Clinical trial NCT03828539
Conditions: Migraine
Keywords: Migraine Episodic migraine Chronic migraine Headache erenumab topiramate CAMG 334 Calcitonin Gene-related Peptide CGRP CGRP receptor agonist monoclonal antibody treatment failure
Sponsor: Novartis Pharmaceuticals
Start date: 2019-02-22; Completion date: 2020-07-29
Enrollment: 777 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study used a single-cohort, 2-treatment arm, parallel-group randomized, double-blind, double-dummy design in adult patients with episodic migraine and chronic migraine, who had to be either naïve or not suitable for or could have failed up to three prophylactic treatments out of: propranolol/metoprolol, amitriptyline, flunarizine. Patients were stratified into groups according to their number of migraine days during the baseline period.

Detailed description:
All patients completing the Baseline period and fulfilling baseline eligibility criteria were invited to participate to the Double-blind, double-dummy Treatment Epoch (DBTE, 24 weeks) .

Eligible patients were randomized to one of two treatment arms. DBTE started with a titration phase for topiramate of a maximum of 6 weeks to determine the maximal tolerated dose and aimed to reach the recommended treatment dose of 100 mg according to the German SmPC. After the titration phase, maintenance phase started (18 weeks). Topiramate dose had to be maintained until the end of the DBTE. Erenumab dose at beginning of the DBTE was determined patient individually by the investigator based on the guidance provided in the SmPC and was either 70 mg or 140 mg. Dose escalation from 70 mg to 140 mg in case of insufficient response was considered at anytime during the DBTE.

Dose reduction of topiramate and erenumab was not allowed during DBTE (Week 0 to Week 24). After Week 24 or if the patient discontinued study drug, a one week double-blind taper off phase followed to ensure proper down titration for topiramate. At the end of the DBTE (24 weeks) the final assessment occurred to address the objectives.

A Follow-Up Visit 4 weeks after last study visit (or 8 weeks after last IMP injection for discontinued patients) was required as part of routine safety monitoring. The primary analysis was triggered when all patients had completed their respective last visit of the DBTE.

The End of study occurred when the last patient completed last visit (LPLV).

Arms: arm 1: 70 mg and 140 mg Erenumab arm 2: Topiramate in the highest tolerated dose (50 - 100 mg/day)
Interventions: intervention 1: Erenumab intervention 2: Topiramate intervention 3: Erenumab matching placebo intervention 4: Topiramate matching placebo
Intervention descriptions: intervention 1: 70mg/1mL (70 mg) or 2x70mg/1mL (140 mg) in pre-filled syringe, administered every 4 weeks intervention 2: Film-coated tablet taken orally:

25 mg administered once daily (first week of titration phase). After the first week, titration was done according to the summary of product characteristics (SmPC) in 25 mg increments each week and aimed to reach the recommended daily treatment dose of 100 mg (50/75/100 mg). 50/75/100 mg were administered twice daily during titration phase and maintenance phase. intervention 3: Erenumab matching placebo pre-filled syringue administered every 4 weeks intervention 4: Topiramate matching placebo administered daily

Protocol documents:
Prot_000.pdf: 
Global Clinical Development - General Medicine 
AMG 334 
Clinical Trial Protocol CAMG334ADE01 / NCT03828539
Randomized, double-blind, multicenter Head-to-head study 
of Erenumab against topiRamate - Migraine study to 
assess tolerability and efficacy in a patiEnt–centered 
Setting (HER-MES) 
Document type: 
Clinical Trial Protocol including Amendment 1 and 2 
EUDRACT number: 
2018-000943-15 
Version number: 
02  
Clinical trial phase: 
4 
Release date: 
06 - June-2019 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.1 (February 2016) 


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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 
Protocol summary ................................................................................................................ 9 
Amendment 1 ........................................................................................................................... 11 
Amendment 2 ........................................................................................................................... 12 
1 
Introduction ....................................................................................................................... 13 
1.1 
Background ............................................................................................................ 13 
1.2 
Purpose .................................................................................................................. 15 
2 
Study objectives and endpoints ......................................................................................... 15 
2.1 
Objectives and related endpoints ........................................................................... 15 
3 
Investigational plan ........................................................................................................... 17 
3.1 
Study design .......................................................................................................... 17 
3.2 
Rationale for study design ..................................................................................... 18 
3.3 
Rationale for dose/regimen, route of administration and duration of treatment .... 18 
3.4 
Rationale for choice of comparator ....................................................................... 19 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 20 
3.6 
Risks and benefits .................................................................................................. 20 
4 
Population .......................................................................................................................... 21 
4.1 
Inclusion criteria .................................................................................................... 21 
4.2 
Exclusion criteria ................................................................................................... 22 
5 
Treatment ........................................................................................................................... 25 
5.1 
Study treatment ...................................................................................................... 25 
5.1.1 
Investigational and control drugs .......................................................... 25 
5.1.2 
Additional treatment.............................................................................. 26 
5.2 
Treatment arms ...................................................................................................... 26 
5.3 
Treatment assignment and randomization ............................................................. 26 
5.4 
Treatment blinding ................................................................................................ 26 
5.5 
Treating the patient ................................................................................................ 27 
5.5.1 
Patient numbering ................................................................................. 27 
5.5.2 
Dispensing the study drug ..................................................................... 28 
5.5.3 
Handling of study and additional treatment .......................................... 28 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 28 


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5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 31 
5.5.6 
Rescue treatments.................................................................................. 31 
5.5.7 
Concomitant medication ....................................................................... 32 
5.5.8 
Prohibited treatments ............................................................................ 32 
5.5.9 
Emergency breaking of assigned treatment code .................................. 33 
5.6 
Study completion and discontinuation .................................................................. 34 
5.6.1 
Study completion and post-study treatment .......................................... 34 
5.6.2 
Discontinuation of study treatment ....................................................... 34 
5.6.3 
Withdrawal of informed consent ........................................................... 35 
5.6.4 
Lost to follow-up ................................................................................... 35 
5.6.5 
Early study termination by the sponsor ................................................. 36 
6 
Visit schedule and assessments ......................................................................................... 36 
6.1 
Information to be collected on screening failures .................................................. 41 
6.2 
Patient demographics/other baseline characteristics ............................................. 41 
6.3 
Treatment exposure and compliance ..................................................................... 41 
6.4 
Efficacy .................................................................................................................. 41 
6.4.1 
Migraine Days ....................................................................................... 41 
6.4.2 
Appropriateness of efficacy assessments .............................................. 42 
6.5 
Safety ..................................................................................................................... 43 
6.5.1 
Physical examination ............................................................................ 43 
6.5.2 
Vital signs.............................................................................................. 43 
6.5.3 
Height and weight ................................................................................. 44 
6.5.4 
Laboratory evaluations .......................................................................... 44 
6.5.5 
Electrocardiogram (ECG) ..................................................................... 44 
6.5.6 
Pregnancy and assessments of fertility ................................................. 44 
6.5.7 
Appropriateness of safety measurements .............................................. 45 
6.6 
Other assessments .................................................................................................. 45 
6.6.1 
Patient Reported Outcomes (PROs) ...................................................... 45 
7 
Safety monitoring .............................................................................................................. 47 
7.1 
Adverse events ....................................................................................................... 47 
7.2 
Serious adverse events ........................................................................................... 49 
7.2.1 
Definition of SAE ................................................................................. 49 
7.2.2 
SAE reporting........................................................................................ 49 
7.3 
Liver safety monitoring ......................................................................................... 50 
7.4 
Reporting of study treatment errors including misuse/abuse ................................ 51 
7.5 
Pregnancy reporting ............................................................................................... 52 


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7.6 
Prospective suicidality assessment ........................................................................ 52 
8 
Data review and database management ............................................................................. 53 
8.1 
Site monitoring ...................................................................................................... 53 
8.2 
Data collection ....................................................................................................... 54 
8.3 
Database management and quality control ............................................................ 54 
8.4 
Data Monitoring Committee .................................................................................. 55 
8.5 
Adjudication Committee ........................................................................................ 55 
9 
Data analysis ...................................................................................................................... 55 
9.1 
Patient demographics and other baseline characteristics ....................................... 55 
9.2 
Treatments ............................................................................................................. 56 
9.3 
Analysis of the primary variable(s) ....................................................................... 56 
9.3.1 
Variable(s) ............................................................................................. 56 
9.3.2 
Statistical model, hypothesis, and method of analysis. ......................... 56 
9.3.3 
Handling of missing values/censoring/discontinuations ....................... 57 
 
 57 
9.4 
Analysis of secondary variables ............................................................................ 57 
9.5 
Analysis of exploratory variables .......................................................................... 58 
9.5.1 
Safety variables ..................................................................................... 58 
9.5.2 
Resource utilization ............................................................................... 59 
9.5.3 
Not applicable. PK/PD .......................................................................... 59 
9.5.4 
DNA ...................................................................................................... 59 
9.5.5 
Blood Biomarkers ................................................................................. 59 
9.6 
Interim analyses ..................................................................................................... 59 
 
 59 
10 Ethical considerations ........................................................................................................ 59 
10.1 
Regulatory and ethical compliance ........................................................................ 59 
10.2 
Informed consent procedures ................................................................................. 59 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 60 
10.4 
Publication of study protocol and results............................................................... 60 
10.5 
Quality Control and Quality Assurance ................................................................. 60 
11 Protocol adherence ............................................................................................................ 61 
11.1 
Protocol amendments............................................................................................. 61 
12 References ......................................................................................................................... 62 
13 Appendices ........................................................................................................................ 64 
Appendix 1: Clinically notable laboratory values ............................................................. 64 


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Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements ......................................................................................................... 65 
 
List of tables 
Table 5-1 
Prohibited Treatments ........................................................................... 33 
Table 6-1 
Assessment Schedule: Double – Blind Treatment ................................ 37 
Table 6-2 
Abbreviated schedule of assessments (ASA) for patients with 
Treatment Discontinuation (TD) ........................................................... 40 
Table 7-1  
Guidance for Capturing the Study Treatment Errors Including 
Misuse/Abuse ........................................................................................ 52 
Table 13-1 
Liver Event and Laboratory Trigger Definitions .................................. 65 
Table 13-2 
Follow Up Requirements for Liver Events and Laboratory Triggers ... 65 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 17 
 


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List of abbreviations 
 
ACE/ARB 
Angiotensin-Converting Enzyme inhibitor / Angiotensin-Receptor Blocker 
AE 
Adverse Event 
Alb 
Albumin 
ALP 
Alkaline Phosphatase  
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
ASA 
Abbreviated Schedule of Assessments 
AST 
Aspartate Aminotransferase 
ATC 
Anatomic Therapeutic Chemical classification 
BDI 
Beck Depression Inventory 
CFR 
US Code of Federal Regulations  
CGRP 
Calcitonin Gene-related Peptide 
CPO 
Country Pharma Organization 
CQA 
Compliance Quality Assurance 
CRA 
Clinical Research Associate 
CRF 
Case Report/Record Form 
CRO 
Contract Research Organization 
CM 
Chronic migraine 
C-SSRS  
Columbia Suicide Severity Rating Scale  
CTCAE 
Common Terminology Criteria for Adverse Events 
DAR 
Dose Administration Record 
DBTE 
Double-Blind Treatment Epoch 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EM 
Episodic Migraine 
EMA 
European Medicines Agency 
EU 
European Union 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
HIT 
Headache Impact Test 
HRQoL 
Health-Related Quality of Life 
HTA 
Health Technology Assessment 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICHD 
International Classification of Headache Disorders 
ID 
Identification 
IEC 
Independent Ethics Committee 
IHS 
International Headache Society 
IMP 
Investigational Medicinal Product 


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IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD/IUS 
Intrauterine Device/System 
LFT 
Liver function test  
MAR 
Missing at Random 
MCS 
Mental Component Summary 
MedDRA 
Medical dictionary for regulatory activities  
MMD 
Monthly Migraine Days 
MMRM 
Mixed Model for Repeated Measurements 
MNAR 
Missing not at Random 
NSAID 
Non-steroidal antiinflammatory -drug 
PCS 
Physical Component Summary 
PFS 
Prefilled syringe 
PK/PD 
Pharmacokinetic/Pharmacodynamic 
PRO 
Patient-reported Outcome 
PSD 
Premature subject discontinuation 
PT 
Prothrombin Time 
q.m. 
once a month 
QM 
Quality Management 
RAS 
Randomized Analysis Set 
SAE 
Serious Adverse Event  
SAF 
Safety Analysis Set 
SF-36 
Medical Outcome Short Form Health Survey 
s.c. 
Subcutaneous 
SGOT 
Serum Glutamic Oxaloacetic Transaminase (Aspartate Aminotransferase) 
SGPT 
Serum Glutamic Pyruvic Transaminase (Alanine Aminotransferase) 
SmPC 
Summary of Product Characteristics 
SoC 
Standard of Care 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TBL 
Total Bilirubin 
TD 
Treatment Discontinuation 
 
 
ULN 
Upper Limit of Normal 
US 
United States 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 
γGT 
Gamma-Glutamyltransferase 


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Glossary of terms 
Calendar month 
A calendar month is the period from a particular date in one month to 
the same date in the next month. 
Cohort  
A specific group of patients fulfilling certain criteria 
Control-IMP 
Drug(s) used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug 
Dosage 
Dose of the study treatment given to the patient in a time unit (e.g. 100 
100 mg once a day, 75 mg twice a day) 
Enrollment 
Point/time of patient entry into the study at which informed consent 
must be obtained (e.g. prior to starting any of the procedures 
described in the protocol) 
Epoch 
A portion of the study, which serves a specific purpose. Typical 
epochs are: screening/recruitment, wash-out, treatment, and follow-up 
Medication pack number 
A unique identifier on the label of each investigational drug package 
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 ID  
A unique number assigned to each patient upon signing the informed 
consent  
Randomization number 
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment 
Study drug/ treatment 
Any single drug or combination of drugs administered to the patient as 
part of the required study procedures; includes investigational drug (s), 
topiramate in the highest tolerated dose/comparator active drug run-
ins or background therapy 
Study Treatment 
Discontinuation (TD) 
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date  
Test-IMP 
The 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.” 
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 patient 
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, and does not allow analysis of already obtained 
biologic material 
 


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Protocol No. CAMG334ADE01 
 
 
Protocol summary 
Protocol number 
CAMG334ADE01 
Title 
Randomized, double-blind, multicenter Head-to-head study of Erenumab 
against topiRamate - Migraine study to assess tolerability and efficacy in 
a patiEnt–centered Setting (HER-MES) 
Brief title 
 
Study of tolerability, safety and efficacy of 70 mg and 140 mg erenumab 
against topiramate in the highest tolerated dose in patients  with 
≥4migraine days/month, who must be either naïve or not suitable for or 
could have failed up to three prophylactic treatments  
Sponsor and Clinical 
Phase 
Novartis  
Phase IV 
Investigation type 
Biological 
Study type 
Interventional  
Purpose and rationale 
The purpose of this study is to determine the safety and efficacy of 70 mg 
and 140 mg erenumab compared to topiramate in the highest tolerated 
dose in patients suffering from ≥4 migraine days/month, who are naïve or 
not suitable for or have previously failed up to three prophylactic migraine 
treatments out of: propranolol/metoprolol, flunarizine and amitriptyline.  
Data from this study, in addition to data from the pivotal trial program, will 
provide important data for clinicians treating migraine patients. In 
addition, this data will also be used to support national health technology 
assessments (HTAs). 
Primary Objective 
The primary objective of this study is to demonstrate the tolerability of 70 
mg and 140 mg erenumab compared to topiramate in the highest 
tolerated dose as assessed by the rate of patients discontinuing 
treatment due to AE during the double-blind epoch of the study.  
Secondary Objectives 
To evaluate the effect of  70 mg and140 mg erenumab compared to 
topiramate in the highest tolerated dose on the proportion of patients with 
at least a 50% reduction from baseline in monthly migraine days 
Study design 
This study has a 24-week 2-arm, double-blind, double-dummy 
randomized, parallel-group treatment design 
Population 
The patient population will be comprised of 700 male and female 
migraine patients between the ages of 18 and 65, inclusive.  
Key Inclusion criteria 
- Documented history of migraine (with or without aura) for ≥12 months 
prior to screening according to the International Classification of 
Headache Disorders, 3rd Edition (ICHD-3) 
- ≥4 migraine days per month (based on ICHD-3 criteria) during 
baseline confirmed by eDiary 
- Patients must be either naïve or not suitable for or have failed up to 
three prophylactic treatments out of:  
o 
propranolol, metoprolol,  
o 
amitriptyline,  
o 
flunarizine 
Key Exclusion criteria 
- Older than 50 years of age at migraine onset 
- Unable to differentiate migraine from other headaches 
- History of cluster headache or hemiplegic migraine headache 
- Patients who have already been treated with topiramate, valproate or 
onabotulinumtoxin A 


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- Any previous use of a prophylactic migraine medication targeting the 
CGRP pathway  
- Use of a prophylactic migraine medication within 5 half-lives, or a 
device or procedure within 1 month prior to the start of the baseline 
phase or during the baseline phase 
- Use of the following for any indication in the 1 month prior to the start 
of the baseline phase or during the baseline phase: 
o 
opioid- or butalbital-containing analgesics ≥4 days/month  
Study treatment 
Erenumab 70 mg and 140 mg / topiramate in the highest tolerated dose 
(50 mg –  100 mg) 
Efficacy assessments 
- Migraine days/month 
 
Key safety 
assessments 
- AE-related treatment discontinuations 
- Adverse event monitoring 
- Physical exams and vital signs 
- Monitoring of laboratory markers in blood  
Other assessments 
Patient-reported outcomes: HIT-6, SF-36 v2; 
 
Data analysis 
The primary analysis will be performed comparing treatments with 
respect to the primary variable in a logistic regression model with the 
factors treatment and stratification factor (migraine days during the 
baseline epoch). The odds ratio and its 95% confidence interval (CI) and 
p-value will be given. The null hypothesis of equal odds will be rejected if 
the 2-sided p-value from the logistic regression model for the factor 
“treatment” is <0.05; however, superiority of erenumab will be claimed 
only if the odds of treatment discontinuation are lower under erenumab 
compared to topiramate. 
The secondary variable will be analyzed by logistic regression model for 
treatment comparison at end of the DBTE with missing data being 
imputed as non-response (non-responder imputation)..   
Key words 
Episodic migraine, chronic migraine, treatment failure, monoclonal 
antibody, CGRP, Calcitonin Gene-related Peptide  


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Amendment 1 
 
The original protocol is being amended to implement a further safety procedure in line with the 
topiramate SmPC and to adjust the safety follow-up period considering the EU approval of 
erenumab. Furthermore, changes have been introduced to correct and clarify certain criteria and 
procedures in the protocol. 
 
