (70 mg or 140 mg): SoC oral 
prophylactic]), open-label design in adult patients with episodic migraine who have previously 
failed 1 or 2 prophylactic migraine treatments. The following periods are included in the study 
design, with study visits at 4-week intervals after completion of screening:
Core Phase:

Screening Period (0-2 weeks) – Required for all subjects to assess initial eligibility and to 
obtain informed consent

Baseline Period (4 weeks) – All subjects successfully completing the Screening Period 
will be invited to participate. Eligibility for randomization will be assessed based on 
migraine frequency and diary compliance during this period. Randomization will be 
stratified by prior prophylactic migraine medication treatment failure (due to insufficient 
efficacy or poor tolerability) reported during Screening/Baseline Period: 1 treatment 
failure (TF1) vs 2 treatment failures (TF2). A 30% cap of randomized subjects to the TF2 
strata will be implemented. The stratification and 30% cap will be implemented within 
IRT.

Open-Label Randomized Treatment Period (52 weeks) – All subjects successfully 
completing the Baseline Period will be invited to participate. Eligible subjects will be 
randomized 2:1 to one of two treatment arms [erenumab s.c. q.m. versus SoC oral 
prophylactic (active comparator)]. Only monotherapy will be allowed in both arms and no 
concomitant use of other prophylactics for migraine specifically should be used. At the 
end of this period, the final assessment to address the effect of erenumab compared to SoC 
oral prophylactic cycling on the net benefit and related objectives will occur. The last dose 
for erenumab will occur at Week 48 (monthly dose) and the last dose for SoC will occur at 
Week 52. 

Switching: Treatment (failure) status and decision on whether or not to switch to a 
new treatment will be checked at every visit and will be based on investigator and 


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subject discretion (based on efficacy/tolerability/satisfaction but not based on pre-
specified cutoffs for certain parameters). In both arms, switching will be allowed 
within approved prophylactics in the respective country for prophylaxis of migraine.
Extension Phase

Post-Trial Access Open-Label Treatment Period (52 weeks) - Patients completing 
visits through week 52 of the Core Phase will be eligible to participate.  Patient eligibility 
will be determined by the investigators opinion as follows: 1) patients treated with
erenumab must have benefited from erenumab treatment and 2) patients on Standard of 
Care (SoC) oral prophylactic must be in need of a treatment switch. PTA to erenumab will 
be provided for up to 52 weeks (based on continued benefit of erenumab treatment) in all 
eligible patients; this will ensure erenumab access until country-level launch and 
subsequent reimbursement decision in all countries.
Should a treatment gap exist between the Core and Extension Phase due to a delay of 
HA/EC approvals or other administrative/logistical reasons, the subject may enter the 
Extension Phase at a later time. During this treatment gap, the patient would remain in the 
main study and is allowed to be treated with any medication as deemed appropriate by the 
investigator to manage the patient’s migraines. Upon HA and EC approval of the 
Extension Phase, the patient will then be administered study drug corresponding to the 
Week 52 dose and will continue dosing every 4 weeks as per protocol.  Patients will be 
required to follow all protocol requirements for treatments allowed and for prohibited 
medications (Section 6.2.2).
End of Trial will occur when the last subject completes their last visit (LPLV) of the study.
Note: Treatment discontinuation does not imply study discontinuation. Every effort should be 
attempted to ensure subjects complete the study visits event if treatment is discontinued. After 
study completion, post-trial access to erenumab will be offered to the study participants as 
needed.
The primary analysis will occur when the last patient completes the Core Phase, prior to the end 
of the Extension Phase. The main study report will be prepared and finalized at this time for all 
data from the Core Phase.
An additional study report will be prepared for the Extension Phase after all patients have 
completed their respective last visit (LPLV) of the Extension Phase and will report data for the 
Extension Phase.


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Figure 3-1
Study Design Schematic
1 Dose adjustments may be done if allowed per label and is not a treatment failure. Switching to oral prophylactic 
in the erenumab arm or switching to a different oral prophylactic in oral prophylactic arm is allowed
2 Treatment Discontinuation does not imply study discontinuation. Every effort should be attempted to ensure 
subjects complete the study visits even if treatment is discontinued.
3 Stratification based on Prior prophylactic migraine treatment - 1 prior treatment failure (70%) vs 2 prior treatment 
failures (30% cap)
4 “Eligible Core Phase Completers” are patients that complete visits through Week 52 on or off of study drug and 
are either benefitting from erenumab treatment or are in need of a treatment switch.  


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4
Rationale
4.1
Rationale for study design
Table 4-1
Rationale for study design
Study Design Aspect
Rationale
Overall (parallel, cross-
over, sequential, factorial)
This will be a parallel study design. During the development 
program placebo-controlled studies only were conducted. This 
study will provide data on erenumab's efficacy and safety when 
compared head-to-head to SoC oral prophylactics. 
Randomization (strata, 
allocation ratio)
Eligible subjects will be randomized 2:1 to one of two treatment 
arms (erenumab versus SoC oral prophylactic(s)) and will be 
stratified by prior prophylactic migraine medication treatment failure 
(due to efficacy or tolerability): 1 treatment failure (TF1) vs 2 
treatment failures (TF2) with a cap of 30% to the TF2 strata.
Unequal randomization favoring the erenumab treatment arm is 
expected to facilitate recruitment, generate additional data on TF1 
to complement previous studies on TF2, and to determine if early 
use of erenumab during the treatment algorithm is associated with 
a favorable long-term sustained benefit.
This randomization will allow for additional long-term efficacy and 
safety data on erenumab
Open-label during core 
phase
Given the difference in treatments (injectable vs. varied oral 
treatments), adequate blinding will not be possible. 
PTA-Open-Label Treatment 
Period
The PTA-Open-Label Treatment Period is a mechanism to provide 
52 weeks of PTA of erenumab for patients who completed visits 
through Week 52 of the Core Phase (see Section 3.0 for details)
4.2
Rationale for dose/regimen and duration of treatment
In order to capture real world, dose/regimen will follow the approved label. After regulatory 
review, erenumab was approved by FDA and EMA as a monthly treatment. The recommended 
dose is 70 mg of erenumab. Some patients may benefit from a dose of 140 mg.
For this study and if randomized to erenumab, the investigator can treat the subject with either 
70 mg or 140 mg. Dose modification/escalation will be allowed as per the approved label. 
Treatment and any modification should be documented. Data supporting the proposed regimen 
is described below.
Registration and elective clinical trials demonstrate that erenumab is safe and effective across 
the episodic migraine (EM) / chronic migraine (CM) spectrum, even in patients with prior 
preventive treatment failures (PPTFs) and medication overuse. (Goadsby et al 2017, 
Dodick et al 2018, Tepper et al 2017, Reuter et al 2018, Tepper et al 2017, Goadsby et al 2017, 
Ashina et al 2017)
Despite some numerical differences, results were largely similar across the 70 mg and 140 mg 
doses in the general trial population in terms of:

Primary efficacy endpoints: 


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
Patients across the EM–CM spectrum who received erenumab (vs placebo) achieved 
significantly greater reductions in monthly migraine day (MMD) frequency 
(Goadsby et al 2017, Dodick et al 2018, Tepper et al 2017)

Both the 70 mg and 140 mg doses were superior to placebo in terms of reducing MM 
(Goadsby et al 2017, Dodick et al 2018, Tepper et al 2017)

For patients with EM, a numerically greater reduction in MMD was observed with 
140 mg compared with 70 mg (Goadsby et al 2017)

Safety and tolerability profiles, as no dose-dependent adverse events were observed 
(Goadsby et al 2017, Tepper et al 2017, Data on File, Amgen)
However, the 140 mg dose demonstrated numerically improved results for:

All secondary endpoints, including the number of monthly migraine days (MMDs) and the 
 
(Goadsby et al 2017, Dodick et al 2018, Tepper et al 2017)

Specific patient populations, e.g. patients with prior preventive treatment failures 
(Goadsby et al 2017, Ashina et al 2017)
 
In the erenumab clinical program, about one third of patients have reported two or more PPTFs. 
In this patient segment of “difficult-to-treat” patients, erenumab achieved significant 
improvements in MMDs, 50% responders and 
 and demonstrated, safety and and 
tolerability, supporting the use of erenumab in this population with a high unmet need. 
(Reuter et al 2018)
Compared with the 70 mg dose, the 140 mg dose achieved numerically greater improvements 
in MMDs in the PPTF subgroups assessed. Odds of achieving ≥ 50% reduction in MMDs were 
numerically greater for 140 mg versus 70 mg in both EM and CM studies, indicating that more 
“difficult-to-treat” patients can benefit from the 140 mg dose compared to the 70 mg dose. 
(Goadsby et al 2017, Ashina et al 2017)
Varied standard of care treatments exist and switching among therapies is common, which does 
not provide for long-term disease control. The duration of this study will provide data on the 
long-term use of erenumab as compared to SoC oral prophylactics.
4.3
Rationale for choice of control drugs (comparator)
Multiple oral prophylactic treatments are approved and vary by country.  A decision to use will 
be based on prior treatment failure options and investigator decision. Only monotherapy will 
be allowed and switching treatment will be evaluated at every visit and will be based on 
investigator and subject discretion. As these are approved and marketed therapies, these 
comparators must be used in accordance with the product label/package insert with the dosing 
captured in the source documents and eCRF. Medications not approved for migraine 
prophylaxis are not allowed as SoC. If at a visit a decision is made to switch treatment, the 
reason and new oral prophylactic should be documented in the source and eCRF. 


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4.4
Purpose and timing of interim analyses/design adaptations
Not applicable
4.5
Risks and benefits
Key risks and benefits are briefly summarized below. For further information, please refer to 
the current package insert/prescribing information and the Investigator Brochure.
As of June 2018, the safety of erenumab in migraine prophylaxis was assessed from integrated 
safety analyses of 2537 migraine patients exposed to at least one dose of erenumab, with a 
cumulative exposure of 2310.3 subject-years (SY). Overall, the safety and tolerability profile 
of erenumab was similar between the 140 mg and 70 mg doses and comparable to placebo. 
Adverse drug reactions include injection site reactions, constipation, muscle spasms, and 
pruritus. The majority were mild or moderate in severity and rarely led to treatment 
discontinuation. To date, no important risk has been identified for erenumab.
Overall, to date, there is no evidence from non-clinical and clinical data of risk of cardiovascular 
effects. On the theoretical basis of the mechanism of action of erenumab, CGRP receptor 
blockade might reduce compensatory vasodilation, particularly under ischemic conditions. 
Therefore, cardiovascular effects continue to be monitored.
 
 
 
 
 
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 patients who are 
unwilling to comply with the protocol-specified contraception requirements. All women of 
child-bearing potential will be screened for pregnancy at each study visit.
An external data monitoring committee was established to review the erenumab safety data for 
Phase 2b and Phase 3a studies, and based on these data, recommended continuation of the 
program. The need for a data monitoring committee (DMC) for this study was assessed, and 
deemed not necessary because erenumab was approved by FDA and EMA for migraine 
prophylaxis and the safety profile of erenumab was well characterized in 4 double-blind, 
placebo-controlled trials in over 2500 patients. The risk to patients in this trial will be minimized 
by compliance with the eligibility criteria, close clinical monitoring, and allowance of acute 
rescue medications.
Initial benefits for erenumab as a migraine prophylactic have been demonstrated in a Phase 2b 
trial (Amgen Study 20120178), in which 70 mg was established as the minimally effective dose 
in EM (Sun et al 2016) with a significant placebo-corrected reduction of 1.1 monthly migraine 


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days compared to baseline, as well as positive results on most secondary endpoints, including 
50% responder rate.
Three additional Phase 2/3 studies, including 2 studies in EM, have been completed with 
erenumab, which have established 70 mg and 140 mg as being effective and safe in patients 
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 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.
As of July 2018, two open-label extension studies (OLE) of erenumab in patients with chronic 
(1 year) and episodic migraine (3 years) were reported confirming sustained efficacy and a 
favorable safety and tolerability profile.
Overall, given the characteristics of erenumab and the large experience in clinical trials, the 
overall benefit-risk assessment is supportive.
5
Population
The study population will consist of adult male and female subjects with a documented history 
of episodic migraine (4 to 14 baseline migraine days), who have failed 1 or 2 previous migraine 
prophylactic treatments for lack of efficacy or tolerability.
The goal is to randomize approximately 600 subjects in approximately 100 centers worldwide. 
Assuming a 25% screen failure rate, approximately 800 subjects will be screened.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed
2. Adults ≥18 of age upon entry into screening.
3. Documented history of migraine (with or without aura) ≥12 months prior to screening 
according to the International Classification of Headache Disorders-3rd Edition (ICHD-3).
4. ≥4 and <15 days per month of migraine symptoms (based on ICHD-3 criteria) on average 
across 3 months prior to screening based on retrospective reporting.
5. <15 days per month of headache symptoms (i.e., migraine and non-migraine).
6. Subjects in need for switching by documented failure of 1 or 2 prophylactic treatments in 
the last 6 months due to either lack of efficacy or poor tolerability (see list of prophylactic 
categories in Exclusion Criteria 4 and definition for lack of efficacy and poor tolerability). 
For subjects with 1 prior treatment failure, the failure should have occurred in the last 6 


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months. For subjects with 2 prior treatment failures, the second treatment failure should 
have occurred in the last 6 months.
7. During baseline: Confirmed migraine frequency of 4 to 14 migraine days and <15 days of 
headache symptoms.
8. During baseline: ≥80% compliance with the headache diary.
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. Unable to differentiate migraine from other headaches.
4. Lack of efficacy or poor tolerability with > 2 treatments from the following 7 medication 
categories for prophylactic treatment of migraine after an adequate therapeutic trial. These 
medication categories are:

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: Serotonin-norepinephrine reuptake inhibitors (for example: venlafaxine, 
desvenlafaxine, duloxetine, milnacipran)

Category 6: Flunarizine, verapamil

Category 7: Lisinopril, candesartan
Efficacy failure is defined as no meaningful reduction in headache frequency, duration, 
and/or severity after administration of the medication for at least 6 weeks at the 
generally accepted therapeutic dose(s) based on the investigator’s assessment.
Tolerability failure is defined as documented discontinuation due to adverse events of the 
respective medication during the last 6 months prior to screening
The following scenarios do not constitute lack of therapeutic response: 
-
Lack of sustained response to a medication
-
Patient decision to halt treatment due to improvement 
5. Used a prohibited medication from the 7 categories of prior prophylactic medications 
within 3 months prior to the start of and during baseline for a non-migraine indication if 
dose is not stable
6. Exposure to botulinum toxin in the head and/or neck region within 4 months prior to the 
start of the baseline period, during the baseline period.
7. Taken the following for any indication in any month during the 2 months prior to the start 
of the baseline period:

Ergotamines or triptans on ≥ 10 days per month, or


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
Simple analgesics (non-steroidal anti-inflammatory drugs [NSAIDs], acetaminophen) 
on ≥ 15 days per month, or

Opioid- or butalbital-containing analgesics on ≥4 days per month.
8. Device, or procedure that potentially may interfere with the intensity or number of 
migraine days within 2 months prior to the start of or during baseline. 
9. Active chronic pain syndromes (e.g., fibromyalgia, chronic pelvic pain).
10. History of major psychiatric disorders (such as schizophrenia or bipolar disorder) or 
current evidence of depression. Subjects with anxiety disorder and/or major depressive 
disorders 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 disorder. Subjects must have been on a 
stable dose within the 3 months prior to the start of the baseline period.
11. History of seizure disorder or other significant neurological conditions other than 
migraine. Note: a single childhood febrile seizure is not exclusionary.
12. 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.
13. Human immunodeficiency virus (HIV) infection by history.
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. 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.
16. Myocardial infarction, stroke, transient ischemic attack, unstable angina, or coronary 
artery bypass surgery or other re-vascularization procedures within 6 months prior to 
screening.
17. Score “yes” on item 4 or item 5 of the Suicidal Ideation section of the 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.
18. Evidence of drug or alcohol abuse or dependence based on Investigator discretion 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 
or barbiturates).
19. Pregnant or nursing (lactating) women
20. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using basic methods of contraception during dosing 
with study treatment. The use of highly effective methods of contraception are required 
for patients treated with oral prophylactic medications that are contraindicated in women 
of child-bearing potential not using highly effective contraception as per their local labels 
(e.g. topiramate, amitriptyline, beta-blockers). As topiramate may reduce oral 
contraception exposure, another form of contraception (e.g. barrier method) must be used 


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in addition to oral contraceptive. If treated with amitriptyline, highly effective methods 
should be used during treatment and continued for 30 days after end of treatment

Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., 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 partner sterilization (at least 6 m prior to screening). The vasectomized 
male partner should be the sole partner for that subject

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)

Basic contraception methods include:

All highly effective methods listed above

Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/ vaginal 
suppository
In case of use of oral contraception, women should have been stable on the same pill for a 
minimum of 3 months before screening.
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.
21. Use of other investigational drugs within 5 half-lives of enrollment, or until the expected 
pharmacodynamic effect has returned to baseline, whichever is longer.
22. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes.
23. Previous exposure to erenumab or exposure to any other prophylactic CGRP-targeted 
therapy prior to the study.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible subjects.