Changes to the protocol 
• A one week taper off phase for Topiramate has been implemented to provide further 
safety for patients and align with the Topiramate SmPC. Patients taking a daily dose of 
75 mg or 100 mg topiramate during the DBTE have to taper off topiramate after visit 
199 or when discontinuing study drug. Tapering off is performed with a daily dose of 
topiramate reduced by 50 mg for one week and double-blinding is maintained during 
taper off phase. (Chapters: 3.1; 5; 5.5.4; 5.6.1; 5.6.2) 
• The Safety follow-up epoch has been adjusted from 12 to 4 weeks. During safety follow-
up patients are only allowed to use rescue treatments including acute migraine 
medication and non-pharmacological treatments. As both IMPs, erenumab and 
topiramate, are approved for migraine prophylaxis and require no safety follow up 
according to the SmPCs, we adjusted the safety follow-up epoch from 12 to 4 weeks in 
order to provide patients faster access to pharmacological migraine prophylaxes 
following the clinical trial. (Chapters: 3.1; 5.6.1; 5.6.2; Figure 3-1; Tables 6-1 an 6-2) 
• 5.6.2 has been updated to clarify visit schedule, tapering off and safety follow-up after 
early discontinuation of study medication 
• Footnotes of the assesment schedules (Table 6-1 and 6-2) have been updated and 
corrected to clarify safety follow-up procedures as described in chapter 5.6.2 
• Visit intervals during visit 102 to 107 were reduced from 7 +/- 2 days to 7 +/- 1 day as 
topiramate blisters do only contain one extra pill (+ 1 day) during this epoch (chapter 
6). Additionally, it was clarified that visit intervals refer to visit 101. 
• Patient initials were removed from the ECG tracing labeling list (chapter 6.5.5). 
• Information about patient stratification have been added to chapter 5.3. 
• Medical history and adverse events terms have been updated to clarify database 
management (chapter 8.3).  
• Minor changes to correct formatting errors within the document were also made. 
 
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 amendment require IRB/IEC and Health Authorities approval prior to 
implementation. 


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Amendment 2 
 
 
 
 
 
Changes to the protocol 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
• In line with the Erenumab SmPC, the investigational product should be stored at room 
temperature for 30 minutes prior to the administration in order to reduce irritation at the 
injection site (Chapter 5.5.4).  
 
 
 
 


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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. It is mainly characterized by recurrent headache lasting 4 to 72 hours, which is usually 
accompanied by other neurological disturbances, nausea, vomiting or other nonspecific 
symptoms. The patient burden and disability as well as the societal impact increase with higher 
attack frequency. The spectrum of migraine disorders is typically differentiated according to 
the frequency of migraine days per month. “Episodic migraine” (EM) is characterized by the 
presence of 4 to 14 migraine days per months, while “Chronic migraine” (CM) is defined as 15 
or more headache days per months including at least 8 typical migraine days.  
Migraineurs are currently being treated for migraine prophylaxis by a variety of drug classes.  
Common prophylactic drugs or drug classes include beta blockers, topiramate, valproate, 
antidepressants (mainly amitriptyline), flunarizine, and certain angiotensin-converting-enzyme 
inhibitor / angiotensin II receptor blockers (ACE/ARBs) such as lisinopril and candesartan. 
Botulinum toxin (Botox®) is approved in most EU countries for use in CM but not for EM. 
Evidence for the use of these therapies in migraine is limited and many are used off-label. 
Amongst current prophylactic therapies for patient suffering from episodic migraine, topiramate 
has the broadest evidence regarding efficacy and safety. Its efficacy has been verified by several 
studies and it is considered efficacious in migraine treatment (Silberstein 2017). German 
migraine guidelines list topiramate amongst the prophylactic drugs of first choice (DGN 2018). 
However, the standard of care varies significantly across different regions. A general consensus 
on treatment recommendations does not exist and treatment decisions are often made on a case-
by-case basis. 
Overall, current migraine prophylactic drugs show variable efficacy and are associated with 
poor tolerability, often leading to discontinuation (Blumenfeld 2013). For example in a recent 
claims database analysis in chronic migraine, one year persistence to oral prophylactic drugs, 
irrespective of class, was as low as 13-16% (Hepp 2016), indicating a high unmet medical need 
for new therapies. Based on emerging evidence, Calcitonin Gene-related Peptide (CGRP) is a 
neuropeptide that prominently contributes to migraine pathophysiology. The potential 
mechanisms of action of CGRP receptor antagonists involve components of the trigeminal-
vascular system and include normalization of CGRP-induced vasodilation, reduction of CGRP-
induced neurogenic inflammation, and inhibition of pain transmission at the trigeminal ganglion 
and trigeminal nucleus (Wang 1995, Zimmermann 1996, Durham 2006). CGRP is an attractive 
target for the development of a migraine-specific prophylactic therapy with the aim of 
minimizing migraine days and improving patient quality of life in this common and often 
disabling disorder. Erenumab is a fully human monoclonal antibody targeting the CGRP 
receptor, which has already obtained marketing authorization in the EU. 
To date studies have been or are currently being conducted in North America, Europe, and Asia. 
Results from the erenumab phase 2 study (study 20120178) in patients with episodic migraine 
demonstrated that the 70 mg dose resulted in statistically significant and clinically meaningful 
reductions in monthly migraine days at Week 12 compared with placebo. The 70 mg dose 
produced statistically significant improvements in multiple secondary and exploratory outcome 


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measures, including the 50% responder rate, monthly headache days, and monthly migraine-
specific medication treatment days.  
Final results from the erenumab phase 2 study (study 20120295) in patients with chronic 
migraine showed a positive outcome. Patients randomized to the 70 mg and 140 mg dose groups 
experienced a mean 6.6-day reduction from baseline in monthly migraine days during Weeks 9 
–12 in both groups. The results were statistically significant compared with 4.2 days observed 
in the placebo group The 50% responder rate was increased to 39.9% and 41.2% with 70 mg 
and 140 mg erenumab, respectively, compared to 23.5% with placebo (Tepper 2017). For 
patients having already failed one or more prophylactic pharmacotherapy treatment with 
erenumab resulted in an even higher proportion of at least 50% responders in MMD reduction 
(40.8% for 140 mg, 34.7% for 70 mg versus 17.3% for placebo). Another analysis of data from 
the STRIVE study (study 2012096 see below) which assessed EM at doses of 70 mg and 140 
mg [10] showed that patients that failed at least 2 prior prophylactic also even had a greater 
benefit versus placebo and even more from the 140 mg dose.For the > 50% MMD reduction 
endpoint, the results showed that the OR was 2.9-fold greater than placebo at 70 mg compared 
to placebo, while 140 mg demonstrated a 4.5-fold greater effect than placebo (Goadsby 2017b). 
In addition, there are no dose-dependent differences in the safety profile from the available data 
in the STRIVE study. For doses of 70 mg and 140 mg, the rate of adverse events is similar  to 
what was seen with placebo (Goadsby 2017a). 
The results from three recently completed phase 3 studies against placebo (studies 20120296 
STRIVE 70 and 140 mg, 20120297 ARISE, 70 mg, and CAMG334A2301 LIBERTY, 140 
mg) in patients with episodic migraine also showed positive outcomes for erenumab.  
In ARISE (study 20120297), patients randomized to the 70 mg dose group experienced a 2.9-
day reduction from baseline in monthly migraine days compared with 1.8 days observed in 
the placebo group with the difference being statistically significant (Dodick 2018). In 
STRIVE (study 20120296), patients randomized to the 70 mg and 140 mg dose groups 
experienced mean 3.2 and 3.7-day reductions from baseline, respectively, compared with 1.8 
days observed in the placebo group over weeks 13-24 (statistically significant versus 
placebo). Another analysis of data from this study shows that patients with a previous 
treatment failure on at least 2 prophylactics benefit particularly from the higher dosage 
(Goadsby 2017a). For the ≥ 50% MMD reduction endpoint, the results showed that OR was 
2.9-fold greater than placebo at 70 mg compared to placebo, while 140 mg demonstrated a 
4.5-fold greater effect than placebo (Goadsby 2017b). LIBERTY, study CAMG334A2301, 
confirmed the efficacy and safety of 140 mg erenumab in a difficult to treat population with 2-
4 prior preventive migraine treatment failures. The proportion of patients achieving ≥50% 
reduction in MMD was significantly increased in erenumabtreated patients compared to 
placebo (30.3% vs 13.7%) meeting the primary endpoint. Additionally, all secondary 
endpoints were met and significant effects of erenumab over placebo were observed as early 
as week 4 (Reuter 2018).  
The safety and tolerability profile of erenumab was similar to placebo in both treatment 
groups for all studies. Most commonly reported AEs (≥3% in any group) included 
nasopharyngitis, fatigue, headache, back pain and influenza. There were no clinically 
significant changes in laboratory values, vital signs and electrocardiograms. The overall safety 
and tolerability profile is similar to placebo for both doses across the phase 2 and 3 study 


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program, so that to date no clinical significant dose related tolerability concerns arose 
(Goadsby 2017a, Dodick 2018, Reuter 2018) 
 
In the absence of a clear dose-dependent safety signal, a comparable overall efficacy trend 
between 70 mg and 140 mg erenumab with a proven efficacy of 140 mg erenumab in patients 
with 2-4 prior preventive migraine treatment failures, both dose groups (70 mg and 140 mg) 
are considered to offer an optimal benefit-risk ratio for the chosen patient population with 
certain patients obtaining an additional benefit from the 140 mg dose. CGRP targeting in 
migraine represents a new and specific approach in migraine therapy. Until now, no active 
comparator studies were conducted in the pivotal CGRP program. In view of the adherence 
issues with current standard of care (SoC) therapies prompted by poor tolerability and/or lack 
of efficacy (Hepp 2014), an important question is whether this new approach can provide 
additional benefit that leads to improved persistence and sustained efficacy for migraine 
patients over SoC therapies. This study was designed to elucidate the possible benefits of a 
targeted migraine therapy in comparison to current SoC prophylactic treatment. 
 
1.2 
Purpose  
The purpose of this study is to determine the safety and efficacy of erenumabcompared to 
topiramate in the highest tolerated dose in patients suffering from ≥4 migraine days/month, who 
are naïve or not suitable for or have failed up to three prophylactic migraine treatments out of: 
propranolol/metoprolol, flunarizine and amitriptyline. Data from this study will provide 
important data for clinicians treating migraine patients as particularly in comparison to current 
treatment options. In addition, this data will also be used to support national health technology 
assessments (HTAs) and reimbursement negotiations. 
2 
Study objectives and endpoints 
2.1 
Objectives and related endpoints 
Objective 
Endpoint 
 
Primary 
To demonstrate the tolerability of 70 mg and 140 mg 
erenumab compared to topiramate in the highest 
tolerated dose assessed by the rate of patients 
discontinuing treatment due to AE during the double-
blind epoch of the study. 
 
 
 
Discontinuation of treatment due to AE during the 
double-blind epoch of the study. 
 
 
 
 


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Objective 
Endpoint 
 
Secondary:  
To evaluate the effect of erenumab compared to 
topiramate in the highest tolerated dose on the 
proportion of patients with at least 50% reduction from 
baseline in monthly migraine days. 
 
 
Achieving at least a 50% reduction from baseline in 
MMD over the last 3 months (months 4, 5, and 6) of 
the double-blind epoch. 
 
Exploratory: 
 
To evaluate the effect of  70 mg and 140 mg  erenumab 
compared to topiramate in the highest tolerated dose 
on functional impairment, as measured by the 
Headache Impact Test (HIT-6) 
 
HIT-6  at week 24 
 
To evaluate the effect of 70 mg and 140 mg  erenumab 
compared to topiramate in the highest tolerated dose 
on generic health-related quality of life, as measured 
by the Short Form-36 (SF-36 v. 2) 
 
SF-36 quality of life at week 24 
 


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3 
Investigational plan 
3.1 
Study design 
This study uses a single-cohort, 2-treatment arm, parallel-group randomized, double-blind, 
double-dummy design in adult patients with episodic migraine and chronic migraine, who must 
be either naïve or not suitable for or could have failed up to three prophylactic treatments out 
of: propranolol/ metoprolol, amitriptyline, flunarizine. Patients will be stratified to into groups 
according to their number of migraine days during the baseline epoch. 
The following epochs are included in the study design:  
• Screening Epoch (0 – 2 weeks) – Required for all patients to assess initial eligibility. 
• Baseline Epoch (4 weeks) – All patients fulfilling eligibility criteria successfully 
completing the Screening Epoch are invited to participate. Eligibility for randomization 
will be assessed based on migraine frequency and diary compliance during this epoch.  
• Double-blind, double-dummy Treatment Epoch (DBTE, 24 weeks) – All patients 
completing the Baseline Epoch and fulfilling baseline eligibility criteria are invited to 
participate. Eligible patients will be randomized to one of two treatment arms. Double-
blind treatment epoch will start with a titration phase for topiramate of a maximum of 6 
weeks to determine the maximal tolerated dose and must aim to reach the recommended 
treatment dose of 100 mg according to the German SmPC. After the titration phase, 
maintenance phase will start (18 weeks). Topiramate dose has to be maintained until the 
end of the DBTE.  Erenumab dose at beginning of the DBTE is determined patient-
individually by the investigator based on the guidance provided in the SmPC and can be 
either 70 mg or 140 mg.  Dose escalation from 70 mg to 140 mg in case of insufficient 
response could be considered at any time during the DBTE (see 5.5.4).  
Dose reduction of topiramate and  erenumab is not allowed during DBTE (Visit 101-199). 
After visit 199 or if the patient discontinues study drug, a one week double-blind taper off 
phase will follow to ensure proper down titration for topiramate.  
At the end of the DBTE (24 weeks) the final assessment to address the objectives will 
occur.  
Follow-Up Epoch (4 weeks) –A Follow-Up Visit 4 weeks after last study visit (or 8 weeks 
after last IMP injection for discontinued patients) will be required as part of routine safety 
monitoring. The primary analysis will be triggered when all patients have completed their 
respective last visit of the double-blind treatment epoch. 
 
End of trial will occur when the last patient completes last visit (LPLV). 
 


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Figure 3-1 
Study design  
 
 
3.2 
Rationale for study design 
The study design was developed in accordance with the International Headache Society (IHS) 
guidelines for Controlled Trials of  Drugs in Migraine (Tfelt-Hansen 2012), including input 
from leading clinical migraine experts. A parallel-group, double-blind design is a standard way 
of assessing efficacy and safety of new agents. Topiramate will be used as comparator in this 
trial, it will be applied according to current SmPC, starting with an uptitration phase to 
100 mg/day. erenumab, a novel antibody therapy for the prophylaxis of migraine in patients 
with ≥4 migraine days/month recently approved by the European Commission, is administered 
according to current product information. Current migraine prophylactic treatments have been 
initially developed for other indications. They are variably effective regarding migraine 
treatment, however, patients often suffer from severe side effects. Hence, the discontinuation 
rates for approved migraine treatments are high. As lack of tolerability is described as the 
biggest problem of current prophylactic migraine treatments leading to an inability to sustain 
efficacy for a chronic disorder, superiority regarding tolerability displayed by treatment 
discontinuation rate due to AE has been chosen as primary endpoint.  
The specifics of population and treatment requirements were designed based on feedback from 
clinical experts and consultations with national HTA body (G-BA).  
3.3 
Rationale for dose/regimen, route of administration and duration 
of treatment 
Phase 2 results for erenumab in EM patients are currently available for the doses of 7 mg and 
21 mg (both of which have proven to be ineffective compared to placebo) and 70 mg, which 
has been shown to be effective. PK-exposure response modelling suggests that with higher 
doses, a potential additional benefit in terms of efficacy might be observed. The safety profile 
of erenumab has been investigated up to 280 mg in healthy volunteers in Phase 1 without a 
Double-blind treatment 
epoch 
Randomization 
Screening 
Epoch 
Week -6  
to Week -4 
 
Day 1 - Week  24 
Baseline 
Epoch 
Week -4 
to Day -1 
Erenumab s.c.  + Topiramate placebo oral 
Follow-Up Epoch 4 weeks after last visit (or 8 weeks 
after last IMP injection) 
Topiramate oral + Erenumab placebo s.c. 
Uptitration Phase; 
until Week 6 
Maintenance Phase 
18 weeks 


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difference in safety profile. For these reasons, an additional dose of 140 mg was introduced into 
the CM Phase 2b trial as well as one of the Phase 3a trials for EM.  
Results from the EM Phase 3 trials and the CM Phase 2b trial showed a significant effect 
compared to placebo across the primary endpoint and the vast majority of secondary and 
exploratory endpoints. The safety and tolerability profile of erenumab was similar to placebo 
in both treatment groups. In addition, the 140 mg dose in EM study 20120296 and in the CM 
20120295 study showed consistently stronger improvement compared to the 70 mg dose across 
patients with one or more prior prophylactic migraine treatment failures, suggesting an 
additional efficacy in this subpopulation of patients with episodic and chronic migraine with 
the higher dose. Additionally, data from the Phase 3b study CAMG334A2301 confirmed the 
efficacy and safety of 140 mg erenumab in a difficult to treat EM population with 2-4 prior 
prophylactic migraine treatment failures compared to placebo (Reuter 2018).  
To ensure treatment according to current product information, both doses (70 mg and 140 mg) 
were selected for this study. 70 mg or 140 mg can selected as starting dose at the choice of the 
investigator and also, dose escalation from 70 mg to 140 mg is allowed during the study, at the 
discretion of the investigator. 
This study features a double-blind, double-dummy approach. Patients will receive either  
erenumab 70 mg or 140 mg q.m. subcutaneously + topiramate placebo orally  or topiramate 
orally + erenumab placebo subcutaneously for 24 weeks in the double-blind treatment epoch. 
The maximally tolerated topiramate dose will be determined throughout the 6 week uptitration 
phase. Within this phase the dose is increased weekly by 25 mg increments and must aim to 
reach 100 mg/day as recommended by the German SmPC. Patients may maintain a dose for 
longer than one week if deemed necessary but must reach at least 50 mg/day within the 
uptitration phase in order to enter the maintenance phase. Thus, the recommended dose to enter 
the maintenance phase is 100 mg/day but may also be 75 mg/day or 50 mg/day for individual 
patients in accordance with the product information. Topiramate dose has to be maintained 
during the 18 week maintenance phase and down titration is not allowed till end of DBTE. As 
200 mg is not likely to improve response but in contrast can add to tolerability issues 
(Silberstein 2017), this dose will not be included in this trial. For 50 mg, 75 mg and 100 mg 
dose, patients will have to take two tablets a day, one in the morning, one in the evening. The 
erenumab dose will be determined for each patient individually by the investigator in 
accordance with the product information. 
 
3.4 
Rationale for choice of comparator 
The choice of a specific therapy for a migraine headache prophylaxis often takes into account 
individual circumstances, comorbidities and patient preferences. Patients are currently being 
treated by a variety of drug classes that were originally developed for other indications, but 
were repurposed for migraine prophylaxis. In Germany approved prophylactic drugs for 
episodic migraine are propranolol, metoprolol, topiramate, amitriptyline and flunarizine.  
Amongst current prophylactic therapies for patient suffering from episodic migraine, topiramate 
has the broadest evidence regarding efficacy and safety. Its efficacy has been verified in several 
RCTs and it is considered an efficacious drug in migraine treatment (Silberstein 2017). Also, 


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German migraine treatment guidelines list topiramate amongst the prophylactic drugs of first 
choice (DGN 2018). Therefore, topiramate is a reasonable comparator choice, which is 
considered to provide patients with an adequate prophylactic treatment for their migraine. 
Topiramate dose will be determined, in accordance to current topiramate SmPC, during a 6 
week titration phase. During the following 18 week maintenance phase, patients may stay on 
the dose they were maximally titrated to of either 50 mg, 75 mg or 100 mg topiramate.  
All patients continue to receive best supportive care in form of acute medications and other non-
pharmacological interventions as appropriate. 
3.5 
Purpose and timing of interim analyses/design adaptations 
The primary analysis will occur when the last patient completes the double-Blind Epoch 
(V199/V199-ASA), prior to the Follow-Up Epoch. A study report will be prepared and finalized 
for the double-Blind Epoch, and a second study report will be prepared incorporating data from 
the Follow-Up Epochs after all patients have completed their respective last visit (LPLV; 
V201/V201-ASA). 
3.6 
Risks and benefits  
Erenumab is being developed for migraine prophylaxis in a large clinical development program 
including more than 3.000 patients and has shown efficacy across the migraine spectrum. Key 
risks and benefits are briefly summarized below. For further information, please refer to the 
most recent Investigator Brochure. 
There were no significant findings in the toxicology studies with erenumab that would predict 
a risk to human patients. There were no significant effects on electrocardiogram (ECG) 
parameters, blood pressure or respiration rate in the single dose cardiovascular study in 
cynomolgus monkeys.  
Safety results from studies (studies 20120178, 20120295, 20120296 and 20120297, and 
CAMG334A2301) indicate that the frequency of treatment-emergent adverse events (AEs) and 
discontinuations due to AE were similar between erenumab and placebo. Overall, there was no 
apparent dose-dependency in the incidence of AEs. Most treatment-emergent adverse events 
were grade 1 or 2 based on the Common Terminology Criteria for Adverse Events (CTCAE). 
Most commonly reported AEs (≥3% in any group) included nasopharyngitis, fatigue, headache, 
back pain and influenza. There were no clinically significant changes in laboratory values, vital 
signs and electrocardiograms.  
As of 31 January 2018 an estimated 4298 subjects (3576.67 subject-years) have been exposed 
to erenumab in clinical trials conducted by Amgen and Novartis since the beginning of the 
development program.  The  integrated safety data set comprised 2537 subjects with migraine, 
representing 2310.3 SY of exposure.  
A theoretical cardiovascular safety risk with CGRP receptor blockade is lack of compensatory 
vasodilation, particularly in the context of the coronary circulation during ischemic-related 
conditions. Overall, to date, there is no evidence from nonclinical and clinical data of risk of 
cardiovascular effects. However, based on the theoretical basis of the mechanism of action of 
erenumab, cardiovascular effects continue to be monitored in clinical trials. 


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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.  
Adverse reactions for erenumab are generally mild in nature and include injection site reactions, 
constipation, muscle spasm and pruritus (common frequency, ≥1/100 to <1/10).  Injection Site 
Reactions includes multiple preferred terms, such as injection site pain and injection site 
erythema. Pruritus includes preferred terms of generalized pruritus, pruritus, and pruritic rash. 
The risk to patients in this trial will be minimized by compliance with the eligibility criteria, 
close clinical monitoring, and use of rescue medications. 
Current migraine prophylaxis treatments are often accompanied by lack of efficacy or 
tolerability issues (Blumenfeld 2013). Commonly reported adverse events of topiramate are 
parasthesia, fatigue, memory/cognitive disturbances and mood problems (Topiramate TEVA 
25 mg SmPC 2015, Topiramate TEVA 50 mg SmPC 2015). Other approved prophylactic 
medications such as propranolol or amitriptyline also face tolerability concerns (Hepp 2014). 
Currently there is a high unmet need for a therapy that is well-tolerated, has sustained response 
rates and excellent compliance.  
 
4 
Population 
The study population will consist of male and female patients, ages 18 – 65, with a documented 
history of episodic migraine (4  – 14 baseline migraine days) or chronic migraine (≥15 baseline 
headache days), who are naïve to or not suitable for or have failed up to three previous 
prophylactic treatments out of: metoprolol/propranolol, amitriptyline, flunarizine due to lack of 
efficacy or tolerability. See inclusion criteria 6 for detailed definitions. 
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study must fulfill all of the following criteria. For inclusion 
purposes, one month equals one full calendar month. 
During the Screening Epoch: 
1. Patient is capable of understanding the nature, significance and implications of the 
clinical trial .Written informed consent must be obtained before any assessment is 
performed 
2. Adults ≥18 to ≤65 years of age upon entry into screening 
3. Documented history of migraine (with or without aura) for ≥12 months prior to 
screening according to the International Classification of Headache Disorders-3rd 
Edition (ICHD-3)  


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4. ≥4 migraine days per month (in at least two separate attacks) (based on ICHD-3 
criteria) on average across the last 3 fully completed calendar months prior to 
screening based on retrospective reporting  
5.    
6. Patients must be either naïve or not suitable for or could have failed up to three  
prophylactic treatments out of:  
• propranolol/metoprolol, amitriptyline, flunarizine 
7. Patients on non-pharmacologic treatments (e.g., biofeedback, psychotherapy or other 
locally accepted and endorsed interventions for migraine) must have been stable on this 
treatment for at least 3 months prior to baseline 
 
* The following definitions are applicable for inclusion criteria 6: 
• Efficacy failure is defined as “no meaningful reduction in headache frequency after 
administration of the respective medication for an adequate period of time (at least 2 –
3 months are recommended by the European Headache Federation treatment 
guidelines) at generally accepted therapeutic dose(s) based on the investigator’s 
assessment within the last 5 years prior to screening.” 
• Tolerability failure is defined as “documented discontinuation due to adverse events 
of the respective medication at any previous time.” 
• “Not suitable” for the purpose of this study is defined as “patient is not considered to 
be suitable for the treatment for medical reasons such as contraindications or 
precautions included in local labels, national guidelines or other locally binding 
documents” as confirmed by the treating physician. 
 
During the Baseline Epoch: 
8. Migraine frequency of ≥4 days during the Baseline Epoch, confirmed by the eDiary 
9. ≥80% eDiary compliance during the Baseline Epoch 
4.2 
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients. Calendar months are used for exclusion 
purposes. 
1. Older than 50 years of age at migraine onset 
2. Unable to differentiate migraine from other headaches 
3. History of cluster headache or hemiplegic migraine headache 
4. Patients who have already been treated with topiramate, valproate or onabotulinumtoxin A 
5. Use of a prophylactic migraine medication within 5 half-lives, or a device or procedure 
within one month prior to the start of the baseline phase or during the baseline phase 
6. Use of the following for any indication in the 1 month prior to the start of the baseline 
phase or during the baseline phase: 


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• Opioid- or butalbital-containing analgesics ≥4 days/month  
7. Anticipated to require any excluded medication (see Section 5.5.8, Table 5-1), device or 
procedure (e.g., occipital nerve stimulators, transcranial magnetic stimulation,) during the 
study 
8. Active chronic pain syndromes (e.g., fibromyalgia or chronic pelvic pain) 
9. History or current evidence of major psychiatric disorder (such as schizophrenia, bipolar 
disorder or type B personality disorder that might interfere with the ability to properly 
report clinical outcomes)  
10. Evidence of drug or alcohol abuse or dependence within 12 months prior to screening, 
based on medical records or patient self-report  
11. Current evidence of depression based on a BDI-II total score of >19 at screening. Patients 
with anxiety disorder and/or major depressive disorder are permitted in the study if they 
are considered by the investigator to be stable and are taking no more than one medication 
per disorder. Patients must have been on a stable dose within the 3 months prior to the 
start of the baseline phase 
12. History of seizure disorder or other significant neurological conditions other than migraine 
13. Score “yes” on item 4 or item 5 of the Suicidal Ideation section of the Columbia Suicide 
Severity Rating Scale (C-SSRS), if this ideation occurred in the past 6 months, or “yes” on 
any item of the Suicidal Behavior section, except for the “Non-Suicidal Self-Injurious 
Behavior” (item also included in the Suicidal Behavior section), if this behavior occurred 
in the past 2 years 
14. Myocardial infarction, stroke, transient ischemic attack, unstable angina, or coronary 
artery bypass surgery or other revascularization procedures within 12 months prior to 
screening 
15. History or current diagnosis of ECG abnormalities indicating significant risk of safety for 
patients participating in the study 
16. 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 
17. Hepatic disease by history or total bilirubin ≥2×ULN or ALT or AST ≥3xULN as assessed 
by central laboratory at initial screening 
18. Pregnant or nursing (lactating) women 
19. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 110 days after stopping of study medication. Highly effective 
contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient). 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 6 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 


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• Male sterilization (at least 6 months prior to screening). For female patients on the 
study, the vasectomized male partner should be the sole partner for that patient and 
should have received medical assessment of surgical success. 
• Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS) or other forms of hormonal contraception that have comparable efficacy (failure 
rate <1%), e.g. hormone vaginal ring or transdermal hormone contraception 
• In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking investigational drug 
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
6 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.  
20. Use of other investigational drugs within 5 half-lives of enrollment, or until the expected 
pharmacodynamic effect has returned to baseline, whichever is longer. 
21. History of hypersensitivity to the study drug or its excipients (including topiramate) or 
latex. 
22. Patients not suitable for treatment with topiramate according to topiramate SmpC. 
Conditions listed under 4.4 Warnings and precautions in topiramate SmPC (e.g., risk 
of/history of nephrolithiasis, decreased renal function, risk of/history of eye disorders, risk 
of/history of metabolic acidosis) could be deemed as exclusion criterion at discretion of the 
investigator. 
23. Any prior exposure to (investigational) prophylactic migraine products targeting the 
CGRP pathway, including previous erenumab studies. 
24. Unlikely to be able to complete all protocol required study visits or procedures, and/or to 
comply with all required study procedures (e.g., independent completion of electronic 
diary items) to the best of the patient’s and investigator’s knowledge 
25. Patients who may be dependent on the sponsor or investigator 
26. Patient has not been committed to an institution by virtue of an order issued either by the 
judicial or the administrative authorities, 
 
 


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5 
Treatment 
5.1 
 Study treatment 
5.1.1 
Investigational and control drugs 
Novartis will supply the investigational medicinal products (IMP) listed below in a double-
dummy setting:  
 
Verum: 
Test-IMP:  
1x Erenumab 70mg/1mL (70 mg), in pre-filled syringe, administered every 4 weeks; 
2x Erenumab 70mg/1mL (140 mg), in pre-filled syringes, administered every 4 weeks; 
 
Dose for erenumab is 70 mg or 140 mg throughout the trial. If the response is insufficient, dose 
may be uptitrated from 70 mg to 140 mg. Down titration from 140 mg to 70 mg is not allowed. 
 
Control-IMP:  
Topiramate 25 mg and 50 mg in blisters, applied according to following scheme: 
Titration phase (6 weeks): 
The recommended dose for Topiramate is 100 mg/day in accordance with the SmPC. 
The titration phase must aim to reach the recommended dose as follows: 
First week: Topiramate 25 mg (1x 25 mg/day) in the evening 
After first week on 25 mg, dose has to be increased weekly by up titration in 25 mg 
increments to the highest tolerated dose. Individual patients may maintain dose for 
longer than one week, if deemed necessary but all efforts should be made to achieve the 
recommended 100 mg dose and only if that is not deemed feasible should the patient 
enter the maintenance phase at a lower dose. The patient will then enter the maintenance 
phase with the highest tolerated dose reached within the 6 week titration phase, whereas 
minimal dose is 50 mg topiramate (2x 25 mg/day), intermediate dose is 75 mg (1x 
25 mg and 1x 50 mg/day) and maximal and recommended dose is 100 mg (2x 
50 mg/day). Starting with the 50mg dose, patients will have to take one tablet in the 
morning and one in the evening. Downtitration is not allowed. 
Maintenance phase (18 weeks): Patients stay on highest tolerated dose determined during 
titration phase 
Tapering off (1 week): Patients taking a daily dose of 75 mg or 100 mg topiramate during the 
DBTE should taper off topiramate after visit 199 or when discontinuing study drug. Tapering 
off is performed with a daily dose of topiramate reduced by 50 mg for one week. 
 


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Placebo for Test-IMP:  
1x Erenumab matching placebo, in pre-filled syringe, administered every 4 weeks; 
2x Erenumab matching placebo, in pre-filled syringes, administered every 4 weeks; 
 
Placebo for Control-IMP: 
Matching topiramate tablets for 25 mg and 50 mg in blisters  
 
 
5.1.2 
Additional treatment 
No additional treatment beyond test-IMP and control-IMP and matching placebos is included 
in this trial. 
5.2 
Treatment arms 
Patients will be assigned to either erenumab or topiramate at the Randomization Visit (Visit 
101), in a 1:1 ratio, 
5.3 
Treatment assignment and randomization  
At visit 101 all eligible patients will be randomized via Interactive Response Technology (IRT) 
to one of the two treatment arms. The investigator or his/her delegate will contact the IRT after 
confirming that the patient fulfills all the inclusion/exclusion criteria. The IRT will assign a 
randomization number to the patient, which will be used to link the patient to a treatment arm 
and will specify a unique medication number for the first packages of study drug to be dispensed 
to the patient. Randomization will be stratified by monthly migraine frequency. The 
randomization number will not be communicated to the caller. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of patient numbers to randomization numbers stratified by monthly 
migraine frequency (4-7 migraine days per month during the Baseline Epoch vs 8-14 migraine 
days per month during the Baseline Epoch vs ≥15 migraine days per month during the Baseline 
Epoch). 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 Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to packs containing the investigational drug(s).  
The randomization scheme for patients will be reviewed and approved by a member of the 
Randomization Group.  
5.4 
Treatment blinding  
Patients, investigator staff, persons performing the assessments, and Novartis personnel and 
their delegates will remain blinded to the identity of the treatment from the time of 
randomization until the conclusion of the double-blind treatment epoch and primary analysis.  


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Following methods will be used: (1) Randomization data are kept strictly confidential until the 
time of unblinding, and will not be accessible by anyone else involved in the study with the 
exception of the randomization office, (2) the identity of the treatments will be concealed by 
the use of study drug that are all identical in packaging, labeling, schedule of administration, 
appearance, taste and odor. 
Unblinding will only occur in the case of patient emergencies (see Section 5.5.9). 
Randomization information will be available to the investigator when the study report has been 
finalized.  
5.5 
Treating the patient 
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
5.5.1 
Patient numbering 
Each patient is uniquely identified by a subject number which is composed by the site number 
assigned by Novartis (4 digits) and a sequential number (3 digits) assigned by the investigator. 
Once assigned to a patient, the subject number will not be reused.  
Upon signing the informed consent form, the patient is assigned the next sequential number by 
the investigator. The first patient is assigned patient number 001, and subsequent patients are 
assigned consecutive numbers (e.g. the second patient is assigned patient number 002, the third 
patient is assigned patient number 003). The investigator or his/her staff will contact the IRT 
and provide the requested identifying information for the patient to register them into the IRT. 
The site must select the eCRF with a matching subject number from the EDC system to enter 
data. Once assigned to a patient, the patient number will not be reused. If the patient fails to be 
randomized for any reason, the IRT must be notified within 2 days that the patient was not 
randomized. The reason for not being randomized will be entered on the Screening Log, and 
the Demography eCRF should also be completed.  
Investigators may re-screen a patient if there is reasonable certainty that reasons for screening 
failure will be resolved prior to or during a repeat screening attempt. Should this occur, the site 
should re-consent the patient and assign a new subject identification number.  
Some examples of re-screening reasons are listed below. If needed, questions regarding re-
screening eligibility may be discussed with Novartis.  
• Laboratory value(s) out of range due to sampling error or that might be within range 
after medically-appropriate supplementation. (Note: Before screen failing and then re-
screening the subject, efforts should be made to repeat the laboratory assessment(s) 
during the original initial screening phase.) 
• The patient has a medical condition that can be stabilized or resolved prior to the 
repeat screening attempt. 
 
Only one re-screening is allowed per patient. Patients who had <4 monthly migraine days 
during Baseline Phase cannot be re-screened. 


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5.5.2 
Dispensing the study drug 
Each study site will be supplied with study drug in packaging of identical appearance. 
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the 2 treatment arms. Investigator staff will 
identify the study drug package(s) to dispense to the patient by contacting the IRT and obtaining 
the medication number(s). Immediately before dispensing the package to the patient, 
investigator staff will detach the outer part of the label from the packaging and affix it to the 
source document (Drug Label Form) for that patient’s unique subject number.  
5.5.3 
Handling of study and additional treatment  
5.5.3.1 
Handling of study treatment  
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designees 
have access. Upon receipt, all study treatment must be stored according to the instructions 
specified on the labels. Clinical supplies are to be dispensed only in accordance with the 
protocol. Technical complaints are to be reported to the respective Novartis CPO Quality 
Assurance. 
Medication labels will comply with the legal requirements and be printed in German. They will 
include storage conditions for the study treatment but no information about the patient 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. Patients will be asked 
to return all unused study treatment and packaging for every study visit and 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, supported by the Novartis monitoring team, will return all unused study treatment, 
packaging, drug labels, and a copy of the completed drug accountability log to the Novartis 
address provided in the investigator folder at each site. 
5.5.3.2 
Handling of additional treatment  
Not applicable. 
5.5.4 
Instructions for prescribing and taking study treatment  
The investigational product dose is either 70 mg or 140 mg depending on the investigators 
decision, which has to be made for each patient individually and in accordance with the product 
information: the recommended dose is 70 mg, some patients may benefit from 140 mg (see 
Section 5.1 of AIMOVIG® SmpC).  
 