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6
Treatment
6.1
Study treatment
6.1.1
Investigational and control drugs
Table 6-1
Investigational and control drug
Investigational/ 
Control Drug
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Description
Sponsor 
(global 
or local)
Core Phase
Treatment 
paradigm A: 
Erenumab (70
mg or 140 mg 
monthly) 
(AMG334)
70 mg/1mL pre-
filled syringes
Subcutaneous
Open label bulk supply. The 
70 mg dose will be 
administered as 1mL dose 
from one syringe. The 140
mg dose will be administered 
as 2 syringes of 70 mg/mL. 
Sponsor 
global
Treatment 
paradigm B: 
Locally 
Approved SoC 
Oral 
Prophylactics 
(daily)
Tablet/capsule
Oral use
Varies
Local
Extension Phase
Treatment: 
Erenumab (70
mg or 140 mg 
monthly) 
(AMG334)
70 mg/1mL pre-
filled syringes
Subcutaneous
See above for erenumab
Sponsor 
global
6.1.2
Additional study treatments
No additional treatment beyond investigational drug and control drug are included in this trial.
6.1.3
Treatment arms/group
At the start of the Open-Label Randomized Treatment Period (Day 1) subjects will be assigned 
to either erenumab (70 mg or 140 mg) or SoC oral prophylactic at the Treatment Visit in a 2:1 
ratio, stratified by prior prophylactic migraine medication treatment failure (1 or 2 treatment 
failures due to efficacy or tolerability, with cap of 30% on 2 treatment failures) reported during 
the Screening/Baseline Period. In the erenumab arm, subjects may be treated with either 70 mg 
or 140 mg based on the investigator's assessment. This information and reason for dose selection 
should be documented in the source and eCRF. Erenumab and SoC oral prophylactics must be 
used in accordance with the locally approved product label/package insert.
Study medication will be:

Erenumab (labelled as AMG334): pre-filled 1mL syringes (PFS) containing 70 mg/1mL 
of erenumab. 


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
Comparator: locally approved oral prophylactic migraine medication.
Eligible subjects that complete the Core Phase (see Section 3.0 for eligibility details) will be 
allowed to enter the Extension Phase and receive erenumab (70 mg or 140 mg).
6.1.4
Treatment duration
The planned duration of treatment is 52 weeks for the Core Phase. Subjects may be discontinued 
from treatment earlier due to unacceptable tolerability, lack of efficacy, and/or treatment is 
discontinued at the discretion of the investigator or the subject, but encouraged to complete the 
subsequent study visits.
Eligible subjects that complete the Core Phase (see Section 3.0 for eligibility details) will be 
allowed to enter the Extension Phase. The duration of the Extension Phase is 52 weeks from 
core phase study completion at Week 52 (Week 52 through Week 104). During the Extension 
Phase subjects may be discontinued from treatment earlier due to unacceptable tolerability, lack 
of efficacy
 and/or treatment may be discontinued at the discretion 
of the investigator or the subject. Once a patient discontinues study drug the patient will 
complete a final study visit as described in Table 8-2.
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 patient was enrolled into the study must be recorded 
in the concomitant medications / significant non-drug therapies eCRF.
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.
6.2.2
Prohibited medication
If a subject is taking a migraine prophylactic from the 7 categories of prior prophylactic 
medications (Section 5.2) for a different pre-existing condition (not for migraine prophylaxis), 
this will be allowed as long as the subject is on a stable dose for at least 3 months prior to 
baseline and the pre-existing condition and corresponding treatment is documented in the 
source and eCRF. 
Only prophylactic migraine monotherapy is allowed during the study in each arm (based on 
approved medications in each respective country for daily oral prophylactic medications). No 
other concomitant prophylactics for migraine specifically should be used, unless it is required 
by the HCPs to cross-titrate from one prophylactic to another. 
Previously taken failed prophylactic treatment should not be re-introduced as a study drug 
treatment.
Use of the treatments displayed in Table 6-2 will NOT be allowed as designated due to the 
potential confounding of efficacy assessments.


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Table 6-2
Prohibited medication
Medication
Prohibition period
Action taken
Botulinum toxin (in the head 
and/or neck region)
Within 4 months of the start of 
the baseline period and 
throughout the study
Discontinue study treatment. 
Treatment discontinuation does 
not imply study discontinuation.
Devices or invasive 
interventions (e.g., nerve 
blocks, occipital nerve 
stimulators, transcranial 
magnetic stimulation)
Within 2 month of the start of 
the baseline period and 
throughout the study
Discontinue study treatment. 
Treatment discontinuation does 
not imply study discontinuation.
Other Calcitonin Gene-related 
Peptide (CGRP) antagonists
for migraine prophylaxis
Prior to the start of the 
baseline period and throughout 
the study
Discontinue study treatment. 
Treatment discontinuation does 
not imply study discontinuation.
6.2.3
Rescue medication
Subjects can continue to use “best supportive care" during the study. 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).
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. 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 on that date, and number of units 
taken.
During the Core Phase the use of rescue medication must only be recorded in the eDiary. During 
the Extension Phase the use of rescue medications will be entered in the concomitant medication 
eCRF. Relevant non-drug therapies as part of “best supportive care” use should be recorded in 
the eCRF.
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.) 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 Treatment Visit (Day 1 of Core Phase), 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 


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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 treatment to be dispensed to the subject.
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 Supply using a validated system that automates the random assignment of 
medication numbers to packs containing the study treatment.
Randomization will be stratified by prior prophylactic migraine medication treatment failure (1 
or 2 treatment failures due to efficacy or tolerability) reported during Screening/Baseline Period. 
The IRT will cap the randomization to the "2 prior treatment failure" strata to 30%.
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office.
Patients that complete the Core Phase will be allowed to enter a 52 week Extension Phase (see 
Section 3.0 for details).
6.4
Treatment blinding
Treatment will be open to subjects, investigator staff, persons performing the assessments, and 
the CTT.
6.5
Dose escalation and dose modification
Dose escalation and dose modifications will be allowed for erenumab and the locally approved 
oral prophylactics to reflect approved labelling and/or current standard of care and should be 
documented in the subjects source documents and in the eCRF. Investigator-initiated 
interruptions will be considered on a case-by-case basis.
6.5.1
Dose modifications
See Section 6.5 above.
6.5.2
Follow-up for toxicities
Subjects whose treatment is interrupted or permanently discontinued due to an adverse event or 
clinically significant laboratory value, must be followed up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts should be consulted as deemed necessary.


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6.6
Additional treatment guidance
6.6.1
Treatment compliance
Core Phase
Erenumab medication is administered by the investigator or designated study staff at each visit. 
This information should be captured in the source document and the eCRF at each visit. All 
erenumab dispensed and returned must be recorded in the Drug Accountability Log. Site staff 
will review eDiary compliance with the patient at each visit, when applicable.
For SoC oral prophylactics, the investigator must promote compliance by instructing the subject 
to take the study treatment exactly as prescribed and by stating that compliance is necessary for 
the subject’s safety and the validity of the study. The subject must also be instructed to contact 
the investigator if he/she is unable, for any reason, to take the study treatment as prescribed. 
Compliance will be assessed by the investigator and/or study personnel at each visit using pill 
counts (if applicable) and information provided by the subject. This information should be 
captured in the source document at each visit. SoC oral prophylactics prescribed and used must 
be recorded in the Drug Accountability Log for Standard of Care, to allow proper 
reimbursement by Novartis.
Extension Phase
After completion of the Core Phase (Week 52 Visit, Table 8-1) patients will be administered 
study drug at the study site (Week 52 Visit) and will then be required to have quarterly study 
visits at the study site.  Between the quarterly visits patients will have study drug injections 
every 28 days either 1) administered by the site staff at brief injection visits at site or 2) self-
administered at home with documented on-site training for correct injection procedure.
Note: If study drug is provided to the patient for self-administration, the patient will need to be 
properly trained with required documentation filed in the patient’s source documents.  The 
documentation will need to indicate that the patient was trained on the correct injection 
procedure, the proper drug storage and required steps for documenting the injection details 
including day of injection, dose location etc. The patient will then need to provide the site with 
the required documentation at each quarterly visit.
6.6.2
Emergency breaking of assigned treatment code
Not applicable as this is an open label study.
6.7
Preparation and dispensation
Each study site will be supplied with erenumab 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 patient 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 to the patient, site 


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personnel will detach the outer part of the label from the packaging and affix it to the source 
document.
During the COVID-19 pandemic that limits or prevents on-site study visits, delivery of study 
drug directly to a participant’s home is generally permitted in the event the Investigator has 
decided that an on-site visit by the participant is no longer appropriate or possible, and that it is 
in the interest of the participant’s health to administer (e.g., self-injection or study staff 
administration at patients’ 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 participant’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 participant for 
instructional purposes, safety monitoring, and discussion of the participant´s health status until 
the participants can again visit the site.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Erenumab 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. During the Extension Phase erenumab may be provided to the patient at 
the quarterly visits if the patient opts to self-administer study medication at home.  For patients 
opting to self-administer study medication at home documented training on the proper storage 
procedures is required. SoC oral prophylactics will be sourced locally and will be reimbursed 
by the Sponsor. Upon receipt, all study treatment must be stored according to the instructions 
specified on the labels and in the prescribing information/package insert. Clinical supplies are 
to be dispensed only in accordance with the protocol. Technical complaints are to be reported 
to the respective Novartis Country Pharma Organization (CPO) 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. Subjects will be asked 
to return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study treatment.
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 Sponsor address provided in the investigator 
folder at each site.
6.7.1.2
Handling of additional treatment
Not applicable


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6.7.2
Instruction for prescribing and taking study treatment
Refer to Section 6.1 for information on the two treatment paradigms. Erenumab will be 
administered as a subcutaneous (sc) injection by qualified staff during the Core Phase dosing 
visits. During Extension Phase subjects have the option to self-administer study drug at home 
for drug dispensing visits after on-site documented training). For purposes of erenumab dosing, 
“qm” refers to a monthly injection regimen. Erenumab administration should occur at study 
visits (or drug dosing visits) and any dose administrations that may occur greater than +/- 5 days
from the 4-week time point (23 to 33 days after the last dose administered; due to e.g., patient 
unavailability or scheduling conflicts) should be discussed with Novartis prior to dosing. The 
anatomical sites for administration of erenumab are the upper arm, upper thigh, or abdomen; 
the location of the injection sites should be documented in the source document. For the 
comparator, the oral prophylactics will be used according to the approved indication and 
package insert. Prescription of previous failed drugs is not allowed.
For subjects randomized to erenumab, injections will be administered by qualified study staff 
at each dosing visit during the Core Phase (i.e., Treatment Week 4, Week 8, through Week 48 
of the Core Phase). Subjects will be administered one of the following, depending on their 
randomization:

Erenumab (70 mg or 140 mg): 70 mg/1mL syringes. 

Locally approved oral prophylactics - dose varies and expenses will be covered by the 
sponsor.
At the completion of the Core Phase patients that enter the Extension Phase will be administered 
erenumab at the site (Week 52) and will then be required to have quarterly study visits at the 
site at which time study drug will be administered by the site personnel. Between the quarterly 
visits patients will have injections of study drug every 28 days either 1) administered at site by 
the site staff at drug administration visits or 2) self-administered at home with documented on-
site training for correct injection procedures.
The investigator must promote compliance administering the study treatment exactly as 
prescribed. There are no temporal restrictions for study drug administration (e.g., proximity to 
meals, sleep or activity). For the comparators, please refer to approved package insert for label 
on dosing and possible temporal restrictions.
All study treatment assigned will be recorded in the IRT. Novartis monitors will reconcile 
treatment assigned versus treatment administered and ensure that the information is congruent 
during their monitoring visits.
7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/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.


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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 ICH 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 prescribing information/package insert/CDS. 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 will be communicated as appropriate, for example, via an investigator notification 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.
Male subjects must be informed that if a female partner becomes pregnant while he is enrolled 
in the study, contact with the female partner will be attempted to request her consent to collect 
pregnancy outcome information.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
Subjects might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience.
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 ICFs by trial 
participant and person obtaining informed consent, etc).
During the COVID-19 pandemic the Investigator should 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 patient visits to site are not possible. This training process needs to be documented 
in the patient’s source documents with the patient’s verbal/e-mail/ or chat function agreement.  
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 ICFs 
by trial participant and person obtaining informed consent, etc.).  Written informed consent 
must be obtained once protocol amendment 2 is approved at the site.


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8
Visit schedule and assessments
Assessment schedule Table 8-1 and Table 8-2 lists all of the assessments and indicates with an 
“X" when those assessments are performed. All data obtained from these assessments must be 
supported in the subject’s source documentation.
Visit windows for each visit must be completed within +-5 days from Day 1 with visits 
occurring every 28 days as described in Table 8-1 and Table 8-2.  In addition, visits need to be 
scheduled within the protocol specified visit windows to ensure that drug is administered within 
dosing windows (23 to 33 days from previous dose).
Subjects should be seen for all visits/assessments as outlined in the assessment schedule 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 final visit will be performed. At this final visit, all dispensed investigational product 
should be reconciled, and the adverse event and concomitant medications recorded on the CRF.
Treatment discontinuation does not imply study discontinuation. Every effort should be 
attempted to ensure subjects complete the study visits event if treatment is discontinued.
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 participant´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 participant 
to visit the site again (see Section 8.3 efficacy, Section 8.4.1 Laboratory evaluations, Section 
8.4.3 Pregnancy, Section 8.5.3
 and Section 8.4  Safety monitoring.


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Table 8-1
Assessment Schedule – Core Phase
Period
Screening
Open Label Randomized Treatment
Visit Name Screening Baseline Treatment Week 
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 
24
Week 
28
Week 
32
Week 
36
Week 
40
Week 
44
Week 
48
Week 52 / 
Early Exit10
Days -42 to -28
-28 to -1
Day 1
28
56
84
112
140
168
196
224
252
280
308
336
364
Weeks
-6 to -4
-4 to -1
1
4
8
12
16
20
24
28
32
36
40
44
48
52
Informed consent
X
Medical history/current medical 
conditions
X
Demography
X
Physical Examination1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs and body measurements
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogram (ECG)
X
X
X
Pregnancy Test (serum)2
X
X
Pregnancy test (urine)2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Central blood chemistry - Erenumab
X
X
X
X
Central blood chemistry – SoC Oral 
Prophylactics3
X
X
X3
X3
X3
X3
X3
X
X3
X3
X3
X3
X3
X3
X
Urine Drug Screen
X
Columbia-Suicide Severity Rating 
Scale (C-SSRS)4
X
Randomization
X
Study drug administration5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Outcome Assessment(s)6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patients' Global Impression of 
Change
X
X
X
X
X


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Period
Screening
Open Label Randomized Treatment
Visit Name Screening Baseline Treatment Week 
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 
24
Week 
28
Week 
32
Week 
36
Week 
40
Week 
44
Week 
48
Week 52 / 
Early Exit10
Days -42 to -28
-28 to -1
Day 1
28
56
84
112
140
168
196
224
252
280
308
336
364
Weeks
-6 to -4
-4 to -1
1
4
8
12
16
20
24
28
32
36
40
44
48
52
Adverse Events9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse Events9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant therapies
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Core phase10 completion
X
X Assessment to be recorded in the clinical database or received electronically from a vendor
1 Full exam at Screening, Week 52.  Height and weight will be measured at full exam. Short physical exam at all other visits.
2 Results of pregnancy tests (serum or urine) will be captured as source and not in eCRF.
3 For subjects randomized to SoC oral prophylactics, central blood chemistry must be done at Screening, Treatment, Week 24, Week 52. All other visits, central blood 
chemistry to be done as needed for monitoring. Any additional safety measurements, if applicable, should be implemented as per label.
4 C-SSRS will be the electronic C-SSRS designed for computer administration (web or phone)
5 At every monthly study visit, the investigator should assess tolerability to randomized treatment (erenumab or SoC oral prophylactics) and determine if switching is 
appropriate.  At Week 48, this will be the last dose of erenumab for subjects randomized to erenumab (monthly treatment). SoC oral prophylactics will continue to be 
dosed through month 12 as per label.
6 Patients will record migraine, headache, and headache medication information daily using the provided electronic diaries.
  
9 AE to be captured from Day 1 onward and SAE collection will be captured after informed consent is obtained.
10 Patients that complete Core Phase visits through Week 52 may be eligible to enter the Extension Phase. All patients will receive erenumab during the Extension Phase.


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Table 8-2
Assessment Schedule – Extension Phase
Period
Post-Trial Access Open-Label Treatment Period
Visit Name
Week 
52
Week 
56
Week 
60
Week 
64
Week 
68
Week 
72
Week 
76
Week 
80
Week 
84
Week 
88
Week 
92
Week 
96
Week 
100
Week 104
Days
364
392
420
448
476
504
532
560
588
616
644
672
700
728
Weeks
52
56
60
64
68
72
76
80
84
88
92
96
100
104
Study drug administration
X
X1
X1
X
X1
X1
X
X1
X1
X
X1
X1
X
Contact IRT
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AEs/ SAEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Con. medications / therapies
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test (urine)
X
X
X
X
X
X
Extension Phase 
Completion
X
X Assessment to be recorded in the clinical database or received electronically from a vendor
1 Study drug administration visit only.


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8.1
Screening
At the Screening visit, all study subjects must be thoroughly informed about all aspects of the 
study, including the study treatment, visit schedule, required evaluations, eDiary compliance, 
and all regulatory requirements for informed consent. For details of screening assessments, refer 
to Table 8-1. The screening assessments must be performed within 4-6 weeks prior to first dose 
of study treatment to confirm subject’s eligibility. Assessments cannot be performed prior to 
signature of the informed consent. If the subject does not fulfill all inclusion/exclusion criteria, 
he/she must be documented as a screening failure (Section 8.1.1). It is permissible to re-screen 
a subject if he/she fails the initial screening criteria. If the subject is re-screened, a new ICF 
must be obtained and re-screening will be documented in the subject's source documents. A 
new subject number will be allocated and the site will record data in a new CRF.
8.1.1
Information to be collected on screening failures
Subjects who sign an informed consent but fail to enter the Open-Label Treatment Period for 
any reason will be considered a screen failure. The reason for not being started on treatment 
will be entered on the screening phase disposition page and baseline phase completion eCRF 
(as applicable). The demographic information, informed consent, and Inclusion/Exclusion 
pages must also be completed for screen failure subjects. No other data will be entered into the 
clinical database for subjects who are screen failures, unless the subject experienced a serious 
adverse event during the screening phase (see SAE section for reporting details). If the subject 
fails to be randomized, the IRT must be notified within 2 days of the screen fail and that the 
subject was not randomized.
8.2
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data will be collected on all subjects. This will 
include age, sex, age, race, ethnicity, source of patient referral (if applicable), and 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, including information 
on the suitability for migraine prophylactics and prior migraine prophylactic treatment failure 
history, will be collected as part of screening and baseline characteristics.
Investigators will have the discretion to record abnormal test findings on the medical history 
eCRF whenever in their judgment the test abnormality occurred prior to the informed consent 
signature.
8.3
Efficacy
Efficacy assessments will include:

Migraine days

Patient study completion
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 


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recommended that the information be completed at the same time every day and this will be 
pre-defined in the eDiary by the vendort. 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 ≥ 30 minutes, 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 a migraine-specific medication (ie, triptan or ergotamine) during aura, or to 
treat a headache on a calendar day, then it will be counted as a migraine day regardless of the 
duration and pain features/associated symptoms.
To further characterize a migraine day, the following information will be collected:

Date and time of start of headache (ie, migraine or non-migraine headache)

Date and time of end of headache

Worst pain severity per headache

Pain features (eg, one-sided, throbbing, worsens with exercise/physical activity)

Symptoms (eg, aura, nausea, vomiting, photophobia, phonophobia, vertigo)

Use of acute headache medications (medication name (from pre-entered list), date and 
time of dosing, number of times taken of each date, number of units taken).