In case of insufficient response, the dose may be escalated from 70 mg to 140 mg. Possible 
reasons for uptitration could be, but are not limited to: 


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- 
insufficient response as deemed by physician and/or patient 
- 
reduction of acute medication use not satisfactory 
- 
insufficient improvement in life quality  
 
An adjustment of the 70 mg dose to 140 mg can be performed at any time during the DBTE. 
The investigational product dose of 140 mg must not be changed once a patient received the 
dose during DBTE.  
Reference treatment doses are determined during the uptitration phase and must aim to reach 
the recommended daily treatment dose of 100 mg topiramate in accordance to the German 
SmPC. The reference treatment dose established during the up titration phase must not be 
changed during the 18-week maintenance phase.  
There are no temporal restrictions for the investigational or the reference treatment (e.g., 
proximity to meals, sleep or activity). 
 
Test-IMP:  
70 mg and 140 mg erenumab or respective placebos will be administered by qualified study 
staff at each dosing visit during the 24 week double-blind treatment epoch (i.e., at Day 1 and 
Week 4, Week 8, Week 12, Week 16 and Week 20). Subcutaneous (s.c.) injections are to be 
given for each investigational product administration. For purposes of study treatment dosing, 
“q.m.” refers to an every 4 weeks injection regimen. The study drug administration date should 
be in 4 week increments (+/ – 4 days) from the first dose of study drug. Any dose 
administrations that may occur greater than +/ – 4 days from the 4 week time point (e.g., patient 
unavailability) should be discussed with the Sponsor prior to dosing. The anatomical sites for 
administration of investigational product are the upper arm, upper thigh, or abdomen; the 
location of the injection site should be documented in the source document. In order to reduce 
irritation at the injection site, the investigational product should be stored at room temperature 
for 30 minutes prior to the administration.  
 
Control-IMP:  
Topiramate and oral placebo will be administered by the patient himself. During the first week 
of the titration phase topiramate 25 mg or matching placebo will be administered once daily. 
After the first week, topiramate titration will be done according to the SmPC in 25 mg 
increments each week and must aim to reach the recommended daily treatment dose of 100 mg 
(50/75/100 mg). Topiramate 50/75/100 mg or matching placebo will be administered twice 
daily during titration phase and maintenance phase. The physician may decide to allow the 
patient to remain on this dose for another week if there are tolerability concerns. If a patient is 
not deemed suitable for uptitration during the 6 weeks titration period, the patient may remain 
on highest tolerated dose throughout the trial. Minimal dose to enter maintenance phase has to 
be 50 mg, patients not tolerating 50 mg topiramate have to be taken off prophylactic study 
treatment, but maintain in study on supportive care. Maximal dose for topiramate is 100 mg. 


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Downtitration is not allowed in this trial. Patients who discontinue study treatment or complete 
the study with a daily dose of 75 mg or 100 mg topiramate should taper off topiramate for one 
week with a daily dose of topiramate reduced by 50 mg.  
 
Titration phase (week 1 till end of week 6) (according to current topiramate product 
information) 
Titration of topiramate has to be made in 25 mg increments each week and must aim to reach 
the recommended migraine treatment dose of 100 mg in accordance to the SmPC. If a patient 
initially cannot tolerate the next dose step, he may stay on the current dose for another week. 
However, at the end of the 6 week titration phase, patients must reach at least the 50 mg 
topiramate dose to maintain in the DBTE.  
Exemplatory titration scheme: 
Week 1: 25 mg topiramate (= 1x 25 mg /day in the evening) 
Week 2 : If patient tolerates 25 mg topiramate--> uptitration to 50 mg topiramate (2x 25 mg/day) 
Week 3: If patient tolerates 50 mg topiramate --> uptitration to 75 mg topiramate (25 mg and 
50 mg, each 1x/day) (=75 mg topiramate/day)  
Week 4: If patient tolerates 75 mg --> uptitration to 100 mg topiramate (2x 50 mg/day) 
 
Week 5 and 6: further uptitration to next dose for patients who had to prolong titration during 
weeks 1 – 4 due to initial  poor tolerability. 
Starting with week 7, patient has to take a stable dose (50 mg, 75 mg or 100 mg topiramate).  
Patients who are not able to tolerate 50 mg have to be discontinued from drug, but should remain 
in the trial for documentation purposes. During this time, patients may use treatments described 
under 5.5.6 for their acute migraine attacks. 
 
Maintenance phase (start of week 7 to end of week 24): 
Control-IMP doses are determined during the uptitration phase and must not be changed during 
the 18-week maintenance phase. Patients have to remain on their highest tolerated dose (50 mg, 
75 mg or 100 mg topiramate) throughout maintenance phase. If a patient cannot tolerate dose 
during maintenance phase, he/she has to be discontinued from all study treatment, but should 
remain in the trial. This patient is allowed to continue using rescue medication as described 
under 5.5.6.  
All kits of study treatment assigned will be recorded in the IRT. Novartis monitors will reconcile 
treatment assigned vs treatment administered and ensure that the information is congruent 
during their monitoring visits. 
 
 
 


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Tapering off  
Control-IMP should be tapered off by patients who complete the study (Visit 199, end of week 
24) or discontinue study treatment after receiving a daily dose of 75 mg or 100 mg Control-
IMP. Tapering off is performed by reducing the daily dose of Control-IMP by 50 mg for one 
week before a patient stops taking the drug.  
Exemplatory Tapering off scheme: 
Patient on 100 mg/day topiramate --> One week 50 mg/day topiramate --> No more medication 
Patient on 75 mg/day topiramate --> One week 25 mg/day topiramate --> No more medication 
Patient on 50 mg/day topiramate --> No more medication (no tapering off required) 
Patient on 25 mg/day topiramate --> No more medication (no tapering off required) 
5.5.5 
Permitted dose adjustments and interruptions of study treatment  
Control-IMP dose adjustments are allowed during the 6-week up titration phase only and must 
be kept stable during the 18-week maintenance phase. Investigational treatment dose 
adjustments from 70 mg to 140 mg can be made throughout the whole trial. Titration for 
topiramate and for erenumab 70 mg to 140 mg can be done independently. Interruptions are 
allowed as specified in Section 5.5.9. Additionally, investigator-initiated interruptions will be 
considered on a case-by-case basis. 
5.5.6 
Rescue treatments 
Patients can continue to use acute migraine medication and non-pharmacological interventions 
as rescue treatments. These may include both pharmacologic interventions (i.e., treatments for 
acute attacks such as triptans and NSAID) and non-pharmacologic treatments (e.g., 
biofeedback, psychotherapy or other locally accepted and endorsed interventions for migraine). 
Non-pharmacological treatment options may only be used as rescue therapy, if patient has been 
stable on the specific non-pharmacological treatment 3 months prior to baseline.  
Patients discontinued from study drug may only use rescue treatments for their migraine attacks 
as described above. 
Site staff will pre-specify the name, dose strength, and route of administration of the patient’s 
acute headache (rescue) medications in the patient’s eDiary. If the patient 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. 
Use of rescue medication must be recorded in the eDiary. The acute headache medications 
reported in the eDiary also will be collected on the Concomitant medications/Significant non-
drug therapies eCRF, but data will include only the drug name, indication, and start and stop 
dates of overall use (i.e., not the individual administration dates). Relevant non-drug therapies 
as part of “best supportive care” use should also be recorded in the eCRF. 


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5.5.7 
Concomitant medication 
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after enrolling into the study. 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. Potential interactions of each concomitant drug with topiramate, according to 
SmPC section 4.5, must be individually assessed as additional clinical monitoring of defined 
parameters might be necessary (e.g., adequate control of diabetic disease state). If in doubt the 
investigator should contact the Novartis medical monitor before randomizing a patient or 
allowing a new medication to be started. 
5.5.8 
Prohibited treatments 
Use of the treatments displayed in Table 5-1 is NOT allowed as designated due to the potential 
confounding of efficacy assessments unless in the context of a different pre-existing condition 
in stable doses for at least 3 months prior to baseline.  
 
 
 
 


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Table 5-1 
Prohibited Treatments 
Treatment 
Prohibition period 
All prophylactic treatments targeting the CGRP pathway Any time before study start and 
throughout the study 
Topiramate 
Any time before study start 
Valproate/Divalproex 
Any time before study start and 
throughout the study 
All oral beta blockers 
Within 5 half-lives of the start of 
the baseline epoch and throughout 
the study  
Flunarizine 
Antidepressants (amitriptyline, venlafaxine, 
desvenlafaxine) 
 Antiepileptics (e.g. gabapentin) 
ACE/ARB (lisinopril, candesartan) 
Botulinum toxin (in the head and/or neck region) for 
medical treatment 
Any time before study start and 
throughout the study 
Botulinum toxin (in the head and/or neck region) for 
cosmetic treatment  
Within 4 months of the start of the 
baseline epoch and throughout the 
study  
Invasive interventions (e.g., nerve blocks, occipital nerve 
stimulators, transcranial magnetic stimulation)  
Within 1 month of the start of the 
baseline epoch and throughout the 
study 
5.5.9 
Emergency breaking of assigned treatment code  
Emergency code breaks must only be undertaken when it is required in order to treat the patient 
safely. Most often, study treatment discontinuation and knowledge of the possible treatment 
assignments are sufficient to treat a study patient who presents with an emergency condition. 
Emergency treatment code breaks are performed using the IRT. When the investigator contacts 
the system to break a treatment code for a patient, he/she must provide the requested patient 
identifying information and confirm the necessity to break the treatment code for the patient. 
The investigator will then receive details of the investigational drug treatment for the specified 
patient and a fax or e-mail confirming this information. The system will automatically inform 
the Novartis monitor for the site and the study team that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide: 
• protocol number 
• study drug name (if available) 


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• patient number 
In addition, oral and written information to the patient must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that unblinding 
can be performed at any time. If a code break occurs, the patient has to discontinue the study. 
5.6 
Study completion and discontinuation  
5.6.1 
Study completion and post-study treatment 
A patient will be considered to have completed the double-blind treatment epoch when the 
patient has completed Visit 199 in the protocol.  
The patient’s completion status will be recorded on the appropriate Study Phase Completion 
eCRF pages. 
For all patients tapering off Control-IMP after study completion, an unscheduled visit has to be 
conducted after finishing the tapering off phase. At this visit, information about Control-IMP 
compliance, AEs, SAEs and concomitant medications have to be collected. 
For all patients a safety follow-up visit (visit 201) should be conducted 4 weeks after the last 
visit or 8 weeks after the last  IMP injection. The information to be collected at this follow up 
visit is outlined in Table 6-1. 
5.6.2 
Discontinuation of study treatment  
Discontinuation of study treatment for a patient occurs when study drug is stopped earlier than 
the protocol planned duration, and can be initiated by either the patient or the investigator.  
The investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of trial participation. 
Study treatment must be discontinued under the following circumstances:  
• Patient wish  
• Pregnancy (see Section 6.5.6 and Section 7.5) 
• Use of prohibited treatment as per recommendations in Table 5-1 
• Any situation in which study treatment might result in a safety risk to the patient 
• Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the patient’s overall status, prevents the patient from continuing 
participation in the study 
If discontinuation of study treatment occurs, the patient should NOT be considered withdrawn 
from the study, and should continue recording in the eDiary as per protocol. Also, patients who 
discontinued treatment from the double-blind treatment epoch will follow the abbreviated visit 
schedule until the follow up visit (week 28) is reached (Table 6-2). These visits should be 
performed with all assessments outlined in Table 6-2. At a minimum, the following data should 
be collected at clinic visits or via telephone visits:  
• new/concomitant treatments 
• adverse events / serious adverse events 


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If the patient cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person pre-designated by the patient. This telephone 
contact should preferably be done according to the study visit schedule.  
 
Patients 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 (Visit 199) will 
be performed. At this final visit, the adverse event and concomitant medications should be 
reconciled on the eCRF. Patients will return for a follow-up visit approximately 8 weeks after 
their last dose of study medication, and perform the study procedures outlined in Table 6-1. 
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment. If study drug discontinuation occurs because treatment code has been broken, please 
refer to Section 5.5.9. Patients who are prematurely withdrawn from the study will not be 
replaced by an equal number of newly enrolled patients.All patients receiving a daily dose of 
75 mg or 100 mg topiramate (for at least one week) should perform a taper off phase for one 
week after discontinuation of study treatment. After the taper off phase an unscheduled visit 
should be performed to record control-IMP compliance, AEs, SAEs and concomitant 
medications. 
 
5.6.3 
Withdrawal of informed consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent from the study is defined as when a patient: 
• Does not want to participate in the study anymore, and 
• Does not want any further visits or assessments, and 
• Does not want any further study related contacts, and 
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient’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 patient 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 patient’s study withdrawal should be made as detailed in the 
assessment table below. 
5.6.4 
Lost to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the patient, e.g. dates of telephone 


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calls, registered letters, etc. A patient cannot be considered as lost to follow-up until the time 
point of his/her scheduled end of study visit has passed. 
5.6.5 
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, or for 
regulatory or medical reasons (including slow enrollment). Should this be necessary, the patient 
must be seen as soon as possible 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 will 
be responsible for informing the Institutional Review Board / Independent Ethics Committee 
(IRBs/IECs) of the early termination of the trial. 
6 
Visit schedule and assessments 
Table 6-1 and Table 6-2 list all of the assessments and indicate with an “X” when the visits are 
performed. 
Patients must be seen for all visits on the designated day, or as close to it as possible. Missed or 
rescheduled visits should not lead to automatic discontinuation.  
During visits 102 to visit 107, intervals between visits must not exceed 7 +/- 1 day calculated 
from Visit 101 (Day1), to ensure continuous supply regarding oral medication. 
During visits 108 to visit 199, intervals between visits should not exceed  28 +/- 4 days 
calculated from Visit 101 (Day 1). If the visit has to be scheduled outside this window,  an 
approval from the sponsor has to be collected to ensure continues supply of oral medication and 
patient safety regarding s.c. medication. 


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Table 6-1 
Assessment Schedule: Double – Blind Treatment 
 
Screen 
Baseline 
Double – Blind Treatment Epoch (Titration) 
Double – Blind Treatment Epoch (Maintenance) 
Follow 
Up2 
Visit number1 
0 
1 
101 
102 
103 
104 
105 
106 
107 
108 
109 
110 
111 
199 
201 
End of Week 
-6 
-4 
0 
1 
2 
3 
4 
5 
6 
8 
12 
16 
20 
24 
28 
Day 
-42 
-28 
1 
8 
15 
22 
29 
36 
43 
57 
85 
113 
141 
169 
197 
Obtain informed 
consent 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Randomization 
  
  
x 
  
  
  
  
  
  
  
  
  
  
  
 
Demography 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Medical history, 
prior medication3  
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Complete Physical 
Exam 
S 
  
  
  
  
  
  
  
  
  
  
  
  
S 
S 
Brief Physical 
Exam  
  
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
 
 
Height 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Weight 
x 
  
x 
  
  
  
  
  
  
  
  
  
  
x 
x 
Vital Signs4 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECG 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Chemistry/ 
Hematology12  
x 
  
x 
  
  
  
  
  
  
x  
  
  
  
x 
x 
Serum Pregnancy 
x 
  
  
  
  
  
  
  
  
  
  
  
  
x 
 
Urine pregnancy13 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
x 


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Screen 
Baseline 
Double – Blind Treatment Epoch (Titration) 
Double – Blind Treatment Epoch (Maintenance) 
Follow 
Up2 
Visit number1 
0 
1 
101 
102 
103 
104 
105 
106 
107 
108 
109 
110 
111 
199 
201 
End of Week 
-6 
-4 
0 
1 
2 
3 
4 
5 
6 
8 
12 
16 
20 
24 
28 
Day 
-42 
-28 
1 
8 
15 
22 
29 
36 
43 
57 
85 
113 
141 
169 
197 
eDiary dispensing 
  
S 
  
  
  
  
  
  
  
  
  
  
  
  
 
eDiary return5 
  
  
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
 
Clinical 
Outcomes 
(eDiary) 
  
Daily eDiary starting at -4 (baseline Epoch) throughout DBTE  
(daily migraine attacks, duration, severity, rescue medication)   
 
SF-36 6 (eDiary) 
  
  
 X 
  
  
  
x 
  
  
x 
x  
x  
 x 
 x 
 
HIT-6 6 (eDiary) 
  
  
 X 
  
  
  
x 
  
  
 x 
x  
x  
 x 
 x 
 
C-SSRS 6,7 
x 
x 
X 
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
BDI-II6 
x 
  
 
  
  
  
  
  
 
  
  
  
  
 
 
Concomitant 
Medications 
 
x 
X 
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
Adverse Events8 
  
  
X 
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
Serious Adverse 
Events8 
x 
x 
X 
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
Study Drug 
Administration 
PFS9 
  
  
X 
 
 
 
x 
 
 
x 
x 
x 
x 
  
 
Oral Study Drug 
Dispensing10 
 
 
X 
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
 
 
Contact IRT11 
x 
x 
X 
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
 
 
 


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Screen 
Baseline 
Double – Blind Treatment Epoch (Titration) 
Double – Blind Treatment Epoch (Maintenance) 
Follow 
Up2 
Visit number1 
0 
1 
101 
102 
103 
104 
105 
106 
107 
108 
109 
110 
111 
199 
201 
End of Week 
-6 
-4 
0 
1 
2 
3 
4 
5 
6 
8 
12 
16 
20 
24 
28 
Day 
-42 
-28 
1 
8 
15 
22 
29 
36 
43 
57 
85 
113 
141 
169 
197 
Baseline Phase 
Completion 
form 
  
x 
  
  
  
  
  
  
  
  
  
 
  
  
 
Double-Blind 
Treatment 
Phase 
Completion 
form 
  
  
  
  
  
  
  
  
  
  
  
 
  
x 
 
Follow-Up 
Phase 
Completion 
form 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
 
x 
 
1 – All study visit target dates are to be calculated from the Day 1 visit date and all study procedures for a given visit should be completed on the same day. 
2 – The Follow-Up Visit is required 8 weeks after last IMP injection (erenumab / corresponding Placebo) for patients who discontinue the study or 4 weeks after V199 for 
patients who complete the study. The Follow-Up visit can be skipped if any other safety follow up visit occurred 8 weeks after last IMP injection.  
3 – Including prior prophylactic medication. 
4 – Includes blood pressure, pulse and temperature. 
5 – Patient brings to each visit for use at site 
6 – To be completed during applicable study visits before study drug administration, where applicable. 
7 – Should also be performed at unscheduled visits. 
8 – SAEs will be collected after signing of the informed consent through the end of the Follow-Up Epoch (8 weeks after the last IMP injection). Non-serious AEs will be 
collected after randomization (Visit 101) through the end of the Follow-Up Epoch (8 weeks after the last IMP injection). 
9 – Study drug is administered by study staff, during the applicable study visits, q.m., s.c..  
10 – Oral study drug will be dispensed to the patient at the center during the applicable study visit for home application.  
11 – Sites will access the Interactive Response Technology (IRT) System to register study early termination.  
12 – Should be additionally performed at any visit if deemed necessary by the investigator due to AEs. 
13 – Should be performed/registered by the investigator prior to dosing during DBTE. 
TD = Treatment discontinuation; PFS  = Prefilled syringe; PSD = Premature subject discontinuation; X = Assessment to be recorded in the source documents and the clinical 
data base; S = Assessment to be recorded as source documentation only. 