For women of child-bearing potential, start and end dates of monthly menses 
8.3.2
Appropriateness of efficacy assessments
The definition of migraine day (Section 8.3.1) is consistent with the diagnostic criteria of 
migraine and probable migraine according to the International Classification of Headache 
(ICHD-3). The monthly migraine days will be calculated using migraine day data collected 
from the eDiary. Migraine days are commonly used as a primary endpoint in pivotal trials as 
acknowledged in the IHS guidelines for controlled trials of drugs in migraine 
(Tfelt-Hansen et al 2012) and is consistent with the erenumab clinical development.


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As the mean change in monthly migraine day (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 subjects that 
achieve a certain clinical benefit, 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. Given that this trial is not considered a pivotal trial but rather should 
provide clinical guidance, the 50% reduction was considered more relevant and therefore 
chosen as part of the primary endpoint. The percentage of patients completing the study 
(retention rates) was selected as part of the composite endpoint based on the long-term data 
from earlier clinical studies (20120255 and 20120296) confirming retention remains high for 
erenumab treated patients at one year (75-80%) and that efficacy is continued over time, which
would be clinically relevant when compared to available prophylactic treatment.
 
 
 
 
 
 
 
8.4
Safety
Safety assessments are specified below with the assessment schedule (Table 8-1 and Table 8-2) 
detailing when each assessment is to be performed.
For details on AE collection and reporting, refer to AE section Section 10.1).
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 schedule visit or more frequently if needed) for safety 
monitoring and discussion of the participant´s health status until the participant can again visit the 
site.
Table 8-3
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, lungs, 
heart, abdomen, back, lymph nodes, extremities, vascular, and 
neurological. If indicated based on medical history and/or symptoms, rectal, 
external genitalia, breast, and pelvic exams will be performed. A complete 
physical exam will be at Screening, and Week 52
A short physical exam will include the examination of general appearance 
and vital signs (blood pressure [SBP and DBP] and pulse). A short physical 
exam will be at all visits starting from Baseline except where a complete 
physical examination is required (see above). 


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Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are present 
prior to signing informed consent must be included in the Medical History 
part of the CRF. Significant findings made after first administration of 
investigational drug which meet the definition of an Adverse Event must be 
recorded on the Adverse Event section of the CRF.
Vital signs
Vital signs include BP and pulse measurements. After the patient has been 
sitting for five minutes, with back supported and both feet placed on the 
floor, systolic and diastolic blood pressure will be measured three times 
using an automated validated device, e.g. OMRON, with an appropriately 
sized cuff. The repeat sitting measurements will be made at 1 - 2 minute 
intervals and the mean of the three measurements will be used. In case the 
cuff sizes available are not large enough for the patient's arm 
circumference, a sphygmomanometer with an appropriately sized cuff may 
be used.
Clinically notable vital signs are defined in Appendix 1.
Height & weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram 
(kg) in indoor clothing, but without shoes) will be measured during full 
physical exams.
Columbia Suicide 
Severity Rating Scale
See Section 10.2.2
8.4.1
Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are provided 
to investigators in the laboratory manual.
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 participant’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). 
Urine Drug Screen
Patients will be tested for substances of abuse at initial screening to confirm patient eligibility. 
During the study, urine drug tests can be performed at the investigator's discretion based on 
clinical suspicion. Urine samples will be analyzed by the central laboratory. If a patient has a 
positive urine drug screen during the study (except for certain prescribed information), the 
investigator should consider discontinuation from the investigational product.
8.4.2
Electrocardiogram (ECG)
ECGs will 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 will be collected. The original ECGs printed on non-heat sensitive paper, 
appropriately signed, must be collected and archived at the study site.


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Each ECG tracing must be labeled with study number, patient initials, subject number, date and 
time, and filed in the study source documents. For any ECGs with patient 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 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 medical 
history/current medical conditions/AE eCRFs as appropriate.
8.4.3
Pregnancy
All pre-menopausal women who are not surgically sterile will have pregnancy testing. Serum 
pregnancy tests will be performed at the Screening and Week 52 visits with urine pregnancy 
tests performed as described in Table 8-1 and Table 8-2.
During COVID-19 pandemic, if a patient cannot visit the site to have pregnancy tests 
conducted the patient may complete a urine pregnancy test at home and report the result to the 
site. It is important that patients 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 patient so that the Site is informed of the 
pregnancy test results.
8.4.4
Appropriateness of safety measurements
The safety assessments were selected based on the safety profile of erenumab as reported in the 
development Investigator Brochure, package insert/prescribing information, and are standard 
for this patient population and drug class.
For SoC oral prophylactics, additional safety measurements, if applicable, should be 
implemented as per label. 
8.5
Additional assessments
The following additional assessments will be done. The timing and frequency of these 
assessments are outlined in Table 8-1:

Clinical Outcome Assessments/Patient Reported Outcomes
8.5.1
Clinical Outcome Assessments (COAs)
Clinical Outcomes Assessments (COAs) will be collected by subjects using an electronic diary 
(eDiary)/site tablet at various frequencies. The eDiary will collect the following daily, at home:

Date and time of start of headache (i.e., migraine or non-migraine headache)

Date and time of end of headache

Worst pain severity per headache

Pain features (e.g., one-sided, throbbing, worsens with exercise/physical activity)


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
Symptoms (e.g., aura, nausea, vomiting, photophobia, phonophobia)

Use of acute headache medications (medication name from pre-entered list, date of 
dosing, dosing and frequency)
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 headache 
(initial onset, continuation, or recurrence of the headache). A qualified headache is defined 
as the following: 

a qualified migraine headache (including an aura-only event that is treated with acute 
migraine-specific medication), or

a qualified non-migraine headache, which is a headache that lasts ≥30 minutes and is 
not qualified as a migraine headache, or

a headache of any duration for which acute headache treatment is administered.

Migraine Day - See Section 8.3.1 for details.
The eDiary will also collect the following patient-reported outcomes (PROs) and questionnaires:

Patients' Global Impression of Change (PGIC)
The site study staff will train the patient on proper use of the eDiary (e.g., turning on/off, 
navigation, data transmission, helpdesk, etc.) and completing the questions. The patient will be 
instructed to interact with the eDiary daily during the Baseline Period and Open-Label 
Treatment Period and to bring the eDiary to every study visit. At Day 1/Treatment, the 
investigator will use the patient's eDiary to review all data entered during the Baseline Period 
and confirm the relevant inclusion/exclusion criteria. The eDiary manual should be used to 
locate additional details.


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8.5.1.7
Patients' Global Impression of Change
The Patients' Global Impression of Change (PGIC) is a global assessment by the subject of the 
change in clinical status since the start of treatment. The PGIC is assessed periodically through 
the treatment period and at the end of the treatment period. The PGIC ratings are as follows:
1 = No change (or condition is worse)
2 = Almost the same, hardly any change at all
3 = A little better, but no noticeable change
4 = Somewhat better, but the change has not made any real difference
5 = Moderately better, and a slight noticeable change
6 = Better, and a definite improvement that has made a real and worthwhile difference
7 = A great deal better, and a considerable difference that has made all the difference


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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 treatment 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, he/she believes that 
continuation would negatively impact the subject's well-being.
Study treatment must be discontinued under the following circumstances: 

Subject/guardian decision

Pregnancy

Use of prohibited treatment as per recommendations in the prohibited treatment section


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
Any situation in which study participation might result in a safety risk to the subject
In addition during the Extension Phase, study treatment should be discontinued under the 
following circumstances 

Patient is no longer clinically benefitting from treatment in the opinion of the investigator
If discontinuation of study treatment occurs, 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.
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see withdraw of informed consent section,). Where possible, they should return 
for the assessments indicated in the assessment schedule. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be made 
to contact the subject/pre-designated contact as specified in the lost to follow-up section. This 
contact should preferably be done according to the study visit schedule.
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at site visits or via telephone/email contact:

new / concomitant treatments

adverse events/Serious Adverse Events
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment.
NOTE: Subjects that wish to enter the Extension Phase and receive PTA access to erenumab 
need to remain in the trial and complete all study visits through Week 52 as described in Table 
8-1. The investigator would then assess eligibility of the patients as described in Section 3.0.
9.1.2
Discontinuation of study
For patients that will discontinue from the study they need to complete the Early Exit Visit /
Week 52 visit at the time of study discontinuation.
9.1.2.1
Replacement policy
Subjects will not be replaced on study.
9.1.3
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


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
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. 
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. 
For US: All biological samples not yet analyzed at the time of withdrawal may still be used for 
further testing/analysis in accordance with the terms of this protocol and of the informed consent 
form. 
For EU: 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. 
9.1.4
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 and until the end of the study.
9.1.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the patient welfare and safety. Should early termination be 
necessary, patients must be seen as soon as possible (provide instruction for contacting the 
patient, when the patient should stop taking drug, when the patient should come for a final visit) 
and treated as a prematurely withdrawn patient. 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 patient’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.


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9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes their Study Completion visit, and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the date 
of that decision. A subject will be considered to have completed the Core Phase when the 
subject has completed the Week 52 Visit. A subject will be considered to have completed the 
Extension Phase when the subject completes the Week 104 Visit.
After study completion, post-trial access to erenumab will be offered to the study participants 
as needed.
10
Safety monitoring and reporting
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. Adverse event collection will begin at Treatment/Day 1 
(treatment emergent adverse events). Any event prior to Treatment/Day 1 should be captured 
in Medical History.
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. The severity grade. 

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
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

Dose Reduced/increased

Drug interrupted/withdrawn
6. its outcome 
a. not recovered/not resolved;
b. recovered/resolved;
c. recovered/resolved with sequelae;
d. fatal; or unknown.
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. Adverse event monitoring should be continued for at least 30 days 
following the last dose of study treatment.
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 
prescribing information/package insert/CDS.
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.


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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).

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 


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within 24 hours of learning of its occurrence. 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.
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 CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis/sponsor 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.
Any SAEs experienced after the 30 day period after the last study visit should only be reported 
to Novartis Safety if the investigator suspects a causal relationship to study treatment.
10.1.4
Pregnancy reporting
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 Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment and 
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 (EMA definition). 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 DAR (dose administration record) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to 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.


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Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dose 
Administration (DAR) 
eCRF (Yes/No)
Document in AE 
eCRF
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 
Please refer to Section 16.2 for complete definitions of liver laboratory triggers and liver events.
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 (ALT, AST, TBL, 
PT/INR, ALP and G-GT) 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 reported, any 
local liver chemistry tests previously conducted that are associated with this event should have 
results reported on the unplanned local laboratory CRF.

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 investigation of the liver event -

These investigations can include based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 


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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.
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 will be administered at Screening.
A validated version of the C-SSRS will be used to capture self-reported C-SSRS data via an 
interactive voice response telephone system (eC-SSRS). The eC-SSRS uses a detailed branched 
logic algorithm to perform the C-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 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.
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 (eCRF). The eCRFs 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 EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff.
The investigator/designee is responsible for assuring that the data entered into eCRF 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. All data should 
be recorded, handled and stored in a way that allows its accurate reporting, interpretation and 
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11.2
Database management and quality control
Novartis personnel (or designated 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.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis. ECG readings will be processed centrally and the results will be sent electronically to 
Novartis. Diary data will be entered into an electronic diary by the subject. The system will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis.
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 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 
complete and accurate, it will be locked 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 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 site medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 


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assessments. All information on CRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed.
12
Data analysis and statistical methods
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
The core phase and extension phase data will be analyzed separately.
12.1
Analysis sets
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been assigned 
by randomization. According to the intent to treat principle, subjects will be analyzed according 
to the treatment and stratum they have been assigned to during the randomization procedure.
The Safety Set includes all subjects who received at least one dose of study treatment. Subjects 
will be analyzed according to the study treatment received, where treatment received is defined 
as the randomized/assigned treatment if the patient took at least one dose of that treatment or 
the first treatment received if the randomized/assigned treatment was never received. Open label 
extension phase analysis set will include subjects who consented to enter Extension Phase and 
who have taken at least one dose of erenumab in Extension Phase.
12.2
Subject demographics and other baseline characteristics
Demographic variables and other baseline characteristics including previous migraine 
treatments will be summarized for FAS. Descriptive statistics (mean, median, standard 
deviation, minimum, and maximum) will be presented for continuous variables for each 
treatment group and for all participants (total). The number and percentage of participants in 
each category will be presented for categorical variables for each treatment group and all 
participants (total). In addition, all relevant medical history will be summarized following the 
same strategy.
12.3
Treatments
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented.
A data listing and a summary of the investigational drug (erenumab or active comparator) 
administered will be provided. Unless otherwise specified, patients assigned to 70 mg or 140


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mg erenumab dose will be analyzed together under one treatment arm erenumab. The analysis 
by dose will be detailed in SAP as needed. 
Concomitant medications and significant non-drug therapies 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.
A data listing and summary of rescue medications will be provided by treatment group.
12.4
Analysis of the primary endpoint(s)
The primary aim of the study is to evaluate the effect of erenumab vs SoC oral prophylactic
medications on the net benefit, a measure of sustained long-term benefit in these two treatment 
paradigms of migraine prophylactic agents.
12.4.1
Definition of primary endpoint(s)
The primary endpoint of the study is the proportion of subjects achieving net benefit, defined 
as completion of one year on the initial treatment AND achieving at least a 50% reduction from 
baseline in monthly migraine days in the last month (month 12).
12.4.2
Statistical model, hypothesis, and method of analysis
The primary analyses will compare the proportion of subjects in FAS who achieve a net benefit 
(defined in previous section) between erenumab vs SoC oral prophylactic medications.
To be tested is the null hypothesis that net benefit odds ratio = 1, versus the alternative 
hypothesis: net benefit odds ratio ≠ 1.
A Cochran-Mantel-Haenszel (CMH) test stratified by number of previous treatment failures (1 
vs. 2) will be used under a 2-sided significance level of 0.05 to evaluate the association between 
the net benefit rate and the treatment. The p-value of the test, and the estimated odds ratio 
between erenumab and active comparator, as well as its 95% confidence interval, will also be 
reported.
The details on primary and supplementary estimand will be provided in estimand charter or 
statistical analysis plan (SAP).
12.4.3
Handling of missing values/censoring/discontinuations
Subjects with missing monthly migraine day data at month 12 of treatment, and subjects that 
discontinue initial treatment prior to month 12 will be imputed as non-responders (not achieving 
a net benefit).
12.4.4
Sensitivity and Supportive analyses
The sensitivity and supportive analysis will be detailed in SAP.


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12.5
Analysis of secondary endpoints
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)

Proportion of subjects completing the treatment period at month 12 on the initially 
assigned treatment
This variable will analyzed same as that of the primary endpoint.

Global satisfaction as measured by PGI at month 12 for subjects completing 
treatment period on initially assigned treatment
Patient will be considered as responder if PGI-I score is 5, 6, or 7. Proportion of responders 
based on PGI-I score at month 12 will be analyzed same as that of the primary endpoint.

Cumulative average change from baseline on the monthly migraine days during the 
treatment period for subjects on the initially assigned treatment (month 1-12)
The average of monthly migraine days will be obtained cumulatively at each month across 12 
months (e.g. at month 2 the average will be based on data from month 1 and 2; at month 3 the 
average will be based on month 1 to 3 and so on). The cumulative average change from baseline 
on the monthly migraine days will be derived using difference between cumulative average at 
each month and baseline monthly migraine days. The change from baseline will be analyzed 
using a linear mixed effects model including treatment group, baseline value, stratification 
factor(s), scheduled visit, and the interaction of treatment group with scheduled visit.
12.5.2
Safety endpoints
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).
The on-treatment period lasts from the date of first administration of study treatment to 112 
days after the date of the last actual administration of any study treatment.
Adverse events
All information obtained on adverse events will be displayed by treatment group and subject.
The number (and percentage) of subjects with treatment-emergent adverse events (events 
started after the first dose of study medication) will be summarized in the following ways:

by treatment, primary system organ class and preferred term.

by treatment, primary system organ class, preferred term and maximum severity.

by treatment, Standardized MedDRA Query (SMQ) and preferred term


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Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation and adverse events 
leading to dose adjustment.
A subject with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class.
Vital signs
All vital signs data will be listed by treatment group, subject, and visit and if ranges are available, 
abnormalities will be flagged. Summary statistics will be provided by treatment.
12-lead ECG
All ECG data will be listed by treatment group, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, subject, and visit and if normal ranges are 
available abnormalities will be flagged. Summary statistics will be provided by treatment. Shift 
tables using the low/normal/high/ (low and high) classification will be used to compare baseline 
to the worst on-treatment value.
 
12.5.3
Pharmacokinetics
Not applicable.
12.5.4
DNA
Not applicable.
12.5.5
Biomarkers
Not applicable.
12.5.6
PK/PD relationships
Not applicable.


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12.7
Interim analyses
Not Applicable.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
The sample size calculation is based on the primary variable, rate of net benefit. The details of 
hypothesis testing are described in Section 12.4.2.
A 2-sided test with significance level 0.05, and a 2:1 randomization ratio are considered. A 
sample size of 591 (394 erenumab arm; 197 control arm) is required to achieve 90% power to 
reject the odds ratio of 1 set by the null hypothesis when the odds ratio is actually 2, and success 
rate in control arm is 0.18.
An odds ratio of 2 and control rate of 0.18 is based on more conservative assumptions for rate 
of net benefit than observed previously (for erenumab in studies NCT02456740, NCT01952574, 
and oral prophylactics in Hepp et al 2017, Shei et al 2015), resulting in a rate difference of 12%. 
Sample size calculations were done using PASS 11 and Cochran-Mantel-Haenszel test.
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.
In the US, Amgen will be the sponsor and all responsibilities for the conduct of this clinical 
study will be transferred to Novartis. In all other countries, Novartis will be the sponsor and 
maintain all responsibilities for the conduct of the clinical study.
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 


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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.
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) 
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.) .
An initial study report will be prepared and finalized for all data from the Core Phase. A second 
and study report will be prepared for the Extension Phase after all patients have completed their 
respective last visit (LPLV) of the Extension Phase.
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 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.


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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.
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
(2017) Global, regional, and national incidence, prevalence, and years lived with disability for 
328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global 
Burden of Disease Study 2016. Lancet p. 1211-1259.
Ashina M, Dodick D, Goadsby PJ, et al (2017) Erenumab (AMG 334) in episodic migraine: 
Interim analysis of an ongoing open-label study. Neurology p. 1237-1243.
Ashina M, Tepper S, Brandes JL, et al (2017) Efficacy of erenumab in chronic migraine 
patients with prior prophylactic treatment failure: Subgroup analysis of the Phase 2, 
randomised, double-blind, placebo-controlled study. Cephalalgia. 2017;37:326-328. Poster 
PO-01-180 presented at IHS 2017. 
 
 
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 p. 644-
55.
Brandes JL, Diener H, Dolezil D, et al (2017) Chronic Migraine Treatment with Erenumab: 
Responder Rates. Headache. 2017; 57(S3): 113-226. Poster PS33 presented at AHS 2017.
 
 
Data on File, Amgen; Integrated Summary of Safety 5.3.5.3 AMG334
Dodick DW, Ashina M, Brandes JL, et al (2018) ARISE: A Phase 3 randomized trial of 
erenumab for episodic migraine. Cephalalgia p. 1026-1037.
Durham PL (2006) Calcitonin gene-related peptide (CGRP) and migraine. Headache p. S3-8.
Goadsby PJ, Paemeleire K, Broessner G, et al (2017) Efficacy of erenumab in subjects with 
episodic migraine with prior preventive treatment failure(s). Cephalalgia. 2017;37(1S):1-24. 
Oral abstract OC-MC-002 presented at IHS 2017. 
Goadsby PJ, Reuter U, Hallström Y, et al (2017) A Controlled Trial of Erenumab for Episodic 
Migraine. N. Engl. J. Med. p. 2123-2132.
Gooriah R, Nimeri R, Ahmed F (2015) Evidence-Based Treatments for Adults with Migraine. 
Pain Res Treat p. 629382.
Hepp Z, Dodick DW, Varon SF, et al (2017) Persistence and switching patterns of oral 
migraine prophylactic medications among patients with chronic migraine: A retrospective 
claims analysis. Cephalalgia p. 470-485.


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Hepp Z, Rosen NL, Gillard PG, et al (2016) Comparative effectiveness of 
onabotulinumtoxinA versus oral migraine prophylactic medications on headache-related 
resource utilization in the management of chronic migraine: Retrospective analysis of a US-
based insurance claims database. Cephalalgia p. 862-74.
Reuter U, Goadsby P, Lanteri-Minet M (2018) Efficacy and Safety of erenumab in episodic 
migraine patients with 2-4 prior preventive treatment failures: Results from the Phase 3b 
LIBERTY Study. Poster 009 presented at AAN 2018..
Reuter U, Goadsby P, Lanteri-Minet M, et al (2018) Efficacy and safety of erenumab in 
episodic migraine patients with 2–4 prior preventive treatment failures: Results from the 
Phase 3b LIBERTY study. Presented at AAN 2018.
Shei A, Woolley JM, Desai PR, et al (2015) Description of prophylactic drug utilization 
patterns in migraine patients. Value in Health p. A285.
Sun H, Dodick DW, Silberstein S, et al (2016) Safety and efficacy of AMG 334 for 
prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 
trial. Lancet Neurol p. 382-90.
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 p. 425-434.
Tepper SJ, Diener H, Ashina M, et al (2017) Efficacy of erenumab for the treatment of 
patients with chronic migraine in presence of medication overuse. Headache. 
2017;57(S3):113-226. Poster PS32 presented at AHS 2017. 
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 p. 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. p. 11480-4.
 
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. p. 
238-45.


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16
Appendices
16.1
Appendix 1: Clinically notable laboratory values and vital signs
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


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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 < TBL £ 2 x ULN
LIVER EVENTS

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 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 TBL > 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
TBL: total bilirubin; ULN: upper limit of normal
Note: INR (International Normalized Ratio) measurements are not collected as part of routine lab 
assessments.  If a patient has a liver event please consider to collect an INR to aid in assessing 
severity.


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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

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
ALT or AST
> 8 × ULN

Discontinue the study treatment 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 × ULN and 
INR > 1.5

Discontinue the study treatment 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
> 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

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT 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, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 to ≤ 5 × ULN 
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 
weeks
ALP (isolated)


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Criteria
Actions required
Follow-up monitoring
> 2 × ULN (in the 
absence of known 
bone pathology)

Repeat LFT within 48 hours

If elevation persists, establish 
causality

Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
TBL (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

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin)
> 1.5 to ≤ 2 × ULN 
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
Jaundice

Discontinue the study treatment 
immediately

Hospitalize the patient

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until 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

Complete liver CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 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.

SAP_001.pdf: 
Clinical Development
AMG334/Erenumab/Aimovig®
AMG334A2401 / NCT03927144
A 12-month prospective, randomized, interventional, 
global, multi-center, active-controlled study comparing 
sustained benefit of two treatment paradigms (erenumab 
qm vs. oral prophylactics) in adult episodic migraine 
patients
Statistical Analysis Plan (SAP) Amendment
Author:
Trial Statistician, 
Document type:
SAP Documentation
Document status:
Final Amendment 2
Release date:
25-Oct-2021
Number of pages:
51
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis  


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SAP Amendment 2
CAMG334A2401
Document History – Changes compared to previous final version of SAP
Date
Time point
Reason for update
Outcome for update
Section and 
title impacted 
(Current)
07-
May-
2019
Prior to DB 
lock
Creation of final 
version
N/A - First version
NA
01-
Oct-
2021
Amendment 
1
COVID-19 impact 
sensitivity 
analysis
Added analysis to study 
impact of randomization, 
study/treatment 
discontinuations, 
dose 
interruptions
Section 2.3.1
Added analysis to study 
impact 
on 
Protocol 
deviations
Section 2.3.2
Added analysis to study 
impact on demographics
Section 2.3.3
Added analysis to study
impact on primary endpoint
Section 2.5.4
Visit 
mapping 
details
Updated details based on 
analysis visit instead of dose 
dates
Section 2.1.1.6
Protocol 
amendment PTA 
phase
Added details about PTA 
phase 
and 
endpoints 
collected during PTA
Section 1.1, 1.2
Updated text to 
clarify 
randomized 
treatment
Updated 
text 
from 
“randomized treatment” to 
“ 
initially 
asssigned 
treatment”
Throughout the 
SAP
Sensitivity 
analyses
with 
corrected 
stratification 
factor 
Added analysis by 
correcting strata for mis-
stratified subjects
Section 2.5.5
Analysis 
for 
COVID-19 
and 
Hypertension AEs 
based on SMQ 
and 
for 
Summary 
of 
treatment 
emergent 
AEs 
will 
be 
provided for COVID-19 and 
hypertension data by SMQ 
levels.
Section 2.8.1


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SAP Amendment 2
CAMG334A2401
Date
Time point
Reason for update
Outcome for update
Section and 
title impacted 
(Current)
constipation based 
on CMQ
Summary 
of 
treatment 
emergent 
AEs 
will 
be 
provided for constipation by 
CMQ and corresponding 
preferred term. 
Summary 
of 
exposure 
adjusted subject incidence 
rates for treatment emergent 
AEs and SAEs will be 
provided by primary system 
organ class and preferred 
terms.
Section 2.8.1
Definitions 
for 
study phases
Details added for study 
phases to provide more 
clarity on core phase and 
safety follow up phase data
Section 2.1.1.6
25-
Oct-
2021
SAP 
amendment 
2
Section 2.5.6
Sensitivity
analysis 
for 
primary endpoint added for 
subjects taking prohibited / 
non-approved medications 
or polytherapy on initially 
assigned treatment
Section 2.5.6


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SAP Amendment 2
CAMG334A2401
Table of contents
Table of contents .................................................................................................................4
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................7
1
Introduction .........................................................................................................................8
1.1
Study design.............................................................................................................8
1.2
Study objectives and endpoints .............................................................................10
2
Statistical methods.............................................................................................................12
2.1
Data analysis general information .........................................................................12
2.1.1
General definitions................................................................................13
2.2
Analysis sets ..........................................................................................................21
2.2.1
Subgroup of interest ..............................................................................21
2.3
Subject disposition, demographics and other baseline characteristics. .................21
2.3.1
Subject disposition ................................................................................21
2.3.2
Protocol deviations................................................................................22
2.3.3
Demographic variables and other baseline characteristics....................23
2.3.4
Medical history......................................................................................24
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................24
2.4.1
Study treatment / compliance................................................................24
2.4.2
Prior, concomitant and post therapies...................................................25
2.4.3
Prohibited treatment..............................................................................25
2.5
Analysis of the primary objective..........................................................................25
2.5.1
Primary endpoint...................................................................................25
2.5.2
Statistical hypothesis, model, and method of analysis..........................26
2.5.3
Handling of missing values/censoring/discontinuations.......................26
2.5.4
Sensitivity / Supplementary analyses....................................................26
2.5.5
Sensitivity analyses with corrected stratification factor........................28
2.5.6
Sensitivity analyses excluding subjects taking non-approved 
medications or prohibited medications or polytherapy.........................28
2.6
Analysis of the key secondary objective ...............................................................28
2.7
Analysis of secondary efficacy objective(s)..........................................................29
2.7.1
Secondary endpoints .............................................................................29
2.7.2
Statistical hypothesis, model, and method of analysis..........................29
2.7.3
Handling of missing values/censoring/discontinuations.......................30
2.7.4
Sensitivity / Supplementary analyses....................................................30
2.8
Safety analyses.......................................................................................................32


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SAP Amendment 2
CAMG334A2401
2.8.1
Adverse events (AEs)............................................................................33
2.8.2
Deaths....................................................................................................34
2.8.3
Laboratory data .....................................................................................34
2.8.4
Other safety data ...................................................................................35
2.9
Pharmacokinetic endpoints....................................................................................36
2.10
PD and PK/PD analyses.........................................................................................36
2.11
Patient-reported outcomes (PRO)..........................................................................36
2.12
Biomarkers.............................................................................................................36
36
2.14
Interim analysis......................................................................................................36
3
Sample size calculation .....................................................................................................36
4
Change to protocol specified analyses ..............................................................................37
5
Appendix ...........................................................................................................................37
5.1
Imputation rules.....................................................................................................37
5.1.1
AE / Concomitant medication date imputation.....................................37
5.1.2
Prior therapies date imputation .............................................................38
5.1.3
Post therapies date imputation ..............................................................38
5.1.4
Other imputations..................................................................................38
5.2
AEs coding/grading ...............................................................................................42
5.3
Laboratory parameters derivations ........................................................................43
5.4
Rule of exclusion criteria of analysis sets..............................................................43
5.5
Statistical models...................................................................................................43
5.5.1
Primary analysis....................................................................................43
5.5.2
Secondary analysis................................................................................44
5.6
Important derivations.............................................................................................44
5.7
MMD derivation, exceptions.................................................................................48
5.7.1
Assigning Headache and Migraine Days to Events Spanning 
Midnight................................................................................................48
5.7.2
Spanning Midnight Rules for Multi-Day Events Longer Than Two 
Days.......................................................................................................49
5.8
Patient Global Impression Change (PGIC)............................................................50
5.9
The Columbia-Suicide Severity Rating Scale (C-SSRS) ......................................50
6
Reference...........................................................................................................................51


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SAP Amendment 2
CAMG334A2401
List of tables
Table 1-1
Objectives and related endpoints ..........................................................10
Table 2-1
Study visit windows ..............................................................................14
Table 2-2
Study intervals for safety analysis.........................................................15
Table 2-3
Study intervals for efficacy endpoints – Erenumab and Oral 
prophylactics .........................................................................................19
Table 2-4
Summary of primary endpoint and analysis methods...........................27
Table 2-5
Summary of secondary efficacy endpoints and analysis methods........31
Table 2-6
Clinically Notable Laboratory Values ..................................................34
Table 2-7
ECG Abnormality Ranges.....................................................................35
Table 2-8
Vital Signs Notable Criteria..................................................................35
Table 5-1
Imputation of AE/Concomitant dates....................................................37
Table 5-2
Rules for handling missing and incomplete eDiary data ......................39
Table 5-3
Deviation Codes Description ................................................................43
Table 5-4
Patient classification..............................................................................43


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SAP Amendment 2
CAMG334A2401
List of abbreviations
AE
Adverse event
ATC
Anatomical Therapeutic Classification
CSR
Clinical Study report
eCRF
Electronic Case Report Form
EOS
End of Study
FAS
Full Analysis Set
IAT
Initially assigned treatment
IP
Investigational Product
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MMD
Monthly Migraine Days
NCI
National Cancer Institute
PD
Protocol Deviation
PK
Pharmacokinetics
PRO
Patient-reported Outcomes
PT
Preferred Term
PTA
Post Trial Access
qm
Monthly once
QoL
Quality of Life
SAP
Statistical Analysis Plan
SAF
Safety Set
SOC
System Organ Class
SoC
Standard of Care
TF
Treatment Failure
TFLs
Tables, Figures, Listings
WHO
World Health Organization


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CAMG334A2401
1
Introduction
This statistical analysis plan (SAP) describes all planned analyses for the Clinical Study Report 
(CSR) of study AMG334A2401, a 12-month phase IV, prospective, randomized, interventional, 
global, multi-center, active-controlled study comparing sustained benefit of two treatment 
paradigms (erenumab qm vs. oral prophylactics) in adult episodic migraine patients.
The content of this SAP is based on protocol AMG334A2401 version 02. This SAP includes 
analysis for core phase data. For extension phase, separate SAP will be developed. 
Data will be analyzed by Novartis according to the data analysis section 12 of the study protocol. 
Important information is given in the following sections and details will be provided, as 
applicable, in Appendix 16.1.9 of the CSR.
1.1
Study design
This study uses 2-treatment arm (AMG334 versus standard of care (SoC) oral prophylactic 
treatment), parallel group randomized (2:1 [AMG334 (70 mg or 140 mg) : SoC oral 
prophylactic]), open-label in adult patients with episodic migraine who have previously failed 
1 or 2 prophylactic migraine treatments. The following periods are included in the study  design, 
with study visits at 4-week intervals after completion of screening: 

Screening period (0-2 weeks): required for all subjects to assess intial eligibility  and to 
obtain informed consent

Baseline period (4 weeks) – All subjects successfully completing the screening period 
will be invited to participate. Eligibility for randomization will be assessed based on 
migraine freqeuncy and diary compiance during this period. Randomization will be 
stratified by prior prophylactic migraine medication treatment failure (due to 
insufficient efficacy or poor tolerability) reported during screening / baseline period: 1 
treatment failure (TF1) vs 2 treatment failures (TF2). A 30% cap of randomized subjects 
to the TF2 strata will be implemented. The stratification and 30% cap will be 
implemented within IRT. 

Open-Label Randomized Treatment Period (52 weeks): All subjects successfully 
completing the Baseline Period will be invited to participate. Eligible subjects will be 
randomized 2:1 to one of two treatment arms [AMG334 s.c. q.m. versus SoC oral 
prophylactic (active comparator)]. Only monotherapy will be allowed in both arms and 
no concomitant use of other prophylactics for migraine specifically should be used. At 
the end of this period, the final assessment to address the effect of AMG334 compared 
to oral prophylactic cycling on the net benefit and related objectives will occur. The last 
dose for AMG334 will occur at Week 48 (monthly dose) and the last dose for SoC will 
occur at Week 52.
•
Switching: Treatment (failure) status and decision on whether or not to switch 
to a new treatment will be checked at every visit and will be based on 
investigator and subject discretion (based on efficacy/tolerability/satisfaction 
but not based on prespecified cutoffs for certain parameters). In both arms, 
switching will be allowed within approved prophylactics in the respective 
country for prophylaxis of migraine. Subject randomized to AMG334 arm can 


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switch to oral prophylactics and subject randomized to oral prophylactics arm 
can switch to only other oral prophylactics and not to AMG334.