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Table 6-2 
Abbreviated schedule of assessments (ASA) for patients with Treatment Discontinuation (TD) 
Visit number 
V105-ASA 
V108-ASA 
V109-ASA 
V110-ASA 
V111-ASA 
V199-ASA 
V201-ASA2 
End of Week1 
4 
8 
12 
16 
20 
24 
28 
Complete Physical Exam 
 
 
 
 
 
S 
 
Brief Physical Exam 
S 
S 
S 
S 
S 
 
 
Weight 
 
 
 
 
 
x 
x 
Vital Signs3 
X 
x 
x 
x 
x 
x 
x 
Chemistry/Hematology12 
 
x 
 
 
 
x 
x 
Serum Pregnancy 
 
 
 
 
 
x 
 
Urine pregnancy 
S 
S 
S 
S 
S 
 
x 
ECG 
 
 
 
 
 
x 
 
Clinical Outcomes (eDiary) 
eDiary should be maintained  
 
 
SF-364(eDiary) 
X 
x 
x 
x 
x 
x 
 
HIT-64 (eDiary) 
X 
x 
x 
x 
x 
x 
 
C-SSRS 
X 
x 
x 
x 
x 
x 
 
Concomitant Medications 
X 
x 
x 
x 
x 
x 
x 
Adverse Events5 
X 
x 
x 
x 
x 
x 
x 
Serious Adverse Events5 
X 
x 
x 
x 
x 
x 
x 
Follow Up Phase Completion form 
 
 
 
 
 
 
x 
 
1 – All study visit target dates are to be calculated from the Day 1 visit date, and all study procedures for a given visit should be completed in the same day. 
2 – The Follow-Up Visit is required for all patients who discontinue study drug early. or complete the study and do not continue commercial drug (if locally available). The Follow-Up visit can 
be skipped if any other safety follow up visit occurred 4 weeks after V199-ASA or the patient continues commercial drug (if locally available). For assessments please refer to table 6-2. 
3 – Includes blood pressure, pulse and temperature. 
4 – To be completed during applicable study visits before study drug administration, where applicable 
5 – SAEs will be collected after signing of the informed consent through the end of the Follow-Up Epoch. Non-serious AEs will be collected after randomization (Visit 101) through the end of 
the Follow-Up Epoch (V201-ASA). 
12 – Should additionally be performed at any visit if deemed necessary by the investigator due to AEs. 
TD = Study treatment discontinuation; PSD = Premature patient discontinuation; X = Assessment to be recorded in the source documents and the clinical data base;  
S = Assessment to be recorded as source documentation only. 
 


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6.1 
Information to be collected on screening failures  
All patients who have signed informed consent but not entered into the next epoch will have 
the study completion page for the Screening Epoch, demographics, inclusion/exclusion, and 
serious adverse event (SAE) data collected. Adverse events that are not SAEs will be followed 
by the investigator and collected only in the source data. 
6.2 
Patient demographics/other baseline characteristics  
Patient demographic and baseline characteristic data will be collected on all patients include: 
year of birth, age, sex, race, source of patient referral, relevant medical history/current medical 
condition present before signing informed consent. Where possible, diagnoses not symptoms 
will be recorded.  
Prior headache characteristics and previous headache medication history, including information 
on the suitability for migraine prophylactics will be collected as part of 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. 
6.3 
Treatment exposure and compliance 
Study medication is administered at the site (test-IMP) or dispensed to the patient (control-IMP) 
by the investigator or designated study staff as outlined in Table 6-1. This information should 
be captured in the source document and the eCRF at each visit. All study treatments dispensed 
and returned must be recorded in the Drug Accountability Log. Site staff will review eDiary 
compliance and control-IMP compliance (topiramate) with the patient at each visit. 
6.4 
Efficacy 
Efficacy assessments will include:  
• Migraine days 
The timing and frequency of these assessments are outlined in Table 6-1. Patients will record 
the efficacy information using the provided eDiary platform. To aid in compliance, it is 
recommended that the information be completed at the same time every day that is convenient 
for the patient. Retroactive completion will be allowed up to 48hours prior to the time of 
completion. Any entries >48 hours will not be allowed and will be considered missing data. 
Data collected in the eDiary will be normalized to a 28 day period.    
6.4.1 
Migraine Days 
A migraine day is defined as any calendar day in which the patient 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: 


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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 patient took a migraine-specific medication (i.e., triptane 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 (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) 
• Symptoms (e.g., aura, nausea, vomiting, photophobia, phonophobia) 
• Use of acute headache medications (medication name (from pre-entered list), date of 
dosing, number of times taken of each date, number of units taken) 
6.4.2 
Appropriateness of efficacy assessments  
The definition of migraine day (Section 6.4.1) is consistent with the diagnostic criteria of 
migraine and probable migraine according to the International Classification of Headache 
Disorder (ICHD-3). The MMD will be calculated using migraine day data collected from the 
eDiary. Migraine days are commonly used as an endpoint in pivotal trials as acknowledged in 
the IHS guidelines for controlled trials of drugs in migraine (Tfelt-Hansen 2012). 
The mean change in MMD however describes a population-based measure and, given the 
natural variability in migraine trials, often is associated with small effect sizes. Thus, a clinically 
important complementary information is the proportion of patients 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.  
 
 Additional PRO scales were included to gather information on functional 
impact of headache (HIT-6, SF-36). 
 
 


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6.5 
Safety  
Safety assessments will include: 
• Treatment discontinuations due to AEs 
• Adverse events (Section 7.1) 
• Physical examination 
• Vital signs 
• ECG 
• Height/weight 
• Laboratory evaluations  
• Pregnancy testing (females of childbearing potential) 
• Columbia Suicide Severity Rating Scale (C-SSRS) (Section 7.6) 
The timing and frequency of these assessments are outlined in Table 6-1 and Table 6-2.  
6.5.1 
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, as well as vascular and neurological examination. If indicated based on medical 
history and/or symptoms, rectal, external genitalia, breast, and pelvic exams will be performed. 
A brief physical exam will include the examination of general appearance and will be at all 
visits starting from Visit 2, except where a complete physical examination is required (see 
above).  
Information for all physical examinations must be included in the source documentation at the 
study site. Clinically relevant findings that are present prior to randomization must be included 
in the Medical History part of the eCRF. 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 eCRF. 
6.5.2 
Vital signs  
Vital signs include blood pressure, pulse and temperature measurements. After the patient has 
been sitting for approximately five minutes, with back supported and both feet placed on the 
floor, systolic and diastolic blood pressure will be measured three times using a validated 
device, with an appropriately sized cuff. The repeat sitting measurements should be made at 
approximately 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. The method to take 
temperature should be consistent throughout the study. 


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6.5.3 
Height and weight  
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor clothing, 
but without shoes) will be measured. 
6.5.4 
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 Appendix 1. 
6.5.4.1 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential counts, 
and platelet count will be measured. 
6.5.4.2 
Clinical chemistry 
Bilirubin (total, direct and indirect), alkaline phosphatase, AST (SGOT), ALT (SGPT), GGT, 
creatinine and estimated creatinine clearance (GFR)  will be measured. Clinical chemistry 
assessment will be performed at Screening (Visit 0), begin of DBTE (Visit 101), during DBTE 
two weeks after topiramate titration phase (Visit 108), at the end of DBTE (Visit 199) and at 
follow up (Visit 201).  
6.5.5 Electrocardiogram (ECG) 
ECGs must be recorded as outlined in the central ECG reading manual. The preferred sequence 
of cardiovascular data collection during study visits is ECG collection first, followed by vital 
signs, and blood sampling. The Fridericia QT correction formula (QTcF) as reported by the 
central reader should be used for clinical decisions. Single 12 lead ECGs are collected. The 
original ECGs, printed on non-heat sensitive paper, appropriately signed, must be collected and 
archived at the study site. Each ECG tracing must be labeled with study number,  subject 
number, date and time, and filed in the study site 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 abnormalities 
must be recorded on the relevant section of the medical history/Current medical conditions/AE 
eCRFs as appropriate. 
6.5.6 
Pregnancy and assessments of fertility  
All pre-menopausal women who are not surgically sterile will have pregnancy testing. Serum 
pregnancy tests will be performed at the beginning and end of the study, with urine pregnancy 
tests performed at the remaining visits. Pregnancy tests during DBTE should be 
performed/registered by the investigator prior to dosing. The specific schedule is outlined in 
Table 6-1 and Table 6-2. 


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6.5.7 
Appropriateness of safety measurements  
The safety assessments have been selected based upon the safety profile of the drug as reported 
in the Investigator Brochure and are standard for this patient population and drug class. 
6.6 
Other assessments 
• Headache Impact Test (HIT-6) 
• SF-36 V2 
• Beck Depression Inventory (BDI)-II 
 
 
The timing and frequency of these assessments are outlined in Table 6-1 and Table 6-2.  
6.6.1 
Patient Reported Outcomes (PROs)  
Patients will complete all Patient Reported Outcome (PRO) questionnaires using the provided 
eDiary platform. For those questionnaires that are completed in-clinic, during visits, completion 
should occur before any other assessments are performed.  
All questionnaires will be completed in German, at the scheduled study visit prior to the patient 
seeing the investigator for any clinical assessment or evaluation. The site staff should check the 
responses to the questionnaire for completeness and encourage the patient to complete any 
missing responses. 
Patients should be given sufficient space and time to complete all study PROs. If patients 
experience any difficulties with submission after they complete the PROs, the study staff should 
assist them with submitting their PRO responses. Attempts should be made to collect responses 
to all PROs for all patients, including from those who prematurely discontinue prior to the study 
evaluation completion visit, however, if patients refuse to complete PROs, this should be 
documented in study source records.  
Completed questionnaires will be reviewed and examined by the investigator, before the clinical 
examination, for responses that may indicate potential adverse events (AEs) or serious adverse 
events (SAEs). The investigator should review not only the responses to the questions in the 
questionnaires but also for any unsolicited comments written by the patient. If AEs or SAEs are 
confirmed, then the physician must record the events as per instructions given in Section 7.1 
and Section 7.2 of the protocol. 
6.6.1.1 
Headache Impact Test (HIT-6) 
The HIT-6 is a short-form self-administered questionnaire based on the internet-HIT question 
pool (Kosinski 2003). The HIT-6 was developed as a global measure of adverse headache 
impact to assess headache severity in the previous month and change in a patient’s clinical 
status over a short period of time. Six items assess the frequency of pain severity, headaches 
limiting daily activity (household, work, school, and social), wanting to lie down when 
headache is experienced, feeling too tired to work or do daily activities because of headache, 
feeling “fed up” or irritated because of headache, and headaches limiting ability to concentrate 


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or work on daily activities. Each of the 6 questions is responded to using 1 of 5 response 
categories: “never,” “rarely,” “sometimes,” “very often,” or “always.”  
For each HIT-6 item, 6, 8, 10, 11, or 13 points, respectively, are assigned to the response 
provided. These points are summed to produce a total HIT-6 score that ranges from 36 to 78. 
HIT-6 scores are categorized into 4 grades, representing little or no impact (49 or less), some 
impact (50 – 55), substantial impact (56 – 59), and severe impact (60 – 78) due to headache. 
No recall period is specified for the first 3 items. The recall period is the past 4 weeks for the 
last 3 items. Patients will complete this in their eDiary during their scheduled clinic visit, at the 
frequency outlined in Table 6-1 and Table 6-2.  
6.6.1.2 
Medical Outcome Short Form Health Survey (SF-36) Version 2 (4-week 
recall period) 
The SF-36 is a widely used and extensively studied instrument to measure health-related quality 
of life (HRQoL) among healthy subjects and patients with acute and chronic conditions. It 
consists of eight subscales that can be scored individually: Physical Functioning, Role-Physical, 
Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health 
(Ware 1993). Two overall summary scores, the Physical Component Summary (PCS) and the 
Mental Component Summary (MCS) also can be computed (Ware 1994). The SF-36 has proven 
useful in monitoring general and specific populations, comparing the relative burden of 
different disease, differentiating the health benefits produced by different treatments, and in 
screening individual subjects. The purpose of the SF-36 in this study is to assess the HRQoL of 
subjects. Given the  nature of this disease and the 4-weekly assessment, the SF-36 version 2, 
with a 4-week recall period, will be used in this study. 
6.6.1.3 
Beck Depression Inventory (BDI)-II 
The BDI-II is a 21-item questionnaire that assesses severity of depression. Each item is scored 
from 0 to 3. The total score is categorized into 4 severity grades: minimal depression (0 – 13), 
mild depression (14 – 19), moderate depression (20 – 28), and severe depression (29 – 63) 
(Beck 1996). 
The questionnaire takes approximately 10 minutes to complete. Patients will be asked to 
complete this in their eDiary during their scheduled clinic visit, at the frequency outlined in 
Table 6-1. The recall period is the preceding two weeks, including the day of completion. 
 
 
 
 
 
 
 
 


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7 
Safety monitoring 
7.1 
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 patient or 
clinical investigation patient from randomization (Visit 101) until the end of study visit (16 
weeks after the last IMP injection). Any events occurring during the Screening and Baseline 
Epochs and conditions that were already present at the time of informed consent should be 
documented as medical history. An AE may or may not be temporally or causally associated 
with the use of a medicinal (investigational) product.  
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred. 
The occurrence of adverse events must be sought by non-directive questioning of the patient at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the patient during or between visits or through physical examination findings, laboratory test 
findings, or other assessments. 
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 patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1. 
Adverse events must be recorded in the Adverse Events eCRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information: 
• 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 
• its relationship to the study treatment  
• Yes 
• No 
 


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• its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported. 
• whether it constitutes a serious adverse event (SAE - See Section 7.2 for definition of 
SAE) and which seriousness criteria have been met. 
• action taken regarding [investigational] 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 single subject. 
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 
• its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent, and assessment must be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions required 
to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any new 
information regarding the safety profile of the medicinal product that is identified between IB 
updates will be communicated as appropriate, e.g., via an Investigator Notification or an 
Aggregate Safety Finding. New information might require an update to the informed consent 
and has then to be discussed with the patient. 
The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the investigator’s 
source documents; however, if the AE meets the criteria of an SAE, it must be reported to 
Novartis. 


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7.2 
Serious adverse events 
7.2.1 
Definition of SAE 
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: 
• is fatal or life-threatening  
• 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 
• 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  
• social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• is medically significant, e.g. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above . 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the patient 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 Annex IV, ICH-E2D Guideline). 
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 patient or might 
require intervention to prevent one of the other outcomes listed above. 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 Annex IV, ICH-E2D Guideline). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
7.2.2 
SAE reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until the completion of the Follow-Up Epoch (8 weeks after the 


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last IMP injection) must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after the completion of the Follow-Up Epoch should only be reported 
to Novartis if the investigator suspects a causal relationship to study treatment.  
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. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to study treatment, 
complete the SAE Report Form in English, and submit the completed form within 24 hours to 
Novartis. Detailed instructions regarding the submission process and requirements for signature 
are to be found in the investigator folder provided to each site.  
Follow-up information is submitted as instructed in the investigator folder. Each re-occurrence, 
complication, or progression of the original event must be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was broken or not, and 
whether the patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment a Drug Safety and Epidemiology 
Department associate may urgently require further information from the investigator for health 
authority reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries. 
Migraine days including migraine-related events (underlying disease) which meet SAE-
definition (e.g. hospitalization) should be reported on the relevant eCRF pages instead of SAE 
form unless, in the judgement of the investigator, a migraine attack is unusually severe or 
unexpected and warrants specific notification as an SAE. 
7.3 
Liver safety monitoring  
To ensure patient 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 (S)AE): 
• Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 


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• Liver events, which will require close observation, follow-up monitoring and completion of 
the standard base liver eCRF pages 
Please refer to Table 13-1-Appendix 2 for complete definitions of liver laboratory triggers and 
liver events.  
Every liver laboratory trigger or liver event as defined in Table 13-1-Appendix 2 should be 
followed up by the investigator or designated personnel at the trial site as summarized below. 
Detailed information is outlined in Table 13-2-Appendix 2. 
For the liver laboratory trigger: 
• Repeating the liver function test (LFT) within the next week to confirm elevation. 
These LFT repeats must be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory must then be performed at central laboratory as soon as possible. If 
a liver event is subsequently reported, any local LFTs previously conducted that are associated 
with this event must be reported on the Liver eCRF pages. 
• If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate. 
For the liver events: 
• Repeating the LFT to confirm elevation as appropriate 
• Discontinuation of the investigational drug if appropriate 
• Hospitalization of the patient if appropriate 
• A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications) 
• An investigation of the liver event which needs to be followed until resolution.  
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion; obtaining more detailed history 
of symptoms and prior or concurrent diseases, history of concomitant drug use, exclusion of 
underlying liver disease. All follow-up information, and the procedures performed must be 
recorded on appropriate eCRF pages, including the liver event overview eCRF pages. 
7.4 
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, patient 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. 


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Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the dose administration record (DAR) 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. 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
 
Table 7-1  
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 
7.5 
Pregnancy reporting  
To ensure patient 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 must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment.  
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
as an SAE. 
7.6 
Prospective suicidality assessment  
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire that prospectively 
assesses Suicidal Ideation and Suicidal Behavior (Posner 2011). The C-SSRS must be 
administered at each visit, including unscheduled visits. 
A validated version of the C-SSRS will be used to capture self-reported C-SSRS data via web-
based interactive response system (eC-SSRS). The eC-SSRS uses a detailed branched logic 
algorithm to perform the C-SSRS patient interview, evaluating each patient’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 


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assesses the patient as having positive suicidal signs, the investigator will be immediately 
notified by either fax, e-mail 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 patient 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 patient is 
referred. 
In addition, all life-threatening events must be reported as SAEs. For example, if a patient 
answers “yes” to one of the questions in the Suicidal Behavior section, an SAE must be reported 
if the event was life-threatening. All events of “Non-Suicidal Self-Injurious Behavior” 
(question also included in the Suicidal Behavior section) should be reported as AEs and 
assigned the appropriate severity grade.  
All SAEs relating to suicidal behavior must be reviewed by the Safety Management Team or 
early project teams. 
8 
Data review and database management  
8.1 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and Good Clinical Practice 
(GCP) compliance and the quality/integrity of the sites’ data. The field monitor will visit the 
site to check the completeness of patient records, the accuracy of entries on the eCRFs, 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. This central analytics organization may also analyze data and 
identify risks and 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 patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by the 
patient (a signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. Novartis monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria, documentation 


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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 patients will be 
disclosed. 
8.2 
Data collection 
Designated investigator staff will enter the data required by the protocol into the EDC system. 
Designated investigator site staff will not be given access to the system until they have been 
trained.  
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the eCRFs are complete and accurate. After database lock, the investigator 
will receive copies of the patient data for archiving at the investigational site.  
8.3 
Database management and quality control 
Novartis staff [or CRO working on behalf of Novartis] review the data entered into the CRFs 
by investigational staff for completeness and accuracy and instruct the site personnel to make 
any required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data. 
Prior/concomitant medications and procedures as well as significant non-drug therapies entered 
into the database will be coded using the WHO Drug Reference List, which employs the 
Anatomical Therapeutic Chemical (ATC) classification system. Medical history/current 
medical conditions and medical history possibly contributing to liver dysfunction as well as 
adverse events will be coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. 
Laboratory samples will be processed centrally in Germany and the results will be sent 
electronically to Novartis (or a designated CRO in Germany). 
ECG readings will be processed centrally and the results will be sent electronically to Novartis 
(or a designated CRO). 
Diary data will be entered into an electronic diary by the patient. The system will be supplied 
by a vendor(s), who will also manage the database. The database will be sent electronically to 
Novartis personnel (or designated CRO). 
Randomization codes and data about all study drug(s) dispensed to the patient 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 database will be sent 
electronically to Novartis (or a designated CRO). 


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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.  
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis.   
8.4 
Data Monitoring Committee 
Not required. 
8.5 
Adjudication Committee 
Not required. 
9 
Data analysis  
The first analysis will be conducted on all patient data when the double-blind treatment epoch 
of the trial ends. The data will be analyzed by Novartis and/or by the designated CRO.  
Analysis sets 
The Randomized Analysis Set (RAS) will consist of all participants who received a 
randomization number, regardless of receiving study medication. 
The Full analysis set (FAS) will consist of all participants who received at least one dose of 
double-blind study medication. In FAS, subjects will be analyzed according to randomized 
treatment, regardless of the actual treatment received. 
The Safety analysis set (SAF) will consist of all randomized subjects who received at least one 
dose of investigational product and will be analyzed based on actual treatment received.  
9.1 
Patient demographics and other baseline characteristics  
Demographic variables and other baseline characteristics including previous migraine 
treatments will be summarized. 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. Any 
condition entered as medical history or current medical conditions at baseline will be coded 
using the MedDRA dictionary. Medical history will be summarized by system organ class and 
preferred term in the MedDRA dictionary. Summaries for migraine specific medical history 
will be provided as well.  


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9.2 
Treatments 
The analysis of study treatment data will be based on the safety set. A data listing and a summary 
of the investigational drug injections and pill counts (erenumab or topiramate) administered 
will be provided. Dose levels achieved and no. /percentage of patients titration per visit will be 
presented for topiramate or matching placebo. The duration of exposure to study treatment will 
be summarized by treatment group. In addition, the number and percentage of participants 
receiving rescue medications, concomitant medications, and significant non-drug therapy will 
be summarized by preferred term (coded by WHO Anatomic Therapeutic Chemical 
classification [ATC]) and by treatment arm, and be listed. 
9.3 
Analysis of the primary variable(s) 
9.3.1 
Variable(s) 
The analysis of the primary variable will be based on the following estimand: 
• Population – Safety Analysis Set (SAF) 
• Variable of Interest: The primary endpoint is the rate of patients discontinuing the 
allocated study treatment due to an adverse event (AE) during the double-blind treatment 
epoch. 
• Intervention effect – effect between erenumab versus topiramate during double-blind 
treatment regardless of adherence to randomized treatment. 
• Summary measure – odds ratio 
9.3.2 
Statistical model, hypothesis, and method of analysis. 
The null hypothesis to be rejected is that the odds of AE-related treatment discontinuations are 
equal in both treatment groups. The corresponding alternative hypothesis is that the odds are 
not equal under erenumab compared to topiramate. 
Let pj denote the proportion of AE-related treatment discontinuations for treatment group j, j=0, 
1, where 
• 0 corresponds to erenumab 
• 1 corresponds to topiramate 
The following hypotheses will be tested: 
H0: (p1 / (1- p1)) / (p0 / (1- p0)) = 1 versus HA: (p1 / (1- p1)) / (p0 / (1- p0)) ≠ 1In other words: 
H0: The odds ratio of AE-related treatment discontinuations for erenumab vs topiramate is 
equal to 1, meaning no difference on AE-related treatment discontinuations between the two 
treatments. HA: The odds ratio of AE-related treatment discontinuations for erenumab vs 
topiramate is different from 1. 
The primary analysis will be performed comparing treatments with respect to the primary 
efficacy variable in a logistic regression model with the factors treatment and stratification 
factor (migraine days during the baseline epoch). The odds ratio and its 95% confidence interval 


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(CI) and p-value will be given. The null hypothesis of equal odds will be rejected if the 2-sided 
p-value from the logistic regression model for the factor “treatment” is <0.05; however, 
superiority of erenumab will be claimed only if the direction is correct, i.e. if the odds of 
response are lower under erenumab compared to topiramate. 
 
9.3.3 
Handling of missing values/censoring/discontinuations 
For every patient, it can be determined whether he/she discontinued for AE-related reasons. 
Non-AE-related discontinuations or losses to follow up will not be counted as AE-related 
discontinuations. AE-related discontinuations are counted as events, discontinuation due to 
other reasons are not counted as events. 
 
  
 
 
 
 
 
   
9.4 
Analysis of secondary variables 
The secondary variable is the achievement of at least a 50% reduction from baseline in monthly 
migraine days (MMD) over the last 3 months (months 4, 5, and 6) of the double-blind treatment 
period.  
The analysis of the primary variable will be based on the following estimand: 
• Population – Full Analysis Set (FAS) 
• Variable of Interest: number of patients with at least 50% reduction from baseline in 
monthly migraine days (MMD)  
• Intercurrent event: discontinuation of study medication – effect between erenumab versus 
topiramate assuming to evaluate treatment policy 
• Intercurrent event: discontinuation of study or lost to follow up – effect between erenumab 
versus topiramate assuming no response could be achieved 
• Summary measure – odds ratio 
All the subjects’ data collected regarding 50% response of MMD will be used in the analysis 
regardless whether subjects complete the study drug or not. Subjects with missing response 
information on this endpoint will be imputed as non-response (non-responder imputation). A 
logistic regression model including treatment group, baseline value, and stratification factor 
will be used to perform the treatment comparison (erenumab vs. topiramate) at end of the 
DBTE. Additional to the odds ratio obtained from the logistic regression, estimates for the risk 
ratio and the risk difference (with corresponding confidence intervals and p-values) will be 
calculated for the secondary endpoint. 


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9.5 
Analysis of exploratory variables 
Exploratory variables are the patient reported outcomes (PROs) HIT-6 and SF-36 
 
 The analysis of PROs 
 will be described in detail in 
the statistical analysis plan (SAP). 
9.5.1 
Safety variables  
9.5.1.1 
Adverse events 
Treatment emergent adverse events (events started after the first dose of study treatment or 
events present prior to the first dose of study treatment but increased in severity based on 
preferred term) will be summarized. 
Adverse events will be summarized by presenting, for each treatment group, the number and 
percentage of patients having any AE, having an AE in each primary system organ class and 
having each individual AE (preferred term). Summaries will also be presented for AEs by 
severity and for study treatment related AEs. If a patient reported more than one adverse event 
with the same preferred term, the adverse event with the greatest severity will be presented. If 
a patient reported more than one adverse event within the same primary system organ class, the 
patient will be counted only once with the greatest severity at the system organ class level, 
where applicable. Serious adverse events will also be summarized. 
Separate summaries will be provided for death, serious adverse event, other significant adverse 
events leading to discontinuation and adverse events leading to dose adjustment (including 
study treatment discontinuation). 
9.5.1.2 
Laboratory data 
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(hematology, serum chemistry and urinalysis). Descriptive summary statistics for the change 
from Baseline to each study visit will be presented. 
These descriptive summaries will be presented by test group, laboratory test and treatment 
group. Change from Baseline will only be summarized for patients with both Baseline and Post-
Baseline assessments. 
For each parameter, the maximum change from Baseline within each study period will be 
analyzed analogously. 
9.5.1.3 
Vital signs 
Analysis of the vital sign measurements using summary statistics for the change from Baseline 
for each Post-Baseline visit will be performed. These descriptive summaries will be presented 
by vital sign and treatment group. Change from Baseline will only be summarized for patients 
with both Baseline and Post-Baseline values. 


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9.5.2 
Resource utilization  
9.5.3 
Not applicable. PK/PD 
Not applicable. 
9.5.4 
DNA 
Not applicable. 
9.5.5 
Blood Biomarkers  
Not applicable. 
9.6 
Interim analyses 
Not applicable. 
 
 
 
 
 
 
 
 
 
 
 
  
10 
Ethical considerations  
10.1 
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 Japanese 
Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in the 
Declaration of Helsinki. 
10.2 
Informed consent procedures  
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation) IRB/IEC-approved informed consent. The patient is capable of 
doing so, he/she must indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. Informed consent must be obtained before 


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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 patient source 
documents.  
Novartis will provide a proposed informed consent form to investigators that complies with the 
ICH GCP guideline and regulatory requirements and is considered appropriate for this study.  
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 requirement for the duration of 
the study. If there is any question that the patient will not reliably comply, they must not be 
entered in the study. 
10.3 
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, patient recruitment procedures (e.g., 
advertisements) and any other written information to be provided to patients. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
10.4 
Publication of study protocol and results 
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results. 
10.5 
Quality Control and Quality Assurance  
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections. 
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance (CQA), a group 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. 


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11 
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 patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol. 
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.  
11.1 
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 intended to eliminate an apparent immediate hazard 
to patients 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 patient included in this study, even if this action 
represents a deviation from the protocol. In such cases, the reporting requirements identified in 
Section 7 must be followed. 


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12 
References 
 
Aimovig® 70 mg Injektionslosung in einer Fertigspritze; Aimovig® 70 mg Injektionslosung 
im Fertigpen, SmPC, Novartis Pharma GmbH90327 Nurnberg, Release August 2018  
 
 
 
Beck AT, Steer RA, Brown GK (1996) BDI-II, Beck depression inventory: manual. San 
Antonio, TX; Psychological Corp. Boston: Harcourt Brace. 
Blumenfeld AW, 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; 
53(4):644-55. 
Bussone G, Diener HC, Pfeil J, Schwalen S. (2005) Topiramate 100 mg/day in migraine 
prevention: a pooled analysis of double-blind randomised controlled trials. Int J Clin 
Pract;59(8):961-8 
Deutsche Gesellschaft für Neurologie (DGN), Deutsche Migräne und 
Kopfschmerzgesellschaft (DMKG) (2018) Leitlinien für Diagnostik und Therapie in der 
Neurologie. Therapie der Migräne. Available from: 
https://www.dgn.org/images/red_leitlinien/LL_2018/PDFs_Download/030057_LL_Migrane_
2018.pdf 
Dodick DW, Ashina M, Brandes JL, et al. (2018) ARISE: A Phase 3 randomized trial of 
erenumab for episodic migraine. Cephalalgia; 38(6):1026-1037.  
Durham PL (2006) Calcitonin gene-related peptide (CGRP) and migraine. Headache; 46 (Suppl 
1):S3-S8. 
Evers S, Afra J, Frese A, et al. (2009) EFNS guideline on the drug treatment of migraine – 
revised report of an EFNS task force. European Journal of Neurology; 16:968-81. 
Gemeinsamen Bundesausschusses über die Änderung (G-BA) (2010) ‘Anlage VI (Off-Label-
Use) Valproinsäure bei der Migräneprophylaxe im Erwachsenenalter‘. Minutes of 
Gemeinsamen Bundesausschusses über die Änderung (G-BA) 16 Sep 2010, Berlin, Germany 
Goadsby PJ, Reuter U, Hallström Y, et al (2017a) A Controlled Trial of Erenumab for Episodic 
Migraine. N Engl J Med; 377: 2123-2132. 
Goadsby PJ,  et al., (2017b) IHC Oral Abstracts: Efficacy of Erenumab in Subjects with 
Episodic Migraine with Prior Preventive Treatment Failure(s). Cephalalgia; 37(1_suppl): 13. 
Hepp A, Bloudek LM, Varon SF (2014) Systematic review of migraine prophylaxis adherence 
and persistence. J Manag Care Pharm; 20(1):22-23. 


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Hurst H, Bolton J (2004) Assessing the clinical significance of change scores recorded on 
subjective outcome measures. J Manipulative Physiol Ther; 27:26-35.3 
 
International Headache Society (IHS) Classification Committee (2013) The International 
Classification of Headache Disorders (ICHD), 3rd edition (beta version). Cephalalgia; 33:629–
808. 
Kosinski M, Bayliss MS, Bjorner JB, et al (2003) A six-item short-form survey for measuring 
headache impact: the HIT-6. Qual Life Res; 12:963–974. 
Posner K, Brown GK, Stanley B, et al (2011) The Columbia–Suicide Severity Rating Scale: 
Initial Validity and Internal Consistency Findings From Three Multisite Studies With 
Adolescents and Adults. Am J Psychiatry. 168:1266–1277. 
Silberstein SD (2017) Topiramate in Migraine Prevention: A 2016 Perspective. Headache; 
57:165-178.  
Tepper S, Ashina M, Reuter U, Brandes JL, 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;16(6):425-434 
Tfelt-Hansen IHS (2012) Guidelines for controlled trials of drugs in migraine: Third edition. A 
guide for investigators. Cephalalgia; 32:6-38. 
 
Topiramate TEVA 25mg, SmPC, TEVA UK Limited, Release 17.02.2015 
Topiramate TEVA 50mg, SmPC, TEVA UK Limited, Release 17.02.2015  
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 USA; 
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Ware JE, Snow KK, Kosinski M, et al (1993) SF36 Health Survey: Manual and Interpretation 
Guide. Lincoln, RI: Quality Metric, Inc. 1993.30. 
Ware JE, Kosinski M, Keller SD (1994) SF-36 physical and mental health summary scales: A 
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13 
Appendices 
Appendix 1: Clinically notable laboratory values  
Only selected lab parameters which have potential to be sensitive to erenumab exposure are 
listed. 
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 


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Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements 
Table 13-1 
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 
Table 13-2 
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 
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion) 


Novartis 
Confidential 
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Clinical Trial Protocol Version No. 02 
 
Protocol No. CAMG334ADE01 
 
 
 
 
Criteria 
Actions required 
Follow-up monitoring 
• 
Complete liver CRF 
> 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) 
 
 
> 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 
AMG 334 (erenumab) 
CAMG334ADE01 / NCT03828539
Randomized, double-blind, multicenter Head-to-head study 
of Erenumab against topiRamate - Migraine study to 
assess tolerability and efficacy in a patiEnt–centered 
Setting (HER-MES) 
Statistical Analysis Plan (SAP) 
Author: 
Statistician, 
  
Statistician, 
 
Document type: 
SAP Documentation 
Document status: 
Final Amendment 2 
Release date: 
01-Oct-2020
Number of pages: 44 
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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Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
01-
Oct-
2020 
Prior 
to 
DB 
Lock 
Implementation 
of 
decisions 
from blind data 
review meeting 
and additional 
corrections 
before database 
lock 
Clarified that only patients who took 
active study medication will be 
included in full analysis set and safety 
analysis set 
Section 2.2 
Analysis Sets 
 
 
Note on handling of patient reported 
outcomes data added 
Section 2.11 
Patient-reported 
outcomes 
 
 
 
Section on allocation of migraine-
specific 
medication 
to 
events 
spanning midnight added 
Section 5.7.3 
Allocation of 
migraine-
specific 
medication to 
events spanning 
midnight 
 
 
 
Clarified that HIT-6 scoring will be 
performed by the license owner 
“Optum” 
Section 5.8.2 
HIT-6 scoring 
 
 
 
Section for approval signatures added Section 7 
Approval 
signatures 
 
 
 
 
 
 


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Table of contents 
 
Table of contents ................................................................................................................. 4 
List of abbreviations ............................................................................................................ 7 
1 
Introduction ......................................................................................................................... 8 
1.1 
Study design ............................................................................................................ 8 
1.2 
Study objectives and endpoints ............................................................................... 9 
2 
Statistical methods ............................................................................................................. 10 
2.1 
Data analysis general information ......................................................................... 10 
2.1.1 
General definitions ................................................................................ 11 
2.2 
Analysis sets .......................................................................................................... 21 
2.2.1 
Subgroup of interest .............................................................................. 21 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 22 
2.3.1 
Patient disposition ................................................................................. 22 
2.3.2 
Demographic variables and other baseline characteristics .................... 23 
2.3.3 
Medical history...................................................................................... 23 
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 ................................................... 24 
2.5 
Analysis of the primary objective .......................................................................... 24 
2.5.1 
Primary endpoint ................................................................................... 25 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 25 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 25 
 
 26 
 
 26 
2.6 
Analysis of the secondary objective ...................................................................... 26 
2.6.1 
Secondary endpoint ............................................................................... 26 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 27 
2.6.3 
Handling of missing values/censoring/discontinuations ....................... 27 
2.6.4 
Subgroup analyses ................................................................................. 27 
2.7 
Analysis of exploratory objectives ........................................................................ 28 
2.7.1 
Exploratory endpoints ........................................................................... 28 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 29 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 31 
2.8 
Safety analyses....................................................................................................... 31 