Follow-Up Period (16 weeks) as per protocol version 0 and 1– A follow-up visit 16 weeks 
after the last dose of treatment (AMG334 or SoC oral prophylactic) will be required as part 
of routine safety monitoring. As per protocol amendment 2, subject may chose to enter 
extension phase or discontinue study. This means follow up data will not be available for 
all subjects.   
Extension Phase (as per protocol amendment 2)

Post-Trial Access Open-Label Treatment Period (52 weeks) - Patients completing visits 
through week 52 of the Core Phase will be eligible to participate. Patient eligibility will be 
determined by the investigators opinion as follows: 1) patients treated with erenumab must 
have benefited from erenumab treatment and 2) patients on Standard of Care (SoC) oral 
prophylactic must be in need of a treatment switch. PTA to erenumab will be provided for 
up to 52 weeks (based on continued benefit of erenumab treatment) in all eligible patients; 
this will ensure erenumab access until country-level launch and subsequent reimbursement 
decision in all countries. Should a treatment gap exist between the Core and Extension Phase 
due to a delay of HA/EC approvals or other administrative/logistical reasons, the subject 
may enter the Extension Phase at a later time. During this treatment gap, the patient would 
remain in the main study and is allowed to be treated with any medication as deemed 
appropriate by the investigator to manage the patient’s migraines. Upon HA and EC 
approval of the Extension Phase, the patient will then be administered study drug 
corresponding to the Week 52 dose and will continue dosing every 4 weeks as per protocol. 
Patients will be required to follow all protocol requirements for treatments allowed and for 
prohibited medications (Protocol Section 6.2.2)
End of Trial will occur when the last subject completes their last visit (LPLV) of the study. The 
primary analysis will occur when the last patient completes the Core Phase, prior to the start of 
the Extension Phase. The main study report will be prepared and finalized at this time for all 
data from the Core Phase. An additional study report will be prepared for the Extension Phase 
after all patients have completed their respective last visit (LPLV) of the Extension Phase and 
will report data for the Extension Phase.
Approximately 591 subjects will be enrolled into the trial. 
There is no planned interim analysis for this study. 
Note: 

Treatment discontinuation does not imply study discontinuation. Every effort should be 
attempted to ensure subjects complete the study visits event if treatment is discontinued. 
After study completion, post-trial access to AMG334 will be offered to the study 
participants as needed. 

Some eligibility criteria will be checked at screening visit and some at baseline. 

Treatment disposition form will be filled for the last drug taken by the subject regardless of 
switching and not only for initially assigned treatment. 


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
There can be gap between end of first treatment and start of switched treatment.
1.2
Study objectives and endpoints
In the table below and throughout this SAP Month 6 is equivalent to Week 24, and Month 12 
is equivalent to Week 52. Also, all analysis is planned for initially assigned treatment where 
initially assigned treatment is refers to randomized treatment.
Table 1-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To demonstrate the superiority of subcutaenous 
erenumab compared to oral prophylactic(s) on 
sustained benefit defined as % subjects completing 
one-year on the initially assigned treatment and 
achieving at least a 50% reduction from baseline in 
monthly migraine days at month 12.

Proportion of subjects who complete 
initially assigned treatment and 
achieve at least 50% reduction from 
baseline in monthly migraine days at 
Month 12
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To evaluate the effect of erenumab compared to 
oral prophylactic(s) on overall subject retention 
defined as % subjects completing study on the 
initially assigned treatment

Proportion of subjects completing the 
study at Month 12 on the initially 
assigned treatment

To evaluate the effect of erenumab compared to 
oral prophylactic(s)  on the change from baseline in 
monthly migraine days during the treatment period

Cumulative average change from 
baseline on the monthly migraine 
days during the treatment period for 
the subjects on initially assigned 
treatment (Months 1-12)

To evaluate the effect of erenumab compared to 
oral prophylactic(s) on the subject's assessment of 
the change in clinical status since the start of 
treatment as measured by the Patients' Global 
Impression of Change (PGIC) Scale

Proportion of responders (PGI-I 
score >= 5) as measured by PGIC 
at month 12 for subjects completing 
the treatment period at Month 12 on
initially assigned  treatment


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2
Statistical methods
2.1
Data analysis general information
The final analysis will be performed by Novartis or a designated CRO. The current version of
SAS or R software or later available versions will be used to perform all data analyses and to 
generate tables, figures and listings.
Data included in the analysis
The analysis cut-off date for the primary analysis of study data will be established after last 
subject completes or discontinues core phase that is when all subjects either complete week 52 
on core phase or complete FU or discontinue early prior to week 52. All statistical analyses will
be performed using all data collected in the database up to the data cutoff date. All data with an 
assessment date or event start date (e.g. vital sign assessment date or start date of an adverse
event) prior to or on the cut-off date will be included in the analysis. Any data collected beyond
the cut-off date will not be included in the analysis and will not be used for any derivations.
All events with start date before or on the cut-off date and end date after the cut-off date will be 
reported as ‘continuing at the cut-off date’. The same rule will be applied to events starting 
before or on the cut-off date and not having documented end date. This approach applies, in 
particular, to adverse event and concomitant medication reports. For these events, the end date 
will not be imputed and therefore will not appear in the listings.
General analysis conventions
Pooling of center: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small size of centers, no center effect will be assessed. 


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Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables
by treatment group; a missing category will be included as applicable. Percentages will be
calculated using the number of subjects in the relevant population or subgroup as the
denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (i.e. mean, standard deviation, median, minimum, and maximum) by treatment group.
2.1.1 General definitions
2.1.1.1
Study treatment
Subjects will be randomized to one of the following treatment groups:

Erenumab labelled as AMG334 (70mg or 140mg): pre-filled 1mL syringes (PFS) containing 
70mg/1mL of AMG334. Note: if and when 140mg/1mL PFS become available, the dose 
may be administered by a single injection.

Comparator: locally approved oral prophylactic migraine medication.
For this trial, study treatment refers to AMG334 or oral prophylactics as assigned to a subject
at randomization. 
Unless otherwise specified, analysis will be presented by initially assigned treatment i.e. 
randomized treatment. 
2.1.1.2
Study dates

Date of first administration study treatment
The date of first administration of study treatment is derived as the date on which a subject is 
administered the first nonzero dose of study treatment following randomization, which may be 
the same day or after the randomization date. For subjects who are randomized but not dosed 
with study treatment after randomization, date of first administration of study treatment is 
considered missing.

Date of last administration of study treatment 
The date of last administration of study treatment is defined as the last date when a nonzero 
dose of study treatment was administered.
2.1.1.3
Study day
Study Day 1 is defined as the first dose date of study treatment during initially assigned 
treatment period. For subjects who are randomized but not dosed after randomization, the 
Study Day 1 is defined as the date of randomization. Also, for subjects who are randomized 
but not dosed during initially assigned treatment period and received dose in switched period, 
the Study Day 1 is defined as the date of randomization.  
Study Day is defined as the number of days from Study Day 1. 

Before Study Day 1: 
Study Day = (Date of Interest – Date of Study Day 1) 


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
On or after Study Day 1: 
Study Day = (Date of Interest – Date of Study Day 1) + 1 
Therefore the day prior to Study Day 1 is -1.
The study day will be displayed in the data listings.
2.1.1.4
Baseline
The baseline period for efficacy analysis is defined as the period between week -4 visit (when 
eDiary device is dispensed to the subject for daily data capture) and the day prior to study day 
1 (study day 1 is not included).
A baseline for subject reported outcome (PRO) and safety (including Columbia-Suicide 
Severity Rating Scale (C-SSRS)) values refers to the last evaluable measurement prior to the 
first administration of the study drug, irrespective of re-screening. In this case, baseline values 
will be the value obtained on the day of the randomization (Day 1, Visit 101), or on an earlier 
visit (scheduled  or unscheduled) which is the closest to Visit 101, if Visit 101 is missing or the 
assessment was not done at baseline.
Baseline weight and height are taken from vital signs screening visit.
eCSSRS is collected at screening or before randomisation and patients should complete 
“lifetime assessment eCSSRS questionnaire” at screening and if need arises during the course 
of the trial complete “since last contact eCSSRS questionnaire”. Hence, we do not have 
“Evaluation timeframe” (TMFRM) variable collected and baseline eCSSRS will correspond to 
the last evaluable measurement prior to the first administration of the study drug, irrespective 
of re-screening. For this analysis, each subject can only be counted once for each event. 
However, a subject can be counted in several different events.
2.1.1.5
Post-baseline measurement
Post baseline measurements are defined as those assessments after the start of study treatment.  
2.1.1.6
Visit remapping and assessment windows
Since the actual visit for a subject may not exactly coincide with their targeted visit date, the 
actual visit date is mapped to a study visit. Also note that month 6 is equivalent to week 24, 
and month 12 is equivalent to week 52.
The next study day window will be utilized to define study visit for lab, vital signs, C-SSRS 
and 
 PROs collected during office visits 
 before dose is administered.
Table 2-1
Study visit windows
Study visit
Target Day 
Study Day 
Baseline
Please refer to Section 2.1.1.4.
Week 4
28
16-43


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Week 8
56
44-71
Week 12
84
72-99
Week 16
112
100-127
Week 20
140
128-155
Week 24
168
156-183
Week 28
196
184-198
Week 32
224
199-239
Week 36
252
240-267
Week 40
280
268-295
Week 44
308
296-323
Week 48
336
324-351
Week 52
364
352-379
Safety follow up
Safety follow-up should be excluded from the analysis
visit windows described above and summarized under
‘safety follow-up’ for safety analyses only. Refer to
Table 2.2.
Note: xx: target day then study day window: (xx-12 days) up to (xx+ 15 days)
For efficacy parameters: If more than one visit (including the unscheduled visits) fall within
the same defined window with non-missing measurements, scheduled visit will be used 
regardless of the distance from the target day. Unscheduled visit will only be used when there 
is no measurement from scheduled visit in the defined window. The closest visit to the target 
day among the same type of visit (i.e., closest of all scheduled visits or if no scheduled visits, 
closest of all unscheduled) will be considered for analysis. If two assessment dates are 
equidistant from the target date, the latter assessment will be considered for analysis. The 
exception is an assessment at early study withdrawal visits along with another assessment 
within a window. In such cases the early-withdrawal assessment will be used. 
For safety parameters: in case of competing assessments within a analysis window, the last 
one closest to the scheduled visit day will be used.
Table 2-2
Study intervals for safety analysis
Start 
time 
point
End time point


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Core 
phase 
Treatment 
start date
1. Subject completes 52 weeks on core phase treatment i.e. if 
trt disposition reason is “COMPLETED” on DS domain
a.
If subject does not enter PTA phase then use week 52 
visit date
b. If subject enters PTA phase then 
i.
Subject enters PTA on week 52 visit date then 
use a day prior to week 52 visit date
ii.
Subject enter PTA phase after week 52 then use 
week 52 visit date
2. Subject completes 52 weeks on core phase but discontinues 
treatment early i.e. core phase treatment disposition reason is 
not equal to “COMPLETED on DS domain
a.
If subject does not enter PTA phase 
i.
if week 52 visit date > treatment end date plus 
27/1 day then use treatment end date 
plus 27/1 day 
ii.
if week 52 visit date < = treatment end date plus 
27/1 day then use week 52 visit date 
b. If subject enters PTA phase 
i.
if week 52 visit date > treatment end date plus 
27/1 day then use treatment end date 
plus 27/1 day 
ii.
if week 52 visit date < = treatment end date plus 
27/1 day then use a day prior to first 
dose in PTA phase 
3. Subject discontinues treatment early and does not complete 
52 weeks on core phase i.e. core phase trt disposition reason 
is not equal to “COMPLETED on DS domain and Week 52 
visit date is not available in SV domain and study 
disposition reason is equal not to “COMPLETED” on DS 
domain
a.
If treatment disposition date > treatment end date 
plus 27/1 day then use treatment end date plus 27/1 
day
b. If treatment disposition date < = treatment end date 
plus 27/1 day then use treatment disposition date 
Safety 
follow 
up
Core 
phase end 
plus 1 day
a) If subject does not enter PTA phase then use study disposition 
date;
b) If subject enters PTA phase then use a day prior to first dose in 
PTA phase
PTA 
phase 
First 
erenumab 
injection 
1. If subject completes 52 weeks on PTA phase then use min 
(trt disposition or study disposition date )


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date in 
PTA 
phase
2. If subject discontinues prior to completing 52 weeks on 
treatment in PTA phase i.e. treatment disposition reason is 
not equal to “COMPLETED” on DS domain then 
a.
If treatment disposition date > treatment end date 
plus 27 day then use trt end date plus 27 day
b. If treatment disposition date < = treatment end date 
plus 27 day then use trt disposition date 
Start time 
point
End time point
Initially 
assigned 
treatment 
(IAT) 
period (core 
phase)
Treatment 
start date
1. Subject completes 52 weeks on IAT i.e. core phase 
treatment disposition reason is “COMPLETED” and 
week 52 visit date is non-missing in SV domain and 
date of switching is missing on DS domain
a.
If subject does not enter PTA phase then use 
week 52 visit date from SV domain 
b. If subject enters PTA phase then 
i.
Subject enters PTA on week 52 visit 
date then use a day prior to 
week 52 visit date
ii.
Subject enter PTA phase after week 52 
then use week 52 visit date
2. Subject completes 52 weeks on core phase but 
permanently discontinues IAT early i.e. trt 
disposition reason is not equal to “COMPLETED” 
on DS domain and week 52 visit date is non-missing 
in SV domain and date of switching is missing on 
DS domain
a.
If subject does not enter PTA phase 
i.
if week 52 visit date > treatment end 
date plus 27/1 day then use 
treatment end date plus 27/1 
day 
ii.
if week 52 visit date < = treatment end 
date plus 27/1 day then use 
week 52 visit date 
b. If subject enters PTA phase 
i.
if week 52 visit date > treatment end 
date plus 27/1 day then use treatment 
end date plus 27/1 day 


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ii.
if week 52 visit date < = treatment end 
date plus 27/1 day then use a day prior 
to first dose in PTA phase 
3. Subject does not complete 52 weeks on study and 
permanently discontinues IAT i.e. week 52 visit date 
is missing in SV domain and date of switching is 
missing on DS domain and core phase treatment 
disposition reason is not equal to “COMPLETED in 
DS domain then use min(trt disposition date, trt end 
date plus 27/1 day)
4. Subject switches IAT then use day prior to date of 
first switch on DS domain
Switched 
treatment 
period (core 
phase)
Date of 
first switch 
on DS 
domain 
1. Subject completes 52 weeks on switched treatment 
i.e. core phase treatment disposition reason is 
“COMPLETED” and week 52 visit date is non-
missing in SV domain 
a.
If subject does not enter PTA phase then use 
week 52 visit date from SV domain 
b. If subject enters PTA phase then 
i.
Subject enters PTA on week 52 visit 
date then use a day prior to week 52 
visit date
ii.
Subject enter PTA phase after week 52 
then use week 52 visit date
2. Subject completes 52 weeks on core phase but 
discontinues switched treatment early i.e. core phase 
trt disposition reason is not equal to “COMPLETED 
on DS domain
a.
If subject does not enter PTA phase 
i.
if week 52 visit date > treatment end 
date plus 27/1 day then use treatment 
end date plus 27/1 day 
ii.
if week 52 visit date < = treatment end 
date plus 27/1 day then use week 52 
visit date 
b. If subject enters PTA phase 
i.
if week 52 visit date > treatment end 
date plus 27/1 day then use treatment 
end date plus 27/1 day 
ii.
if week 52 visit date < = treatment end 
date plus 27/1 day then use a day prior 
to first dose in PTA phase 
3. Subject does not complete 52 weeks on switched 
treatment i.e. core phase trt disposition reason is not 


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equal to “COMPLETED” on DS domain and week 
52 visit date is missing in SV domain then use 
min(treatment disposition date, treatment end date 
plus 1 day) 
Note: DS: Disposition domain; SV:Visit domain; IAT: Initially assigned treatment
Monthly interval for efficacy endpoints (from ediary)
Monthly efficacy measurements will be calculated based on the subject’s starting dose and 
visit schedule defined below using eDiary data collected from beginning of the baseline 
phase (week -4 visit) up to week 52 visit if subjects do not have safety follow up visit. For 
subjects with safety follow up, consider data up to the safety follow-up visit. The algorithm 
remains the same for initially assigned treatment and switched treatment. ediary data will be 
collected during core phase only and will not be collected during extension phase.
Table 2-3
Study intervals for efficacy endpoints – Erenumab and Oral 
prophylactics
Study phase
Assessment 
Time point
Interval based on dose dates
Start date
End date
Baseline 
period
Baseline
From ediary device 
assignment date 
(or week -4 visit)
Day prior to study day 1
Treatment 
Period
Week 4
Study day 1

Week 4 visit date - 1

Study day 1 + 27 days if 
Week 4 visit is missed
Note: if day 1 dose is the last
dose subject received, the rest 
of monthly rates during 
treatment period will be
calculated based on
consecutive 28-day interval 
beginning 
Week 8

Week 4 visit date 

Week 4 analysis visit end 
date + 1 day if Week 4 
visit is missed

Week 8 visit date – 1

Week 4 analysis visit start 
date + 27 days if Week 8 
visit is missed
Week 12

Week 8 visit date 

Week 8 analysis visit end 
date + 1 day if Week 8
visit is missed

Week 12 visit date – 1

Week 12 analysis visit 
start date + 27 days if 
Week 12 visit is missed
Week 16

Week 12 visit date 

Week 16 visit date – 1


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
Week 12 analysis visit 
end date + 1 day if Week 
12 visit is missed

Week 16 analysis visit 
start date + 27 days if 
Week 16 visit is missed
Week 20

Week 16 visit date 

Week 16 analysis visit 
end date + 1 day if Week 
16 visit is missed

Week 20 visit date – 1

Week 20 analysis visit 
start date + 27 days if 
Week 20 visit is missed
Week 24

Week 20 visit date 

Week 20 analysis visit 
end date + 1 day if Week 
20 visit is missed

Week 24 visit date – 1

Week 24 analysis visit 
start date + 27 days if 
Week 24 visit is missed
Week 28

Week 24 visit date 

Week 24 analysis visit 
end date + 1 day if Week 
24 visit is missed

Week 28 visit date – 1

Week 28 analysis visit 
start date + 27 days if 
Week 28 visit is missed
Week 32

Week 28 visit date 

Week 28 analysis visit 
end date + 1 day if Week 
28 visit is missed

Week 32 visit date – 1

Week 32 analysis visit 
start date + 27 days if 
Week 32 visit is missed
Week 36

Week 32 visit date 

Week 32 analysis visit 
end date + 1 day if Week 
32 visit is missed

Week 36 visit date – 1

Week 36 analysis visit 
start date + 27 days if 
Week 36 visit is missed
Week 40

Week 36 visit date 

Week 36 analysis visit 
end date + 1 day if Week 
36 visit is missed

Week 40 visit date – 1

Week 40 analysis visit 
start date + 27 days if 
Week 40 visit is missed
Week 44

Week 40 visit date 

Week 40 analysis visit 
end date + 1 day if Week 
40 visit is missed

Week 44 visit date – 1

Week 44 analysis visit 
start date + 27 days if 
Week 44 visit is missed
Week 48

Week 44 visit date 

Week 44 analysis visit 
end date + 1 day if Week 
44 visit is missed

Week 48 visit date – 1

Week 48 analysis visit 
start date + 27 days if 
Week 48 visit is missed
Week 52

Week 48 visit date

Week 48 analysis visit 
end date + 1 day if Week 
48 visit is missed

MIN (Week 48 visit date 
+ 27, EoS) 
MIN (Week 52 analysis visit 
start date + 27 days if Week 
48 visit is missed , EoS) 
Where EoS date is the date of the end of study visit.