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2.8.1 
Adverse events (AEs) ............................................................................ 31 
2.8.2 
Deaths .................................................................................................... 32 
2.8.3 
Laboratory data ..................................................................................... 32 
2.8.4 
Other safety data ................................................................................... 33 
2.9 
Pharmacokinetic endpoints .................................................................................... 34 
2.10 
PD and PK/PD analyses ........................................................................................ 34 
2.11 
Patient-reported outcomes ..................................................................................... 34 
2.12 
Biomarkers ............................................................................................................. 34 
2.13 
Other Exploratory analyses.................................................................................... 34 
2.14 
Interim analysis ...................................................................................................... 34 
 
 34 
 
 35 
 
 35 
 
 35 
5 
Appendix ........................................................................................................................... 36 
5.1 
Imputation rules ..................................................................................................... 36 
5.1.1 
Study drug ............................................................................................. 36 
5.1.2 
Concomitant medication date imputation ............................................. 36 
5.2 
AEs coding/grading ............................................................................................... 37 
5.3 
Laboratory parameters derivations ........................................................................ 38 
5.4 
Statistical models ................................................................................................... 38 
5.4.1 
Primary analysis .................................................................................... 38 
5.4.2 
Key secondary analysis ......................................................................... 38 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 38 
 
 38 
 
 38 
 
 39 
 
 
 39 
 
 
 39 
 
 
 40 
5.8 
Appendix C: Patient-reported Outcome Scoring rules/Forms/Instruments ........... 40 
5.8.1 
BDI-II scoring ....................................................................................... 40 
5.8.2 
HIT-6 scoring ........................................................................................ 41 
5.8.3 
SF-36v2 scoring .................................................................................... 41 


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 41 
5.8.5 
C-SSRS scoring ..................................................................................... 43 
6 
Reference ........................................................................................................................... 43 
7 
Approval signatures ........................................................................................................... 44 


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List of abbreviations 
 
AE 
Adverse event 
ASA 
Abbreviated schedule of assessments 
ATC 
Anatomic Therapeutic Chemical classification  
CRO 
Contact Research Organisation 
DBTE 
Double-Blind Treatment Epoch 
ECG 
Electroencephalography 
eCRF 
electronic Case Report Form 
EoS 
End of the Study 
FAS 
Full Analysis Set 
HRQoL 
Health Related Quality of Life 
IMP 
investigational medicinal product 
IRT 
Interactive Response Technology  
LPLV 
last patient last visit  
MCS 
Mental Component Summary 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
MMD 
Monthly Migraine Days 
ODS 
Output Delivery System  
PCS 
Mental Component Summary 
PRO 
Patient Reported Outcome 
PT 
Preferred Term  
RAS 
Randomized Analysis Set 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
statistical analysis plan  
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class  
TEAE 
Treatment-Emergent Adverse Event  
TFLs 
Tables, Figures, Listings 
WHO 
World Health Organization 


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1 
Introduction 
The purpose of this statistical analysis plan (SAP) is to provide details of the statistical analysis 
according to Section 9 of the study protocol v02 for AMG 334 Study CAMG334ADE01 dated 
June 6, 2019.  The scope of this plan includes the primary, secondary, and exploratory analyses, 
which will be executed by the CRO (
).  
1.1 
Study design 
This study uses a single-cohort, 2-treatment arm, parallel-group randomized, double-blind, 
double-dummy design in adult patients with episodic migraine and chronic migraine, who must 
be either naïve or not suitable for or could have failed up to three prophylactic treatments out 
of: propranolol/ metoprolol, amitriptyline, flunarizine.  
The following epochs are included in the study design: 
• 
Screening Epoch of 2 weeks: Required for all patients to assess initial eligibility. 
• 
Baseline Epoch of 4 weeks: All patients fulfilling eligibility criteria successfully 
completing the Screening Epoch are invited to participate. Eligibility for randomization will 
be assessed based on migraine frequency and diary compliance during this epoch (migraine 
frequency of ≥ 4 and ≥80% eDiary compliance). 
• 
Double-blind, double-dummy Treatment Epoch (DBTE) of 24 weeks: All patients 
completing the Baseline Epoch and fulfilling baseline eligibility criteria are invited to 
participate. Eligible patients will be randomized to one of two treatment arms. Double-blind 
treatment epoch will start with a titration phase for topiramate of a maximum of 6 weeks to 
determine the maximal tolerated dose and must aim to reach the recommended treatment 
dose of 100 mg according to the German SmPC. After the titration phase, maintenance 
phase will start (18 weeks). Topiramate dose has to be maintained until the end of the DBTE. 
Erenumab dose at beginning of the DBTE is determined patient-individually by the 
investigator based on the guidance provided in the SmPC and can be either 70 mg or 140 
mg. Dose escalation from 70 mg to 140 mg in case of insufficient response could be 
considered at any time during the DBTE. 
Dose reduction of topiramate and erenumab is not allowed during DBTE (Visit 101-199). 
After visit 199 or if the patient discontinues study drug, a one week double-blind taper off 
phase will follow to ensure proper down titration for topiramate. 
At the end of the DBTE (24 weeks) the final assessment to address the objectives will occur. 
• 
Follow-Up Epoch (4 weeks) –A Follow-Up Visit 4 weeks after last study visit (or 8 weeks 
after last IMP injection for discontinued patients) will be required as part of routine safety 
monitoring. The primary analysis will be triggered when all patients have completed their 
respective last visit of the double-blind treatment epoch. 
End of trial will occur when the last patient completes last visit (LPLV). 
 


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Figure 1-1 Study Design 
 
Patients will be stratified into groups according to their number of migraine days during the 
baseline epoch (4 - 7 vs. 8 - 14 vs. ≥ 15 monthly migraine days).  
The study will recruit approximately 375 patients per arm (750 total) including up to a 
maximum of 35 patients with ≥ 15 monthly migraine days per arm (approx. 10 % of patients 
per arm). Assumptions were based on clinical studies with topiramate and erenumab. 
No interim analysis is planned. 
1.2 
Study objectives and endpoints 
The purpose of this study is to determine the safety and efficacy of erenumab compared to 
topiramate in the highest tolerated dose in patients suffering from ≥4 migraine days/month, who 
are naïve or not suitable for or have failed up to three prophylactic migraine treatments out of: 
propranolol/metoprolol, flunarizine and amitriptyline. 
Objective  
Endpoint  
Primary 
 
To demonstrate the tolerability of erenumab 
compared to topiramate assessed by the rate 
of patients discontinuing treatment due to AE 
during the double-blind epoch of the study. 
Discontinuation of treatment due to AE 
during the double-blind epoch of the study. 
Secondary  
 
To evaluate the effect of erenumab compared 
to topiramate on the proportion of patients 
with at least 50% reduction from baseline in 
monthly migraine days.  
Achieving at least a 50% reduction from 
baseline in MMD over the last 3 months 
(months 4, 5, and 6) of the double-blind 
epoch.  
 
Exploratory: 
 


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To evaluate the effect of erenumab 
compared to topiramate on functional 
impairment, as measured by the Headache 
Impact Test (HIT-6)  
HIT-6 at week 24  
 
To evaluate the effect of erenumab 
compared to topiramate on generic health-
related quality of life, as measured by the 
Short Form-36 (SF-36 v2)  
SF-36 quality of life at week 24  
 
2 
Statistical methods 
2.1 
Data analysis general information 
The primary analysis will be conducted on all patient data after database lock (after LPLV). 
Analyses will be performed by 
. 
SAS Version 9.2 or higher will be used for all analyses. Tables and lists will be produced by 
the SAS Output delivery system (ODS) as rtf document which is transferred into docx-Format 
to reduce size. 
General descriptive statistical rules:  
Parameters which are at least interval scaled will be tabulated by the following sample statistics: 
Number of non-missing data, mean, standard deviation, minimum, median, and maximum. 


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Parameters which are nominally or ordinally scaled will be tabulated by absolute and relative 
frequencies. In general, missing values are not considered for calculation of percentages (i.e., 
adjusted percentages are calculated) if not otherwise specified. 
General information on treatment arm handling, decimal places and other output-related 
information will be specified in tables, figures and listing (TFLs) shells accompanying this 
analysis plan. 
2.1.1 
General definitions  
Study treatment 
Novartis will supply the investigational medicinal products (IMP) listed below in a double-
dummy setting:  
 
Verum for Test-IMP:  
• 1x Erenumab 70mg/1mL (70 mg), in pre-filled syringe, administered every 4 weeks;  
• 2x Erenumab 70mg/1mL (140 mg), in pre-filled syringes, administered every 4 weeks;  
 
Dose for erenumab is 70 mg or 140 mg throughout the trial. If the response is 
insufficient, dose may be uptitrated from 70 mg to 140 mg. Down titration from 140 
mg to 70 mg is not allowed.  
 
Verum for Control-IMP:  
• Topiramate 25 mg and 50 mg in blisters applied according to following scheme: 
 
Titration phase (6 weeks) 
The recommended dose for Topiramate is 100 mg/day in accordance with the SmPC. 
The titration phase must aim to reach the recommended dose as follows: 
 
First week: Topiramate 25 mg (1x 25 mg/day) in the evening 
 
After first week on 25 mg, dose has to be increased weekly by up titration in 25 mg 
increments to the highest tolerated dose. Individual patients may maintain dose for 
longer than one week, if deemed necessary but all efforts should be made to achieve the 
recommended 100 mg dose and only if that is not deemed feasible should the patient 
enter the maintenance phase at a lower dose. The patient will then enter the maintenance 
phase with the highest tolerated dose reached within the 6 week titration phase, whereas 
minimal dose is 50 mg topiramate (2x 25 mg/day), intermediate dose is 75 mg (1x 25 
mg and 1x 50 mg/day) and maximal and recommended dose is 100 mg (2x 50 mg/day). 
Starting with the 50 mg dose, patients will have to take one tablet in the morning and 
one in the evening. Downtitration is not allowed. 
 
Maintenance phase (18 weeks) 
 Patients stay on highest tolerated dose determined during titration phase 
Tapering off (1 week) 


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 Patients taking a daily dose of 75 mg or 100 mg topiramate during the DBTE should 
taper off topiramate after visit 199 or when discontinuing study drug. Tapering off is 
performed with a daily dose of topiramate reduced by 50 mg for one week. 
 
Placebo for Test-IMP:  
 
• 1x Erenumab matching placebo, in pre-filled syringe, administered every 4 weeks;  
• 2x Erenumab matching placebo, in pre-filled syringes, administered every 4 weeks;  
 
Placebo for Control-IMP:  
• Matching topiramate tablets for 25 mg and 50 mg in blisters 
Erenumab 
When not specifically specified, “erenumab” refers to the individual erenumab dose of 70 mg 
or 140 mg. 
Topiramate 
When not specifically specified, “topiramate” refers to the highest tolerated dose of topiramate.  
Tablets Dose Level per visit in the titration phase 
Titration phase (i.e. day 1 to week 6) tablets dose level per visit is defined as follows: 
• At day 1: Dose level is equal to first dose in the study. 
• At week 1 to 6: Dose level is defined as the mode of the documented doses in the interval 
[target date of the visit, target date of visit + 7 days]. 
Doses documented after date of discontinuation of double-blind treatment (i.e. tapering-off 
doses) are not considered for calculation of dose level in the titration phase. 
Migraine-specific medication 
Medication belonging to the triptan or ergotamine family. 
Compliance with the eDiary (daily and retro) 
The protocol requirement is 80% compliance with the eDiary (daily or retro) during baseline 
period. See Appendix A: Calculation rules for eDiary day calculation. Compliance with the 
eDiary at each month is calculated as  
a number of eDiary entered in baseline period or between IMP syringe doses/ number of actual 
days in Baseline period or interval between IMP syringe doses*100% 
Stratification factor (for randomization) 
Monthly Migraine Days (MMD) category (4 - 7, 8 - 14, ≥ 15 MMD) at baseline as used for 
randomization of patients. 
2.1.1.1 
Study dates 
eDiary Device Assignment Date  


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The date on which an eDiary device is assigned to a subject for the first time after completion 
of initial screening, i.e. the date of baseline visit. 
Randomization Date in DBTE  
Randomization date in DBTE is the date on which a patient is assigned to one of the two 
treatment arms via Interactive Response Technology (IRT). 
First IMP Dose Date 
The first IMP dose date is the date on which a subject is administered the first dose of IMP (i.e. 
verum test- or control-IMP) following randomization, which may be the same day or after the 
randomization date. For subjects who are randomized but not dosed with double-blind IMP 
after randomization, first IMP Dose Date is considered missing. 
Last IMP Syringe Dose Date 
The last IMP syringe dose date for each subject is defined as the latest date of a syringe 
administration. 
Last IMP Tablet Dose Date out of tapering off phase 
The last IMP tablet dose date out of tapering off phase for each subject is defined as the date 
of the last tablet administration prior to the start date of tapering off phase.  
Last IMP Tablet Dose Date (tapering off phase included) 
The last IMP tablet dose date for each subject is defined as the date of the latest 
administration of a tablet. 
Study Day 
Study Day 1 is defined as the first IMP dose date. For patients who are randomized but not dosed 
after randomization, 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)  
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. 
Baseline 
The baseline period for efficacy endpoints collected by the eDiary (e.g. monthly migraine 
days) is defined as the period between the eDiary device assignment date and the day prior to 
study day 1 (study day one is not included).  
A baseline for PROs (for SF-36v2, HIT-6, BDI-II) and safety endpoints (including C-SSRS) 
refers to the last evaluable measurement prior to or on the study day 1.  
Note: Assessments on the day of randomization are assumed to have been taken as per protocol, 
i.e. if the assessment should be performed before dosing, the assessment will be treated as pre-
dose as per protocol. Practically, i.e. that the time part of the date/time entry will be ignored. 


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Exception: In case there is a protocol deviation or a comment that specifically indicates that the 
assessment has been taken post-dose, the assessment will not be treated as pre-dose. 
Patient-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 Completion eCRF page. 
2.1.1.2 
Visit and analysis window 
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. 
The nearest study day window will be utilized to define study visit for lab, vital signs, ECG, 
C-SSRS and some PROs collected during office visits (HIT-6, SF-36v2, 
) before 
dose is administered. 
 
Table 2.1.1.2-1. Study Visit Windows in the DBTE 
Study visit 
Target day  
Study Day 
Week 0 
1 
1 
Week 1 
8 
2 - 11 
Week 2 
15 
12 - 18 
Week 3 
22 
19 - 25 
Week 4 
29 
26 - 32 
Week 5 
36 
33 - 39 
Week 6 
43 
40 - 49 
Week 8 
57 
50 - 70 
Week 12 
85 
71 - 98 
Week 16 
113 
99 - 126 
Week 20 
141 
127 - 154 
Week 24 
169 
155 - 182 
 
2.1.1.3 
Demographics and other baseline characteristics 
Beck Depression Inventory II (BDI-II) 
The BDI-II is a 21-item questionnaire that assesses severity of depression with the recall period 
of two weeks, including the day of completion. Each item is scored from 0 to 3. The total score 
varies between 0 and 63 and can be categorized into 4 severity grades:  
• 
minimal depression (0-13)  
• 
mild depression (14-19) 


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• 
moderate depression (20-28)  
• 
severe depression (29-63) 
The BDI-II is completed once during the study at screening visit via eDiary. Moderate and 
severe depression belong to the study exclusion criteria.  
Please refer to BDI-II scoring for scoring details. 
 
2.1.1.4 
Efficacy endpoints 
eDiary 
Patients record the efficacy information using the provided eDiary platform. If a patient did not 
made a contribution to the eDiary at a particular day, it is possible to provide information 
retrospectively (retro diary). In this case, by the next eDiary usage a patient will be first asked to 
provide information on up to 48 hours prior to the time of completion of this diary and then about 
the actual state.  
eDiary Day 
A calendar day to which the information from the eDiary refers. Please refer to Appendix A: 
Calculation rules for calculation details. 
Headache Day 
A headache day is any calendar day on which the subject experiences a qualified migraine or 
non-migraine headache (initial onset, continuation or recurrence of the headache).  Please see 
exceptions in Appendix B: MMD derivation, exceptions.  A qualified headache is defined as: 
• 
a qualified migraine headache or 
• 
a qualified non-migraine headache, which is a headache that lasts ≥ 30 minutes and is 
not a qualified migraine headache, or 
• 
a headache of any duration for which acute headache treatment is administered. 
Unknown medications (with no available information on the type of treatment) will 
not be counted as acute headache treatment.  
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 patient experiences a qualified 
migraine headache (onset, continuation, or recurrence of the migraine headache). Please see 
exceptions in Appendix B: MMD derivation, exceptions. 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: 
• ≥2 of the following pain features: 
• Unilateral 
• Throbbing 
• Moderate to severe 


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• Exacerbated with exercise/physical activity 
• ≥1 of the following associated symptoms: 
• Nausea and/or vomiting 
• Photophobia and phonophobia 
If the patient took a migraine-specific medication (i.e., triptane 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. In case of a retro diary spanning the last 
two days, documentation regarding aura will be considered to apply for both days. 
Monthly Migraine Days (MMD) 
Monthly migraine days at baseline are the number of migraine days in the baseline period that 
are normalized in a 28-day interval. Monthly migraine days after baseline are the number of 
migraine days between each monthly IMP dose that are normalized in a 28-day interval. Days 
without eDiary data in each normalized monthly interval will be prorated. Calculation details 
are described in eDiary data.  
Monthly Intervals for Monthly Migraine Days  
Monthly migraine days will be calculated based on the patient’s IMP dosing schedule defined 
below using eDiary data collected from beginning of the baseline epoch up to the end of the 
DBTE. 
Table 2.1.1.4-1. Monthly Intervals for MMD 
Study 
Epoch 
Assessment 
Time point  
Interval Based on Syringe Dose Dates  
 
Start date 
End date 
Baseline 
Epoch 
Baseline 
From eDiary device 
assignment date (i.e. 
baseline visit)  
Day prior to study day 1 
Double-
Blind 
Treatment 
Epoch 
Week 4 
(Month 1) 
• 
Study Day 1 
• 
Week 4 syringe dose date 
-1 
• 
Study day 28 if Week 4 
syringe dose is not 
received (either missed or 
IMP discontinued prior to 
Week 4) 
 
Week 8 
(Month 2) 
• 
Week 4 syringe dose 
date 
• 
Study day 29 if Week 4 
syringe dose is not 
received or IMP 
• 
Week 8 syringe dose date 
-1 
• 
Study day 56 if Week 8 
syringe dose is not 
received (either missed or 


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discontinued prior to 
Week 4 
IMP discontinued prior to 
Week 8) 
 
Week 12 
(Month 3) 
• 
Week 8 syringe dose 
date 
• 
Study day 57 if Week 8 
syringe dose is not 
received or IMP 
discontinued prior to 
Week 8 
• 
Week 12 syringe dose 
date -1 
• 
Study day 84 if Week 4 
syringe dose is not 
received (either missed or 
IMP discontinued prior to 
Week 12) 
 
Week 16 
(Month 4) 
• 
Week 12 syringe dose 
date 
• 
Study day 85 if Week 12 
syringe dose is not 
received (either missed 
or IMP discontinued 
prior to Week 12) 
• 
Week 16 syringe dose 
date -1  
• 
Study day 112 if Week 16 
syringe dose is not 
received (either missed or 
IMP discontinued prior to 
Week 16) 
 
Week 20 
(Month 5) 
• 
Week 16 syringe dose 
date  
• 
Study day 113 if Week 
16 syringe dose is not 
received (either missed 
or IMP discontinued 
prior to Week 16) 
• 
Week 20 syringe dose 
date -1  
• 
Study day 140 if Week 20 
syringe dose is not 
received (either missed or 
IMP discontinued prior to 
Week 20) 
 
Week 24 
(Month 6) 
• 
Week 20 syringe dose 
date  
• 
Study day 141 if Week 
20 syringe dose is not 
received (either missed 
or IMP discontinued 
prior to Week 20) 
• 
Week 20 syringe dose 
date + 27 if Week 20 
syringe dose is received 
• 
Study day 168 if Week 20 
syringe dose is not 
received (either missed or 
IMP discontinued prior to 
Week 20) 
 
Monthly migraine days over the last three months (months 4, 5, and 6) of the double-blind 
epoch 
Monthly migraine days over the last three months are calculated as the mean MMD over 
months 4, 5, and 6. In case of missing data at some time point, mean value will be calculated 
based on available data.  
 