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2.2
Analysis sets
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been 
assigned by randomization. According to the intent to treat principle, subjects will be 
analyzed according to the treatment and stratum they have been assigned to during the 
randomization procedure. Tabulations of demographic and baseline characteristics, 
disposition, and important protocol deviations (PD) will utilize FAS.
The Safety Set (SAF) includes all subjects who received at least one dose of study treatment.
Subjects will be analyzed according to the study treatment received, where treatment received 
is defined as the randomized/assigned treatment if the subject took at least one dose of that
treatment or the first treatment received if the randomized/assigned treatment was never 
received.
Screen failures will not be included in any analysis sets. 
Please refer to appendix 5.4 for Rules of exclusion criteria of analysis sets.
 
 
2.3
Subject disposition, demographics and other baseline 
characteristics.
2.3.1 Subject disposition
Subject disposition will be summarized on FAS. The number and percentage (based on the 
number of subjects within each randomized treatment arm) of subjects who completed / 
discontinued the study will be displayed by initially assigned treatment and overall. The primary 
reason for premature study discontinuation will be displayed by initially assigned treatment and 
overall. The core phase completers are defined as subjects who either complete week 52 on 
study or complete safety follow up visit. 
Treatment completion will be summarized in the same manner as subject disposition. The 
number and proportion of subjects, who complete the study treatment or discontinue the study 
treatment prematurely along with the primary reason for study drug discontinuation will be 
presented.
Disposition and treatment completion data will also be presented in listings.
Screen Failures: The total number of subjects screened and the number of subjects screened, 
but not randomized (discontinued prior to screening or baseline phase completion) will be 
summarized, including the reason for screening failure. Data on screen failures will also be 
presented in listings. 
Analysis sets: The number of subjects within each of the analysis sets used in the study will be   
summarized.


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The impact of COVID-19 pandemic on study subjects with respect to randomization, study and 
treatment discontinuations, protocol deviations and dose interruptions will be assessed and 
summarized for pre- and during COVID-19 phases. The pandemic phase will be defined based 
on start date of pandemic. For Italy start date of pandemic will be used as 23Feb2020 and for 
rest of the world start date of pandemic will be used as 01March2020.
2.3.2 Protocol deviations
The number of subjects with PDs according to the applicable standard operating procedures 
(SOP-7035752 V4.0) will be presented. The results of the PDs will be grouped using the broad 
categories defined in the applicable SOP, which currently are:

Eligibility: Subject did not satisfy entry criteria

Withdrawal: Subject developed study/treatment withdrawal criteria during the study, but 
was not withdrawn

Study Drug: Subject received the wrong treatment or incorrect dose

Concomitant Medication: Subject took a prohibited concomitant medication

Other GCP deviation
A complete list of the PDs can be found in the Edit Check Specifications document in CREDI.
Subjects with PDs and PDs leading to data exclusion from analysis sets will be listed.
In addition to the pre-defined standard PD terms, Novartis has also defined 6 new protocol
deviations and the corresponding relationship (health status related vs. site lockdown, patient 
concerns, etc.) to the COVID-19 pandemic in line with “FDA Guidance on Conduct of Clinical 
Trials of Medical Products during COVID-19 Public Health Emergency” (March 2020) and 
“Guidance on the management of clinical trials during the COVID-19 (coronavirus) pandemic” 
(April 2020) from EMA as listed below. The following deviations related to the COVID-19 
pandemic will be summarized.

Missing visits

Changes in procedures and assessments

Planned visits not done at sites

Changes in drug supply method

Treatment not given

Patient discontinuation due to COVID-19 situation

Other study specific PDs
A cross-tabulation of COVID-19 related PD vs. corresponding relationship will also be 
produced. 


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2.3.3 Demographic variables and other baseline characteristics
Demographic variables and other baseline characteristics including previous migraine 
treatments will be summarized for each initially assigned treatment group and for all subjects
(total) using FAS.
At baseline (end of the baseline period; see Section 2.1.1.4, baseline definition), the following 
demographic and baseline characteristics will be summarized:

Categorical variables:
-
Age (< 65 years, >= 65 years)
-
Sex
-
Ethnicity
-
Race
-
Acute headache medication (none, migraine-specific/non migraine-specific) during 
baseline phase
-
Strata: Prior prophylactic migraine medication treatment failure (due to insufficient 
efficacy or poor tolerability) reported during screening / baseline period: 1 treatment 
failure (TF1) vs 2 treatment failures (TF2)
-
Aura status during baseline: Migraine with aura (ever experienced a migraine with aura 
during the baseline period), migraine without aura (never experienced any migraine with 
aura during the baseline period)

Continuous variables:
-
Age
-
Height (cm)
-
Weight (kg)
-
Body Mass Index (BMI, kg/m2)
-
Age at onset of migraine (years)
-
Disease duration of migraine with or without aura (years)
-
Monthly migraine days during baseline phase
-
Monthly migraine attacks during baseline phase
-
Monthly headache days during baseline phase
-
Monthly acute migraine-specific medication use in days during baseline phase
-
Monthly acute headache medication use in days during baseline phase
Descriptive statistics (mean, median, standard deviation, minimum, and maximum) will be 
presented for continuous variables for each initially assigned treatment group and for all 
subjects (total) using FAS. The number and percentage of subjects in each category will be 
presented for categorical variables for each treatment group and all subjects (total).


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If multiple races have been reported for a subject, the subject will be categorized as multiple 
races. 
Summary of prior migraine prophylactic treatment and reasons for discontinuation will be 
presented by treatment group. 
Subject disease history characteristics (listed below) collected on the “Headache and Migraine 
Frequency History” CRF page will be listed by treatment:

Age at onset of migraine (years)

Disease duration of migraine with or without aura (years) – derived.

Frequency of migraines over the past 3 months (average days per month subject had 
migraines)

Frequency of headache (migraine and non-migraine) over the past 3 months (average days 
per month subject had headache)
The impact of COVID-19 pandemic on subject demographics will be assessed by summarizing
data for subjects randomized in pre- and during- COVID-19 phases. The pandemic phase will 
be defined based on either start date of pandemic as a global cutoff or by region.
2.3.4 Medical history
Relevant medical history/current medical conditions present before signing the Informed 
consent will be recorded on the ‘Medical History’ CRF page. 
Any condition entered will be coded using the latest version Medical Dictionary for Regulatory 
Activities (MedDRA) prior to database lock and summarized by primary system organ class 
(SOC) and preferred term (PT) for each initially assigned treatment group and for all 
participants (total) using FAS. The SOCs will be presented in alphabetical order. Preferred 
terms will be ordered within each SOC by decreasing order of frequency in the AMG334 arm. 
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1 Study treatment / compliance
Exposure will be calculated for subjects in the SAF. Descriptive statistics will be produced to 
describe the exposure to initially assigned study drugs as well as for switched drugs. 
A listing of dose administration with the initially assigned study treatments along with switched 
drugs will be provided.
The duration of exposure since first injection/dose will be summarized descriptively by study 
treatment. 
Additionally, the number and percentage of subjects with dose change and reason for dose 
change will be summarized by treatment group.
Summary of subjects switching to oral prophylactics from initially assigned study treatment 
with reasons for switching will be presented. 


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2.4.2 Prior, concomitant and post therapies
The number and percentage of participants receiving prior/concomitant medications, and 
significant non-drug therapy in SAF population will be summarized by Anatomic Therapeutic 
Chemical classification [ATC] (coded by WHO), preferred term and by treatment group. 
Summary of concomitant medications will be provided by initially assigned and switched drugs 
separately. As per B3 format there will be one record for each CMTRT variable value and the 
newly created CMCLS variable in SDTM.CM contains only lowest ATC class.
Use of acute headache medication during the baseline phase and the treatment period will be 
summarized by category of medication for each treatment group.
Use of alternative migraine therapies during the baseline phase and the treatment period will be 
summarized by category of medication for each treatment group.
2.4.3 Prohibited treatment
Analysis of concomitant medications, procedures that are prohibited as per protocol (see
Protocol Section 6.2.2) and given during the conduct of the study will be addressed by the 
currently planned outputs of the Protocol deviations. 
No separate outputs will be produced related to prohibited medications.
2.5
Analysis of the primary objective
2.5.1 Primary endpoint
The primary aim of the study is to evaluate the effect of AMG334 vs oral cycling on the net 
benefit, a measure of sustained long-term benefit in these two treatment paradigms of migraine 
prophylactic agents.
The primary endpoint of the study is the proportion of subjects achieving net benefit, defined 
as completion of one year on the initially assigned treatment and achieving at least a 50% 
reduction from baseline in monthly migraine days in the last month (week 52).
Subjects who complete one year on the initially assigned treatment and achive at least a 50% 
reduction from baseline in monthly migraine days in the last month (week 52) are considered
as responders for the purpose of primary endpoint. 
A subject will be considered as a non-responder if
- a subject does not complete one year on the initially assigned treatment or
- a subject does not achieve at least 50% reduction from baseline in monthly migraine days or 
- does not satisfy both of the above conditions
Analysis of the primary endpoint will utilize the FAS. Subjects will be analyzed according to
their initially assigned treatment group regardless of the actual treatment received during the 
study.


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2.5.2 Statistical hypothesis, model, and method of analysis
The primary analyses will compare the proportion of subjects in FAS who achieve a net benefit
(defined in previous section) between AMG334 vs oral cycling.
Below is the hypothesis to be tested for primary analysis:
Null hypothesis: In subjects with episodic migraine, the AMG334 treatment group has the same 
effect as oral prophylactics group, in terms of the net benefit i.e. net benefit odds ratio =1. 
Alternative hypothesis: In subjects with episodic migraine, the AMG334 treatment group is 
different from oral prophylactics group, in terms of the net benefit i.e. net benefit odds ratio ≠ 
1.
Randomization will be stratified by prior prophylactic migraine medication treatment failure 
(due to insufficient efficacy or poor tolerability) reported during screening / baseline period: 1 
treatment failure (TF1) vs 2 treatment failures (TF2).
A Cochran-Mantel-Haenszel (CMH) test stratified by number of previous treatment failures (1
vs. 2) will be used under a 2-sided significance level of 0.05 to evaluate the association between
the net benefit rate and the treatment. The p-value of the test, and the estimated odds ratio
between AMG334 and active comparator, as well as its 95% confidence interval, will also be
reported.
2.5.3 Handling of missing values/censoring/discontinuations
Subjects with missing monthly migraine day data at week 52 of treatment, and subjects that 
discontinue initially assigned treatment prior to the week 52 visit will be imputed as non-
responders (not achieving a net benefit).
2.5.4 Sensitivity / Supplementary analyses
For the primary endpoint sensitivity analyses under missing at random (MAR) assumption will 
be performed. Multiple imputation (MI) techniques applying MAR approach will be used to 
assess the impact of missing values on the interpretation of the results from primary analysis.
Since primary endpoint is composite, missing data imputation can be used only when subject 
completes 52 weeks on initially assigned treatment and has missing MMD value at week 52. 
To assess impact of these missing values on interpretation of results will be analyzed using 
below given sensitivity analyses: 
1.1 Sensitivity analysis I: This data will be multiply imputed using the MAR assumption. The 
analysis method remains same as primary endpoint analysis. The multiple imputation 
model will be based on similar subjects in the same treatment arm.
Points to note:

Due to composite primary endpoint off-treatment data cannot be used for primary 
analysis. 
If MMD data is available say up to week 36 then data will be imputed from week 40 till week 
52.


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Table 2-4
Summary of primary endpoint and analysis methods
Endpoint
Analysis
Imputation
The proportion of subjects 
achieving 
net 
benefit, 
defined as completion of one 
year on the initially assigned
treatment and achieving at 
least a 50% reduction from 
baseline 
in 
monthly 
migraine days in the last 
month (week 52)
Primary analysis:
A Cochran-Mantel-Haenszel 
(CMH) 
test 
stratified 
by 
number of previous treatment 
failures (1 vs. 2) will be used 
under a 2-sided significance 
level of 0.05 to evaluate the 
association between the net 
benefit rate and the treatment.
No imputation.
Sensitivity analysis: 
A Cochran-Mantel-Haenszel 
(CMH) 
test 
stratified 
by 
number of previous treatment 
failures (1 vs. 2) will be used 
under a 2-sided significance 
level of 0.05 to evaluate the 
association between the net 
benefit rate and the treatment.
Missing MMD data will be 
imputed using multiple 
imputation under MAR 
assumption. The multiple 
imputation model will be 
build based on similar 
subjects 
in 
the 
same 
treatment arm.
Supplementary analysis to assess impact of COVID-19 pandemic:
The primary endpoint is composite and one component is the completion of intially assigned 
treatment for 52 weeks. The impact of COVID-19 pandemic will be assessed by following 
analysis:
a) The summary of discontinuations for initially assigned treatment and last available 
switched treatment will be provided by due to COVID-19 and non-COVID-19 reasons. 
b) In light of COVID-19 pandemic and its potential impact on treatment effect, an 
important scientific question of interest to address is to estimate the treatment effect had 
COVID-19 pandemic not occurred.

The target population is defined by all subjects in the study who received at least one 
dose of study treatment. 

The variable of interest is reduction in MMD from baseline to week 52 on initially 
assigned treatment.

The intercurrent event describes how events that may occur after randomization are 
considered when assessing the treatment effect


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o
Discontinuation of initially assigned treatment due to non COVID-19 related 
reason: Subjects who discontinue due to non COVID-19 related reasons prior to 
week 52 will be considered as non-responders. 
o
Discontinuation of initially assigned treatment due to COVID-19 related reason 
(hypothetical strategy): All MMD data up to discontinuation of initially assigned 
treatment will be used. Ignore all the MMD data after treatment discontinuation 
and impute MMD data till week 52 using missing at random approach (MAR). 
The discontinuation reason due to COVID-19 pandemic will be identified from 
the defined COVID-19 protocol deviations.

The summary measure is the odds ratio between two treatment arms. It will be obtained 
by CMH test similar to primary endpoint analysis. A subject will be responder if subject 
has at least 50% reduction in MMD from baseline at week 52 and completed initially 
assigned treatment for one year; otherwise subject will be a non-responder.  
c) Summary statistics will be provided for change from baseline in MMD for subjects with 
COVID-19 infection separatele for before and after COVID-19 infection period. The 
information about whether subject has COVID-19 infection is collected on AE CRF. 
2.5.5 Sensitivity analyses with corrected stratification factor
The sensitivity analyses will be performed by deriving the correct stratification factor for 
subjects who have been mis-stratified. Such subjects can be identified by PD criteria as 
specified below: 

For subjects with a INCL06 PD = 0 treatment failure (TF) (These subjects should be 
excluded from analysis as not in strata 1 or 2)

For Subjects with a EXCL04 PD = 3 (or greater) TF (These subjects should be excluded 
from analysis as not in strata 1 or 2)

For subjects with assigned (IRT) strata of TF1 (but have a TRT07 PD present), correct strata 
= TF2

For subjects with assigned (IRT) strata of TF2 (but have a TRT07 PD present), correct strata 
= TF1
Analysis for primary endpoint will be repeated using corrected strata.
2.5.6 Sensitivity analyses excluding subjects taking non-approved 
medications or prohibited medications or polytherapy 
Subjects who have taken non-approved medications or prohibited medications or polytherapy 
(data is identified using protocol deviations) during initially assigned treatment are excluded
from sensitivity analysis for primary endpoint. The analysis for primary endpoint will be 
repeated after excluding these subjects. 
2.6
Analysis of the key secondary objective
There is no key secondary objective. 


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2.7
Analysis of secondary efficacy objective(s)
2.7.1 Secondary endpoints
The secondary efficacy variables are as listed below and respective definitions of responders / 
non-responders are added in subsequent sections:

Proportion of subjects completing the study at Month 12 on the initially assigned treatment 

Cumulative average change from baseline in monthly migraine days during the treatment 
period week 4 to week 52 (Months 1-12) 

Proportion of responders as measured by PGIC at month 12 on the initially assigned
treatment
2.7.2 Statistical hypothesis, model, and method of analysis
Analysis of above mentioned secondary endpoint will utilize the FAS. 

Proportion of subjects completing the study at Month 12 on the initially assigned treatment
The responders and non-responders for this endpoint are defined as given below: 
Subjects who complete one year on the initially assigned treatment are considered as responders. 
A subject will be considered as a non-responder if a subject do not complete one year on the 
initially assigned treatment. This includes (a) subjects who discontinue initially assigned 
treatment permanently (b) subjects who switched to oral prophylactics other than initially 
assigned treatment.
In subjects with episodic migraine, the proportion of subjects completing 12 months on initially 
assigned treatment will be compared between the AMG334 treatment group and oral 
prophylactics group, in terms of odds ratio. Thus, below hypothesis will be tested between 
initially assigned treatment groups:
Null hypothesis: Odds ratio =1   vs   Alternative hypothesis: Odds ratio ≠ 1.
A Cochran-Mantel-Haenszel (CMH) test stratified by number of prior prophylactic migraine 
medication failures (1 vs. 2) will be used under a 2-sided significance level of 0.05. The p-value 
of the test, and the estimated odds ratio between AMG334 and active comparator, as well as its 
95% confidence interval, will also be reported.

Cumulative average change from baseline on the monthly migraine days during the 
treatment period week 4 to week 52 (Months 1-12)
The average of monthly migraine days will be obtained cumulatively every 4 weeks across 52 
weeks (e.g. at week 8 the average will be based on data from week 1 to week 8; at week 12 the 
average will be based on week 1 to week 12 and so on). The cumulative average change from 
baseline in monthly migraine days will be derived using difference between cumulative average 
of each month and baseline monthly migraine days. 
The change from baseline will be analyzed using a linear mixed effects repeated measures
model including treatment group, baseline value, stratification factor(s), scheduled visit, and 
the interaction of treatment group with scheduled visit. If applicable, in the repeated statement, 


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an unstructured covariance structure is assumed. Least squares means (LSMs) for each 
treatment group and its associated 95% confidence intervals, difference of LSMs compared to 
SoC treatment group and the associated 95% confidence interval of the differences, as well as 
the nominal two-sided p-values, will be tabulated by visit and treatment. 

Proportion of responders as measured by PGIC at month 12 on the initially assigned
treatment
The Patients' Global Impression of Change (PGIC) is a global assessment by the subject of the 
change in clinical status since the start of treatment. The PGIC is assessed periodically through 
the treatment period and at the end of the treatment period. The PGIC ratings are as follows: 
1 = No change (or condition is worse) 
2 = Almost the same, hardly any change at all 
3 = A little better, but no noticeable change 
4 = Somewhat better, but the change has not made any real difference
5 = Moderately better, and a slight noticeable change
6 = Better, and a definite improvement that has made a real and worthwhile difference
7 = A great deal better, and a considerable difference that has made all the difference
Subject will be considered as responder if PGIC score is 5, 6, or 7 at month 12 on initially 
assigned treatment. Subject will be considered as non-responder if subject does not complete 
12 months on initially assigned treatment or if subject does not have score 5, 6 or 7 at month 
12. 
Proportion of responders based on PGIC score at month 12 will be analyzed same as that of the 
primary endpoint.
2.7.3 Handling of missing values/censoring/discontinuations
Subjects with missing PGIC score data at week 52 of treatment, and subjects that discontinue 
initially assigned treatment prior to week 52 will be imputed as non-responders (not achieving 
a net benefit).
For MMD values there will not be any missing data imputation. 
2.7.4 Sensitivity / Supplementary analyses
Sensitivity analysis for secondary endpoint:
To assess impact of missing values on interpretation of results sensitivity analyses will be 
performed for secondary endpoint “Cumulative average change from baseline on the monthly 
migraine days during the treatment period week 4 to week 52 (Months 1-12)”. Missing MMD 
data will be imputed using multiple imputation under MAR assumption. The multiple 
imputation model will be build based on similar subjects in the same treatment arm.
Supplementary analysis for secondary endpoint:
The supplementary analysis for secondary endpoint “Cumulative average change from 
baseline on the monthly migraine days during the treatment period week 4 to week 52


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(Months 1-12)” is defined considering hypothetical strategy for subjects who are 
discontinuing early or switching initially assigned treatment.
This analysis will evaluate what if subject would have continued initially assigned treatment 
for 52 weeks
- if subject discontinues initially assigned treatment and does not switch to other SoC then 
missing data after discontinuation will be imputed using MAR. This is because we are 
considering what if subject would have continued initially assigned treatment. 
- if subject switched to other SoC drug then for switched period until week 52 data will be 
considered as missing and such missing data will be imputed using MAR. 
Points to note:

The off-treatment MMD data and MMD data from switched drug cannot be used for 
analysis since it will not represent MMD values under initially assigned treatment.

If MMD data is available say up to week 36 then data will be imputed from week 40
till week 52.
Table 2-5
Summary of secondary efficacy endpoints and analysis methods
Endpoint
Analysis
Imputation
Proportion 
of 
subjects 
completing the study at 
Month 12 on the initially 
assigned treatment
A Cochran-Mantel-Haenszel 
(CMH) test stratified by 
number of prior prophylactic 
migraine medication failures 
(1 vs. 2) will be used under a 
2-sided significance level of 
0.05.
No imputation.
Cumulative average change 
from baseline on the monthly 
migraine days during the 
treatment period week 4 to 
week 52 (Months 1-12)
The change from baseline 
will be analyzed using a 
linear mixed effects repeated 
measures
model including 
treatment group, baseline 
value, stratification factor(s), 
scheduled visit, and the 
interaction 
of 
treatment 
group with scheduled visit.
No imputation.
Sensitivity analysis: 
The change from baseline 
will be analyzed using a 
linear mixed effects repeated 
measures
model including 
treatment group, baseline 
Missing MMD data will be 
imputed 
using 
multiple 
imputation 
under 
MAR 
assumption.  The multiple 
imputation model will be 


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2.8
Safety analyses
For safety endpoints, all randomized subjects who received at least one dose of study treatment 
will be analyzed based on the actual treatment received (defined as the randomized treatment 
unless a subject has received the incorrect treatment during the treatment period).
Unless otherwise specified, all safety summaries and listings will be provided by initially 
assigned treatment group. 
Missing data will not be imputed for safety endpoints.
value, stratification factor(s), 
scheduled visit, and the 
interaction 
of 
treatment 
group with scheduled visit.
build 
based 
on 
similar 
subjects 
in 
the 
same 
treatment arm.
Supplementary analysis: 
The change from baseline 
will be analyzed using a 
linear mixed effects repeated 
measures
model including 
treatment group, baseline 
value, stratification factor(s), 
scheduled visit, and the 
interaction 
of 
treatment 
group with scheduled visit.
This 
analysis 
will 
be 
performed 
considering 
hypothetical 
strategy 
for 
subjects
who 
are 
discontinuing 
early 
or 
switching initially assigned
treatment.
Intermittant missing MMD 
data will be imputed using 
multiple imputation under 
MAR assumption. 
To get imputed data for entire 
treatment period:
- if subject discontinues 
initially assigned treatment 
and does not switch to other 
SoC then missing data after 
discontinuation will be 
imputed using MAR. 
- if subject switched to other 
SoC drug then for switched 
period until week 52 data will 
be considered as missing and 
such missing data will be 
imputed using MAR.
Proportion of responders as 
measured 
by 
PGIC 
at month 12 on the initially 
assigned treatment
A Cochran-Mantel-Haenszel 
(CMH) test stratified by 
number of prior prophylactic 
migraine medication failures 
(1 vs. 2) will be used under a 
2-sided significance level of 
0.05.
No imputation.


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2.8.1 Adverse events (AEs)
The Medical Dictionary for Regulatory Activities (MedDRA) version 20.0 or later will be used 
to code all adverse events (AE) to a system organ class (SOC) and a preferred term (PT All 
adverse event tables will be summarized by treatment group.
For all AEs tables presented by SOC and PT (and grade), the SOCs will be presented in 
alphabetical order and PTs will be ordered within the SOC by decreasing order of frequency in 
the AMG334 treatment group. AE tables by preferred term only will be sorted in descending 
order of frequency in the AMG334 treatment group. A subject with multiple adverse events 
within a primary system organ class is only counted once towards the total of the primary system 
organ class.
Separate summaries by initially assigned treatment will be provided for study medication 
related adverse events, death, serious adverse events, adverse events leading to 
discontinuation and adverse events leading to dose adjustment. 
All AEs, deaths, serious adverse events (SAE) and AEs leading to permanant study treatment 
discontinuation will be listed seperately.
Summary of all AEs by SOC, PT and severity will also be provided by switched treatment. A 
separate listing of all AEs by initially assigned treatment and switched treatment will be 
provided.
Summary of treatment emergent AEs will be provided for COVID-19 and hypertension data by 
SMQ levels.
Summary of treatment emergent AEs will be provided for constipation by CMQ and 
corresponding preferred term. 
Summary of exposure adjusted subject incidence rates for treatment emergent AEs and SAEs 
will be provided by primary system organ class and preferred terms. 
2.8.1.1
Clinical trial safety disclosure (CTSD) reports
For clinicaltrials.gov and EuDRACT, two required tables on treatment emergent adverse events 
(TEAE) which are not SAEs with an incidence greater than a certain threshold based on the 
final database and on treatment emergent serious adverse events and SAEs suspected to be 
related to study drug will be provided by system organ class and PT on the safety set population. 
If for a same subject, several consecutive AEs (irrespective of study drug causality, seriousness 
and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 

more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 


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The number of deaths resulting from SAEs suspected to be related to study treatment and   SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
2.8.2 Deaths
Deaths will be listed by treatment including the start date of the study treatment, the last date 
on study treatment, the death date and the primary cause (and contributing cause if any) for 
death.
2.8.3 Laboratory data
Summary statistics will be presented for absolute as well as change from baseline of laboratory 
blood chemistry results by visit, initially assigned treatment and laboratory test category. 
Subject incidence of liver enzyme abnormalities (including AST, ALT, Total Bilirubin (TBL) 
and Alkaline Phosphatase (ALP)) will also be summarized by treatment group.
Shift from baseline for some liver enzyme level categories (specified in the Tables, Figures and 
Listings (TFL) shells; for e.g. ALP<=1 x ULN) will also be provided by initially assigned 
treatment group. 
Clinically notable laboratory values will be flagged and listed by treatment.
Parameters measured in the urine at screening including urine drug tests will be listed.
Table 2-6
Clinically Notable Laboratory Values
Notable 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 mol/L
Alkaline Phosphatase
F
>832 U/L
>832 U/L
Alkaline Phosphatase
M
>1032 U/L
>1032 U/L
HEMATOLOGY VARIABLES
Neutrophils
Both
<1.5x 103/uL
<1.5x109/L
Note: Only selected lab parameters which have potential to be sensitive to AMG334 exposure 
are listed.


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2.8.4 Other safety data
2.8.4.1
ECG and cardiac imaging data
The ECG measurements from this clinical study will be performed as per standard of care for
routine safety monitoring, rather than for purposes of assessment of potential QTc effect. 
Subject incidence of abnormal ECG diagnosis (see Table 2-7) will be summarized by treatment 
group and by visit for initially assigned treatment. 
ECG measurements with abnoramlities will be listed by treatment. 
However, since these evaluations may not necessarily be performed under the rigorous 
conditions expected to lead to meaningful evaluation of QTc data, these data are not expected 
to be useful for meta-analysis with data from other trials.
Table 2-7
ECG Abnormality Ranges
ECG Parameter
Abnormality Flags
Absolute
Relative*
RR Interval
Low: < 600 msec ; High: > 1200 
msec
Low: ≤ -20%; High: ≥ 20%
PR interval
Low: < 120 msec ; High: > 200 
msec
Low: ≤ -20%; High: ≥ 20%
QRS Interval
Low: < 60 msec ; High: > 109 
msec
Low: ≤ -20%; High: ≥ 20%
QT Interval
Low: < 320 msec ; High: > 450 
msec
Low: ≤ -20%; High: ≥ 20%
QTcB Interval 
(Bazett's correction)
Low: < 320 msec ; High: > 450 
msec
Low: ≤ -20%; High: ≥ 20%
QTcF Interval 
(Fridericia's 
correction)
Low: < 320 msec ; High: > 450 
msec
Low: ≤ -20%; High: ≥ 20%
*Relative change from previous measurement in percent (%)
2.8.4.2
Vital signs
The vital signs data is collected prior to dosing. The analyses of vital signs (systolic/diastolic 
blood pressure, pulse rate) and weight will include summary statistics of change from baseline 
by treatment group and by visit for initially assigned treatment. 
The number and percentage of subjects with clinically relevant abnormality (see Table 2-8) at 
any post-baseline visit will be presented for initially assigned treatment. This vital sign data will 
also be listed. 
Table 2-8
Vital Signs Notable Criteria
Vital Sign Variable
Notable Criteria
Pulse (beats/min)
           > 120bpm or Increase of 15 bpm from baseline
Or
          < 50bpm or Decrease of 15 bpm from baseline


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Systolic BP (mmHg)
>180 mm Hg or Increase of 20 mm Hg from baseline
Or
< 90 mm Hg or Decrease of 20 mm Hg from baseline
Diastolic BP (mmHg)
> 105 mmHg or Increase of 15 mm Hg from baseline
Or
< 50 mmHg or Decrease of 15 mm Hg from baseline
2.8.4.3
Columbia-Suicide Severity Rating Scale (C-SSRS)
The number and percentage of subjects reporting any suicidal ideation or any suicidal behavior 
at baseline and any time post-baseline will be summarized descriptively by treatment group and 
all subjects. Refer to section 5.9 for details on scores. 
2.9
Pharmacokinetic endpoints
Not Applicable.
2.10
PD and PK/PD analyses
Not Applicable.
2.11
Patient-reported outcomes (PRO)
PRO based on PGIC score is a secondary endpoint and it is detailed in section 2.7. 
 
 
2.12
Biomarkers
Not Applicable.
 
 
2.14
Interim analysis
Not Applicable.
3
Sample size calculation
The sample size calculation is based on the primary variable, rate of net benefit. The details of 
hypothesis testing are described in section 2.5.2. 
A 2-sided test with significance level 0.05, and a 2:1 randomization ratio are considered. A 
sample size of 591 (394 erenumab arm; 197 control arm) is required to achieve 90% power to 
reject the odds ratio of 1 set by the null hypothesis when the odds ratio is actually 2, and success 
rate in control arm is 0.18. 


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An odds ratio of 2 and control rate of 0.18 is based on more conservative assumptions for rate 
of net benefit than observed previously (for erenumab in studies NCT02456740, NCT01952574, 
and oral cycling in Hepp et al 2017, Shei et al 2015), resulting in a rate difference of 12%. 
Sample size calculations were done using PASS 11 and Cochran-Mantel-Haenszel test was used.
4
Change to protocol specified analyses
Not applicable. 
5
Appendix
5.1
Imputation rules
Subjects may miss specific data points for a variety of causes. In general, data could be missing 
due to a subject’s early withdrawal from study, a missed visit, or inability to evaluate an 
endpoint at a particular point in time. For this study, most of the efficacy endpoint will be 
collected via eDiary and subjects could miss entering several days of data in each 28-
consecutive day interval. The general procedures outlined below describe what will be done 
when a data point is missing.
5.1.1 AE / Concomitant medication date imputation
Missing or incomplete dates will be listed as it is in any listings. 
Incomplete start date of an adverse event or concomitant medication taken will be handled by 
following rule: 
Table 5-1
Imputation of AE/Concomitant dates
Missing
Imputation
Exception
Start date 
(AE, concomitant 
medication) 
Day
01
Default to Study Day 1 if an 
adverse event starts the same 
year and month as Study Day 
1 and the flag indicates that 
the adverse event started on 
or after the first dose on the 
Adverse Events eCRF 
Day/Month
01Jan
Default to Study Day 1 if an 
event started the same year 
as Study Day 1 and the flag 
indicates that the adverse 
event started on or after the 
first dose on the Adverse 
Events eCRF 


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Day/Month/Year
No imputation
5.1.2 Prior therapies date imputation
For prior medications with a stop date prior to the treatment phase (not possible to be at or 
after first drug administration), the start date will be imputed as the earliest possible start date 
and the stop date as the latest possible stop date:
For a missing/incomplete start date the minimum of the following will be imputed:
•
The maximum of the earliest possible start date and the imputed birth date;
•
The latest possible start date;
•
The latest possible stop date.
For a missing/incomplete stop date the maximum of the following will be imputed:
•
The minimum of the latest possible stop date and the date of first drug 
administration -1;
•
The earliest possible stop date;
•
The earliest possible start date.
Here, the earliest (latest) possible date is defined as:
•
The date itself if it is complete;
•
The date of the first (last) day of the month, if month and year are available but day is 
missing;
•
The date of the first (last) day of the year, if year is available but day and month are 
missing;
•
A very early (late) date, e.g., 01JAN1000 00:00hrs (01JAN3000 23:59hrs), if the date 
is completely missing.
5.1.3 Post therapies date imputation
NA.
5.1.4 Other imputations
5.1.4.1
eDiary data
The eDiary includes the following clinical outcome assessments:
• Incidence of headache (ie, migraine with or without aura or non-migraine headache)
• Time of onset of headache
• Time of resolution of headache
• Pain severity per headache


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• Symptoms (eg, nausea, vomiting, photophobia, phonophobia) 
• Presence of aura
• Use of acute medication during aura or to treat headache
as well as, patient-reported outcomes (PROs) measures.
Missing eDiary data in the calculation of monthly measurements about subjects’ migraine and 
non-migraine headaches will be handled using the following method: 
1. For monthly intervals with ≥ 14 days of eDiary days (including retrospective eDiary days) 
in each interval: 
a) Monthly frequency measurements (including migraine days, headache days, migraine 
attacks, 
) will be prorated to 
28-day equivalents. Prorated result does not need to be rounded. 
 
 
 
2. For monthly intervals with < 14 days of eDiary use (including retrospective eDiary days), 
all monthly measurement will be set as missing and will be handled as described in Section 
5.1.5.3.
Table 5-2
Rules for handling missing and incomplete eDiary data
Monthly Endpoint
Condition
Proration Method (does not 
need to be rounded)
Monthly frequency 
measurements (including 
migraine days, headache 
days, migraine attacks, hours 
of migraine headaches, 
 
 
 
)
If diary days in entire 
baseline or interval post 
baseline >=14 
(including retrospective 
eDiary days), then do 
proration;
Else monthly 
measurement is set to 
missing
[diary days is a day with 
all headache related 
questions completed 
retrospectively or not]
Number of observed 
migraine days * 28/ 
Number of information 
days in interval
[information day is a diary 
day or headache day]


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Missing PROs scheduled to be collected at office visit at certain assessment will not be 
imputed.
5.1.4.2
Missing Baseline Evaluation
Missing baseline evaluations will not be imputed.
All subjects included in the full analysis set will have baseline monthly rate or monthly average 
of migraine and non-migraine headaches related measurements after applying proration rule 
defined in Section 5.1.5.1 since only subject with ≥ 80% compliance of eDiary use during 
baseline will be eligible for randomization.
5.1.4.3
Missing Post-baseline Evaluation
Primary analysis will be conducted using the stratified CMH test on observed data without 
imputation (see Section 5.5.1).
In the sensitivity analysis on primary and secondary efficacy endpoints, missing continuous 
efficacy endpoints will be handled using multiple imputation (MI) with assumption of missing 
at random (MAR). See below for more details.
To address the impact of missing data on primary efficacy analysis, the amount of missing
data, the distribution of missing data among treatment groups, and the reasons for missing
data will be examined.
If the proportion of missing data in primary endpoint is high (e.g., > 20% for primary analysis
at week 52) or if substantial imbalance occurs amongst the treatment groups, further analysis 
will be performed to
• examine the frequency and reason of missing data
• determine if there are any patterns in the missing data
• distinguish true missing values from other unknown values (e.g., due to measurement or 
sample processing error)
Additional sensitivity analyses, including those based on alternative missing data ssumptions,
will be performed as deemed appropriate and necessary.
5.1.4.3.1 Multiple Imputation (MI) and MCMC Method
The multiple imputation assume that the missing data are missing at random (MAR), that is,
the probability that an observation is missing may depend on the observed values but not the 
missing values. It also assumes that the parameters q of the data model and the parameters f of 


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the missing data indicators are distinct. That is, knowing the values of q does not provide any 
additional information about f, and vice versa. If both MAR and the distinctness assumptions 
are satisfied, the missing data mechanism is said to be ignorable. The MI procedure provides 
three methods for imputing missing values and the method of choice depends on the type of 
missing data pattern. For monotone missing data patterns, either a parametric regression 
method that assumes multivariate normality or a nonparametric method that uses propensity 
scores is appropriate. For an arbitrary missing data pattern, a Markov chain Monte Carlo 
(MCMC) method that assumes multivariate normality can be used.
In MCMC, one constructs a Markov chain long enough for the distribution of the elements to
stabilize to a common, stationary distribution. By repeatedly simulating steps of the chain, it
simulates draws from the distribution of interest.
In Bayesian inference, information about unknown parameters is expressed in the form of a 
posterior distribution. MCMC has been applied as a method for exploring posterior 
distributions in Bayesian inference. That is, through MCMC, one can simulate the entire joint 
distribution of the unknown quantities and obtain simulation-based estimates of posterior 
parameters that are of interest.
Assuming that the data are from a multivariate normal distribution, data augmentation is 
applied to Bayesian inference with missing data by repeating a series of imputation and
posterior steps. These two steps are iterated long enough for the results to be reliable for a 
multiply imputed data set (Schafer 1997). The goal is to have the iterations converge to their 
stationary distribution and then to simulate an approximately independent draw of the missing 
values.
Sample SAS code for MI using MCMC method will be provided as instruction to TFLs.
Further, as a sensitivity analysis, the pattern-mixture model approach is used to model the 
distribution of a response as the mixture of a distribution of the observed responses and a 
distribution of the missing responses, for which the missing values can be imputed under a 
plausible scenario for which the missing data are missing not at random. The control-based 
pattern imputation, in which, the set of observations from control group are used to derive the 
imputation model.
5.1.4.3.2 Multiple imputation sensitivity analyses steps
The following steps are followed in order to create the structure of the analysis dataset where 
missing values and appropriate variables could be imputed.
•
Obtain subject id, treatment group, stratification factor, sex, race group, age group, 
BMI group (subjid trt01pn mmstratn sexn race agemedn bmimedn)  from ADBS, 
ADSL.
•
Obtain number of prior migraine prophylactic treatment failed, baseline disease 
duration group (prophfln durmedn) from ADBS.
•
Obtain avisitn paramcd param aval avalc base chg dtype from ADATTACK
•
Perform minor data manipulation, as required, to reinstate the missing data, eg if
dtype="LOCF" then aval=., avalc=” “ and chg=.


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•
Ensure the baseline values are included in the chg variables before data 
transformation, eg if avisitn=2000 is baseline then chg=base; 
•
Transpose all the data so you have one observation per subject and each visit becomes 
a variable within its own right, eg rows where avisitn=2004, 2008, 2012 etc become 
the column week4, week8, week 12 etc.
•
Impute the missing data for MAR according to the methods in next steps
MAR multiple imputations steps:
Note that the some variable has missing values and there is a mix of categorical and 
continuous variables in the modelling of the missing data. Therefore, fully conditional 
specification (FCS) methods are employed within proc mi to impute the missing data. 
•
FCS logistic is used for dichotomous variables (mmstratn sexn agemedn bmimedn 
prophgrp durmedn); discrim is used for categorical variables with more than 2 
categories (race); regpmm is used for continuous variables (wk0, wk4, wk8,... wk52).
•
wk4, wk8 , ... and wk52 represent the chg variable for each of the visits respectively, 
and wk0 is baseline.
MAR modeling step:
•
For the primary endpoint, first, define 50% Responders based on imputed MMD data 
under the assumption of MAR.Then, use the same method as for primary variable -  
the stratified CMH test to get estimates for numbers of responders in each treatment 
group and odds ratio at week 52 for each dataset.
•
For change from baseline in MMD it is used a linear mixed effects model on imputing 
data under the assumption of MAR. There is no gaps in imputed data, therefore, all the 
data is available to analyze and can use a fixed effects model looking only at the 
avisitn=2052/week52 data.
MAR combining step:
•
The output dataset with the treatment LS means (LSMEANS) and the treatment 
differences (DIFF) are then sorted, manipulated and read into proc mianalyze to 
combine the individual sets of imputed results into one set of overall results, see all 
steps SAS codes in TFLs document.
5.2
AEs coding/grading
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA)
terminology. Adverse event severity is graded as shown below: 

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities


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5.3
Laboratory parameters derivations
NA.
5.4
Rule of exclusion criteria of analysis sets 
The protocol deviations during screening, baseline and treatment periods are defined below 
(Table 5-3). The deviation ID, deviation code and it’s corresponding text description are 
explained in Table 5-3. Subjects exclusion based on protocol deviations and non- protocol 
deviations criteria are in Table 5-4.
Table 5-3
Deviation Codes Description
Deviation code
Text description
Deviation ID
1
SELECTION CRITERIA NOT MET
INCLXX ; EXCLXX
2
PATIENT NOT WITHDRAWN AS PER 
PROTOCOL
WITHXX
3
PROHIBITED CONCOMITANT MEDICATION
COMDXX
4
TREATMENT DEVIATION
TRTXX
998
OTHER
OTHXX
Table 5-4
Patient classification
Analysis Set
PD ID that
cause subjects to be excluded
Non-PD criteria that cause 
subjects to be excluded
FAS
NA
Not randomized
SAF
NA
Not randomized;
No study drug taken
5.5
Statistical models
5.5.1 Primary analysis
The null hypothesis stating that the odds ratio between the two treatment arms less than or equal 
to 1 will be tested against the one-sided alternative.
H0: θ1 ≤ 1 vs H1: θ1 > 1
where θ1 is the odds ratio of AMG334 over standard of care oral prophylactics.
After the missing data are imputed as non-response a Cochran-Mantel-Haenszel (CMH) test 
stratified by prior treatment failure=1 versus prior treatment failures=2 will be used under a 
significance level of 0.025, one-sided (0.05, two-sided) to evaluate the association between the 
50% responder rate at month 12 and the treatment. The estimated common odds ratio, 95% 
confidence intervals and two-sided p-values will be reported. 


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Additionally, the estimated common relative risk and risk difference with their asymptotic 
(Wald) confidence limits will be provided. 
The test can be implimented using SAS, PROC FREQ with options CMH, RELRISK, 
RISKDIFF under TABLE statement.
5.5.2 Secondary analysis
Follow same instructions as Section 5.5.1 for secondary analysis using CMH test.
Linear mixed models using repeated measurements:
The secondary endpoint of the study cumulative average change from baseline on MMD will 
be tested for AMG334 compared to standard of care oral prophylactics, respectively.

Null Hypothesis: In subject with episodic migraine, the AMG334 treatment group is the 
same as SoC, in terms of the reduction from baseline in cumulative mean monthly
migraine days in month 12

Alternative Hypothesis : In subject with episodic migraine, the AMG334 treatment 
group is different as SoC, in terms of the reduction from baseline in cumulative mean 
monthly migraine days in month 12
It will be analyzed using a linear mixed effects repeated measures model with treatment group,
baseline value, stratification factor, scheduled visit, and the interaction of treatment group with 
scheduled visit. In repeated statement, an unstructured covariance matrix will be used.
The test can be implemented using SAS, PROC MIXED procedure. 
5.6
Important derivations

Subject-level End of Study (EOS) Date
The end of study (EOS) date for each subject is defined as the last date on which the 
subject  participated in the study. The date will be recorded on the study disposition 
eCRF page.

Duration of exposure of study treatment
For AMG334 calculation of exposure, dose date refers to receiving dose > 0, but can 
include partial doses. The duration of exposure for AMG334 is computed as of last 
injection of study drug + 27 days - date of first injection of study drug +1.
For oral prophylactics arm calculation of exposure, dose date refers to receiving dose >
0. The duration of exposure for initially assigned treatment is computed as last dose date 
– First Dose Date + 1.

Compliance with the eDiary 
The protocol requirement is 80% compliance in 28 days. That means a minimum 23  
diaries must be completed within 28 days. Compliance to eDairy at each month is 
calculated as 


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o
(Number of eDiary entered in baseline period or between IP doses/28days)*100% 
if the number of actual days in Baseline period or between IP doses interval is 
<= 28 days
o
(Number of eDiary entered in baseline period or between IP doses/ number of 
actual days in Baseline period or between IP doses interval)*100% if the number 
of actual days in Baseline period or between IP doses interval is > 28 days

eDiary Device Assignment Date
The date on which an eDiary device is assigned to a subject for the first time after 
completion of initial screening at week -4 visit.

eDiary Day 
A day in which a subject uses the eDiary. 

Information Day
A day which is either a headache day or an eDiary day.

Migraine Day
A migraine day is defined as any calendar day in which the subject experiences a 
qualified migraine headache (onset, continuation, or recurrence of the migraine 
headache). Please see exceptions in Appendix 5.7. A qualified migraine headache (IHS, 
2013) is defined as a migraine with or without aura, lasting for ≥ 30 minutes, and 
meeting at least one of the following criteria:
1. ≥ 2 of the following pain features:
o
Unilateral
o
Throbbing
o
Moderate to severe
o
Exacerbated with exercise/physical activity
2. ≥ 1 of the following associated symptoms:
o
Nausea and/or vomiting
o
Photophobia and phonophobia
If the subject took a migraine-specific medication (ie, triptan or ergotamine) during aura, 
or to treat a headache on a calendar day, then it will be counted as a migraine day 
regardless of the duration and pain features/associated symptoms.

Monthly Migraine Days 
Number of migraine days between each analysis visit that are normalized in a 28-day 
interval. Monthly migraine days at baseline are the number of migraine days in the 
baseline period that are normalized in a 28-day interval. Days without eDiary data in 
each normalized monthly interval will be prorated. All details of calculation are in 
Section 5.1.4 (The same proration method will be applied for other efficacy endpoints 
thereafter).


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
Duration of Migraine
The duration of migraine in years (migraine with aura or migraine without aura, 
whichever is earlier) is calculated by the following formula: current age (in years) - age 
at migraine onset (in years). 
Current age is calculated by the following formula, the date of informed consent – birth 
date (at least the year). 
If the current age calculated as detailed above or the age at migraine onset is missing 
then duration of migraine will be missing.

Achievement of at least a 50% reduction from baseline in monthly migraine days at 
month 12
Calculated based on the following: if (monthly migraine days in the last month of the 
treatment period - baseline monthly migraine days)*100/baseline monthly migraine 
days is less than or equal to - 50%

Migraine Attack 
An episode of any qualified migraine headache or migraine specific medication intakes 
for aura only. The following rules will be used to distinguish an attack of long duration 
from two attacks, or to distinguish between attacks and relapses: 
a) A migraine attack that is interrupted by sleep, or temporarily remits, and then recurs 
within 48 hours will be considered as one attack and not two. 
b) An attack treated successfully with medication but with relapse within 48 hours will 
be considered as one attack. 
c) A migraine attack lasting more than 48 hours will be counted as one attack.

Monthly Migraine Attacks 
Number of migraine attacks between each analysis visit. Monthly migraine attacks at 
baseline are the number of migraine attacks in baseline period. Days without eDiary 
data are handled by proration according to Section 5.1.4.

Headache Day 
A headache day is any calendar day in which the subject experiences a qualified 
migraine or non-migraine headache (initial onset, continuation or recurrence of the 
headache).  A qualified headache is defined as:
o
a qualified migraine headache (including an aura-only event that is treated with 
acute migraine-specific medication), or
o
a qualified non-migraine headache, which is a headache that lasts ≥ 30 minutes 
and is not a qualified migraine headache, or
o
a headache of any duration for which acute headache treatment is administered. 

Monthly Headache Days 


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Number of headache days between each analysis visit.  Monthly headache days at 
baseline are the number of headache days in baseline period.  Days without eDiary data 
in each monthly interval are handled by proration according to Section 5.1.4.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Response
At least 50%
 reduction from baseline in monthly migraine days.

Cumulative Monthly Migraine Days  
Cumulative monthly migraine days during treatment period is the sum of qualified 
monthly migraine headache days during the entire treatment period normalized into the 
28-day period. If eDiary compliance>=50% (definition in Section 5.6) then the 
cumulative monthly migraine days are calculated according to the formula: 
28*(Total number of observed eDairy migraine days /Number of information days 
during treatment period);
If eDiary compliance is <50%, it is set up to missing.

Change from baseline


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When change from baseline is of interest, the following formula will be used for each 
scheduled visit and time-point where baseline and post-baseline values are both 
available:
Change from baseline = post-baseline value – baseline value; and
Percent change from baseline = change from baseline *100/ baseline value 
The change from baseline in monthly efficacy measurement is the monthly efficacy 
measurement in the monthly interval prior to the given time point minus the baseline 
monthly efficacy measurement. Please, refer to the monthly intervals for efficacy 
endpoints defined in Table 2-3. For example, change from baseline in monthly migraine 
days in the last month (month 52) of the treatment period will be calculated based on 
the following: 
(Monthly migraine days in the last month of the treatment period) – (monthly migraine 
days during the baseline phase)
If baseline or post-baseline values are missing, then the change from baseline will be
missing.
5.7
MMD derivation, exceptions
5.7.1
Assigning Headache and Migraine Days to Events Spanning Midnight
The diagram below shows all of the possible scenarios for time-based determination of 
assignment of events to days when the events span midnight


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5.7.2
Spanning Midnight Rules for Multi-Day Events Longer Than Two Days
When an event spans two or more full days, with “tail” conditions (event lasts for less than 30 
minutes or less on one side of midnight or the other), the “tail” conditions must be checked 
separately at each end of the event (beginning and end) to determine which days are included 
in the event expanse.  The example below shows an event spanning 3 days.  For events spanning 
more than 3 days, where there are n total days of the event, the endpoints would be Day 1 (Day 
1 in the example below), Day n (Day 3 in the example below), and Days 2 to n-1 (Day 2 in the 
example below).
Example 
A headache event starts 28 minutes before midnight (Day 1), extends across a full day (Day 2), 
and ends 25 minutes after the next midnight (Day 3)


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In this example, because the midnight scenario between Day 1 and Day 2 (Scenario 6) 
determines that Day 1 will NOT be counted as a headache/migraine day, and the midnight 
scenario between Day 2 and Day 3 (Scenario 2) determines that Day 3 will NOT be counted 
as a headache/migraine day, the event that started on Day 1 and ended on Day 3 will only 
count as a headache/migraine day on Day 2.
5.8
Patient Global Impression Change (PGIC)
5.9
The Columbia-Suicide Severity Rating Scale (C-SSRS)
Category number
C-SSRS category
Suicidal Ideation


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1
Wish to be dead
2
Non-specific active suicidal thoughts
3
Active suicidal ideation with any methods (not plan) without intent to act
4
Active suicidal ideation with some intent to act, without specific plan
5
Active suicidal ideation with specific plan and intent
Suicidal behavior
6
Preparatory acts or behavior
7
Aborted attempt
8
Interrupted attempt
9
Actual attempt
10
Completed suicide
Self-injurious behavior, without suicidal intent
11
Non-suicidal self-injurious behavior
6
Reference
Breslow, N. E. and Clayton, D. G. (1993). Approximate Inference in Generalized Linear 
Mixed Models, Journal of the American Statistical Association, 88, 9–25.
Headache Classification Committee of the International Headache Society (IHS, 2013), The 
International Classification of Headache Disorders, 3rd edition (beta version), Cephalalgia, Vol. 
33(9) 629–808.
Koch G. G., Amara I. A., Davis G. W., and Gillings D. B. (1982). A review of some statistical 
methods for covariance analysis of categorical data, Biometrics, 38(3), 553–595. 
Koch G. G., Carr G. J., Amara I. A., Stokes M.E., and Uryniak T. J. (1990). Categorical Data 
Analysis, In Statistical Methodology in the Pharmaceutical Sciences, Ed. by Berry DA. New 
York: Marcel Dekker, 291–475.
Schafer, J. L. (1997). Analysis of Incomplete Multivariate Data, New York: Chapman and Hall.
SOP-7035752 V4.0: Defining Processing and Reporting Protocol Deviations
COVID-19 (Coronavirus) Guidance V3.0: Start and End Dates by Region for Sensitivity 
Analyses
FDA Guidance: “FDA Guidance on Conduct of Clinical Trials of Medical Products during 
COVID-19 Public Health Emergency” (March 2020) 
EMA Guidance: “Guidance on the management of clinical trials during the COVID-19 
(coronavirus) pandemic” (April 2020)