Achievement of at least a 50% reduction from baseline in monthly migraine days over 
the last three months (months 4, 5, and 6) of the double-blind epoch 
A patient achieves at least 50% reduction from baseline over the last three months, if 


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(𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑀𝑀𝐷− 𝑎𝑣𝑒𝑟𝑎𝑔𝑒 𝑀𝑀𝐷 𝑜𝑣𝑒𝑟 𝑡ℎ𝑒 𝑙𝑎𝑠𝑡 𝑡ℎ𝑟𝑒𝑒 𝑚𝑜𝑛𝑡ℎ 𝑜𝑓 𝐷𝐵𝑇𝐸) ∗100
𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑀𝑀𝐷
 ≥50 
 
Achievement of at least a 50% reduction from baseline in monthly migraine days during 
the first month of the double-blind epoch  
A patient achieves at least 50% reduction from baseline in the first month of DBTE, if 
(𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑀𝑀𝐷− 𝑀𝑀𝐷 𝑖𝑛 𝑡ℎ𝑒 𝑓𝑖𝑟𝑠𝑡 𝑚𝑜𝑛𝑡ℎ 𝑜𝑓 𝐷𝐵𝑇𝐸) ∗100
𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑀𝑀𝐷
 ≥50 
 
Headache Impact Test (HIT-6) 
The Headache Impact Test (HIT-6) is a short-form self-administered questionnaire based on 
the Internet-HIT question pool. The HIT-6 was developed as a global measure of adverse 
headache impact to assess headache severity in the previous month and change in a patient’s 
clinical status over a short period of time. Six questions cover:  
• severe pain,  
• limitation of daily activity (household, work, school and social),  
• wanting to lie down when headache is experienced,  
• feeling too tired to work or do daily activities because of headache,  
• feeling fed up or irritated because of headache, and  
• headache limiting ability to concentrate or work on daily activities. 
 
The points are summed over six questionnaire items using special algorithm to produce a total 
HIT-6 score that ranges from 36 to 78. HIT-6 scores can be categorized into 4 grades, 
representing  
• little or no impact (49 or less) 
• some impact (50-55)  
• substantial impact (56-59)  
• severe impact (60-78)  
due to headache. No recall period is specified for the first 3 items. The recall period is the past 
4 weeks for the last 3 items.  
Subjects complete the HIT-6 using the eDiary during their scheduled clinic visit. Please refer 
to HIT-6 scoring for scoring details. 
 
Short Form Health Survey Version 2, 4-week recall period (SF-36v2)  
The SF-36 is a widely used measure of health-related quality of life (HRQoL) among healthy 
subjects and patients with acute and chronic conditions. It consists of eight subscales that can 
be scored individually:  
• 
Physical Functioning 
• 
Role-Physical 
• 
Bodily Pain 
• 
General Health 
• 
Vitality 
• 
Social Functioning 
• 
Role-Emotional  


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• 
Mental Health  
Two overall summary scores, the Physical Component Summary (PCS) and the Mental 
Component Summary (MCS) also can be computed.  
Subscale- and component summary scores are scaled to vary between 0 and 100 with 0 
indicating worst possible health state and 100 best possible health state.  
Calculation of SF-36 scores utilizes general population norm values. Scores are constructed to 
have an average value of 50 and a standard deviation of 10. Therefore, patients with the SF-36 
scores below 50 have a health state below the average health state level of the general population. 
Patient’s SF-36 score values below 40 may indicate impaired health state. Please refer to SF-
36v2 scoring for scoring details. 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
2.1.1.5 
Safety Endpoints 
 
Analyses on Adverse Events will be performed for the entire study without differentiating 
between the DBTE and Follow-up epoch. Independently, whether a patient is an ASA-patient 
or not, AEs will be analysed in the following analysis window:   
[Study Day 1; EoS Date] 
 
Remaining safety analyses will be performed for the DBTE and Follow-up Epoch separately. 
Laboratory, vital signs, ECG and C-SSRS are assessed during study visits and, therefore, will 
be assigned to the DBTE based on (Table 2.1.1.2-1). 
Concomitant medications will be assigned to the DBTE based on the following analysis window:  
[Study Day 1; Week 24 visit date if the visit was performed / MIN(EoS, study day 169) if the 
visit was not performed] 
 
Discontinuation of treatment due to AE during the DBTE  
Discontinuation of treatment due to AE during the DBTE is determined by the flag on the 
Treatment Completion eCRF page. “Death” as a reason for treatment discontinuation will be 
also included in AEs leading to treatment discontinuation. 
 
Treatment-Emergent Adverse Event (TEAE) 
Treatment emergent adverse events are defined as AEs occurred on or after the first dose of 
study treatment. AEs registered prior and after the first dose of study treatment are considered 


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as treatment emergent if they have increased severity based on preferred term any time after 
the first dose of study treatment. 
In case of missing data on a day of AE start date, the AE is considered as treatment emergent 
if  
 date of first dose of study treatment ≤ latest possible start date  
 
Please, see AE and Concomitant medication date imputation for “latest possible start date” 
definition. 
 
Serious Adverse Event (SAE) 
SAEs are determined by the flag on the Adverse Events eCRF page.  
 
Treatment-Related Adverse Event 
Treatment-emergent adverse event is defined as treatment-related, if investigator considered it 
as having a reasonable possibility to be related to study treatment, which is reflected in the 
eCRF with a corresponding flag. 
 
Adverse Event leading to dose adjustment 
Adverse event is defined as leading to dose adjustment if at least one of the following actions 
was taken with the study treatment due to AE: 
• 
dose increased 
• 
dose reduced  
• 
drug interrupted 
• 
drug withdrawn 
 
Adverse Event leading to pausing in uptitration 
Adverse event leading to pausing in uptitration are determined by the flag on the Adverse 
Events eCRF page. 
 
Columbia-Suicide Severity Rating Scale (C-SSRS)  
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire that prospectively 
assesses Suicidal Ideation and Suicidal Behavior based on following categories: 
Suicidal Ideation 
• 
Cat. 1 - Wish to be dead 
• 
Cat. 2 - Non-specific active suicidal thoughts 
• 
Cat. 3 - Active suicidal ideation with any methods (not plan) without intent or act 
• 
Cat. 4 - Active suicidal ideation with some intent to act, without specific plan 
• 
Cat. 5 - Active suicidal ideation with specific plan and intent 
Suicidal behavior 
• 
Cat. 6 - Actual attempt (non-fatal) 
• 
Cat. 7 - Interrupted attempt 
 
• 
Cat. 8 – Aborted or self-interrupted attempt  
• 
Cat. 9 - Preparatory acts or behavior 
• 
Cat. 10 - Suicide 


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The C-SSRS is administered at each visit, including unscheduled visits. Two versions 
depending on the type of visits will be used in this study: Screening and Since Last Visit. Please 
refer to C-SSRS scoring for scoring details.  
 
Duration of exposure to Test-IMP 
For all calculations of exposure, dose date refers to receiving dose > 0. 
The duration of exposure to test-IMP is computed as  
min (last IMP syringe dose date + 27, EoS date) – first IMP syringe dose date + 1. 
 
Duration of exposure to control-IMP (tapering off phase included) 
For all calculations of exposure, dose date refers to receiving dose > 0. 
The duration of exposure to control-IMP is computed as 
last IMP tablet dose date - first IMP tablet dose date + 1. 
Duration of exposure to control-IMP out of tapering off phase 
For all calculations of exposure, dose date refers to receiving dose > 0. 
The duration of exposure to topiramate out of tapering off phase is computed as 
last IMP tablet dose date out of tapering off phase – first IMP tablet dose date + 1 
 
Subject Incidence 
The subject incidence for a given event in a given period is defined as the number of subjects 
with at least one reported occurrence of the event divided by the number of subjects who entered 
that period. For subjects with multiple occurrences of the same event, the event will only be 
counted once per subject. 
 
 
2.2 
Analysis sets 
 
The Randomized Set (RS) will consist of all participants who received a randomization 
number, regardless of receiving study medication.  
 
The Full analysis set (FAS) will consist of all participants who received at least one dose of 
active study medication. In FAS, subjects will be analyzed according to randomized 
treatment, regardless of the actual treatment received.  
 
The Safety analysis set (SAF) will consist of all randomized subjects who received at least one 
dose of active study medication and will be analyzed based on actual treatment received. 
2.2.1 
Subgroup of interest 
Subgroup analyses are planned only for the primary endpoint (see Subgroup analyses).  


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2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
Screening and baseline epoch patient disposition will be based on all screened patients data. 
A patient disposition summary for the screening and baseline epoch will include number and 
percentage of patients, concerning 
• 
Screening 
A patient is defined as screened if signed informed consent is available 
• 
Screening failure 
A patient is defined as screening failure if he was screened but not randomized 
• 
Randomization 
Subjects are considered randomized if they have been assigned a randomization 
number. 
• 
Non-randomization 
- 
Reason for non-randomization 
The total number of patients screened and the number of patients with screening failure will be 
summarized, including the reason for screening failure.  
The reason for non-inclusion into the study will be listed for screened/baseline patients who 
discontinued from study prior to randomization.   
Patient disposition for the DBTE and follow-up epoch will be presented based on the 
randomized set (RS).  
A corresponding summary will include number and percentage of patients (treatment group 
specific and overall), concerning 
• 
Completion of double-blind treatment 
A patient is defined as completer for the double-blind treatment if double-blind 
treatment completion status on the eCRF page is ticked as not prematurely discontinued 
• 
Discontinuation of double-blind treatment 
- 
Reason for discontinuation of double-blind treatment 
• 
Study completion  
A patient is defined as completer for the study if study completion status on the eCRF 
page is ticked as not prematurely discontinued  
• 
Discontinuation of the study 
- 
Primary reason for discontinuation of the study 
 
Protocol deviations (PDs) will be summarized separately for PDs not related to COVID-19 and 
for PDs related to COVID-19. For PDs not related to COVID-19, the number of patients with 
at least one PD will be presented (based on RS) and the results of the PDs will be grouped using 


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the broad categories (Inclusion/Exclusion Criteria (Study eligibility), Withdrawal criteria met, 
but subject not discontinued, Treatment Deviation, Prohibited Concomitant Medication, Other). 
For PDs related to COVID-19, the number of patients with at least one PD will be presented 
(based on RS) and the results of the PDs will be grouped by category of COVID-19 PD and 
type of relationship to COVID-19. 
The number of patients within each of the analysis sets (RS, FAS, SAF) used in the study will 
be given. 
 
2.3.2 
Demographic variables and other baseline characteristics 
Demographic variables and other baseline characteristics including previous migraine 
treatments will be summarized for each randomized treatment group and for all participants 
(total) using FAS.  
For continuous variables mean, median, standard deviation, minimum, and maximum will be 
reported, whereas for categorical variables the number and percentage of participants in each 
category. 
Patient demographic data includes age (years), sex, race, weight (kg), height (cm), BMI 
(kg/m2), and source of patient referral. 
Baseline disease characteristics contain following information assessed at baseline (see 
Section 2.1.1.1 for baseline definition):  
• 
Monthly migraine days  
• 
Monthly headache days 
• 
Acute headache medication (none vs. migraine-specific vs. non migraine-specific) 
• 
Prior treatment failure status (naïve vs. prior treatment failure, related to the 
prophylactic migraine treatments propranolol/metoprolol, amitriptyline, flunarizine) 
• 
Beck Depression Inventory - II (BDI-II, minimal depression (0-13) vs. mild 
depression (14-19)) 
 
2.3.3 
Medical history 
Relevant medical history/current medical conditions present before signing the Informed 
consent will be recorded on the ‘Medical History’ eCRF page. 
General medical history data includes medical history term, which will be summarized by 
system organ class and preferred term in the MedDRA dictionary. 
Medical history possibly contributing to liver dysfunction data includes medical history term, 
which will be summarized by system organ class and preferred term in the MedDRA dictionary. 
Headache and migraine frequency history data includes frequency of migraines over the past 
3 months before screening (average days per month subject had migraines), frequency of 
headache (migraine and non-migraine) over the past 3 months before screening (average days 
per month subject had headache) and patient’s age at migraine onset. 
 


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2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The analysis of study treatment data will be based on the SAF.  
For Control-IMP (topiramate or placebo):  
• 
dose level distribution (number and percent of patients with particular dose) per visit in 
the titration phase summarized by treatment group 
• 
duration of exposure out of tapering off phase summarized descriptively by treatment 
group 
• 
duration of exposure including tapering off summarized descriptively by treatment 
group 
For Test-IMP (AMG 334 or placebo):  
• 
Number and percentage of patients receiving 1/2/3/4/5/6 doses of Test-IMP summarized 
by treatment group 
• 
Duration of exposure summarized descriptively by treatment group 
• 
Number and percentage of patients with starting dose of 70 mg or 140 mg.  
• 
Reason for starting dose of 140 mg 
• 
Number and percentage of patients with dose change from 70 mg to 140 mg and the 
corresponding reason 
2.4.2 
Prior, concomitant and post therapies 
Number and percentage of patients with prior prophylactic migraine treatment failure will 
be presented based on RAS. A summary will be done for each failed treatment category with 
the primary reason for treatment discontinuation specified. 
The number and percentage of patients receiving acute medications (during baseline and 
double-blind treatment epoch) will be reported. The number and percentage of patients 
receiving concomitant medications and significant non-drug therapy (during the double-blind 
treatment period) will be summarized by ATC level 1 and preferred name (coded by WHO 
Anatomic Therapeutic Chemical classification [ATC]) and by treatment group.  
The use of concomitant medications and significant non-drug therapy during the follow-up 
period will be summarized in the same way, in a separate table.  
2.5 
Analysis of the primary objective 
The primary objective of the study is to demonstrate the tolerability of erenumab compared to 
topiramate assessed by the rate of patients discontinuing treatment due to AE during the double-
blind epoch of the study. 


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2.5.1 
Primary endpoint 
The primary endpoint of the study is discontinuation of treatment due to AE during the double-
blind epoch of the study.  
Analysis on primary endpoint should be done based on Full Analysis Set (FAS). 
2.5.2 
Statistical hypothesis, model, and method of analysis 
Null hypothesis: odds of AE-related treatment discontinuations are equal in both treatment 
groups 
Alternative hypothesis: odds are not equal when comparing erenumab to topiramate 
Statistical hypothesis:  
H0:  (p1 / (1- p1)) / (p0 / (1- p0)) = 1,  
where 
pj –probability of AE-related treatment discontinuations for the treatment group j 
j = 0 corresponds to topiramate group 
j = 1 corresponds to erenumab group 
The odds ratio not significantly different from one would mean that there is no evidence for a 
difference in AE-related treatment discontinuations between the two treatment groups.  
 
Statistical hypothesis will be tested in the frame of logistic regression analysis controlling for 
the stratification factor (4-7 vs. 8-14 vs. ≥ 15 MMD at baseline): 
 logit (proportion) = treatment group  + stratification factor 
Odds ratio, its 95% confidence interval and the corresponding p-value will be presented. 
Significance level will be set at 5%. By significant test results (p(odds ratio = 1) ≤ 0.05) the 
superiority of erenumab will be claimed only by the correct direction, i.e. if the erenumab odds 
are lower than topiramate odds.  
Additionally to the odds ratios, estimates for the relative risk and the risk difference (with 95% 
confidence intervals and p-values) will be calculated for the primary endpoint. Confidence 
intervals and p-values for the relative risks and risk difference will be calculated based on the 
normal distribution.  
In case of zero events in only one treatment arm add 1 patient with 0.5 events to each treatment 
arm for calculation of the relative risk. Odds ratio will not be estimated in this case. 
In case of zero events in both treatment arms no odds ratio will be estimated, the null hypothesis 
will not be tested and no difference between treatment arms can be claimed. Additionally, no 
relative risk will be calculated. 
2.5.3 
Handling of missing values/censoring/discontinuations 
For every patient, it can be determined whether he/she discontinued for AE-related reasons. 
AE-related discontinuations are counted as events. Discontinuation due to the other reasons as 
non-AE-related treatment discontinuations or losses to follow up should not be counted as event. 


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2.6 
Analysis of the secondary objective 
The secondary objective of the study is to evaluate the effect of erenumab compared to the 
topiramate on the proportion of patients with at least 50% reduction from baseline in monthly 
migraine days.  
Analysis on primary endpoint should be done based on the Full Analysis Set (FAS).  
2.6.1 
Secondary endpoint 
The secondary endpoint is an achievement of at least 50% reduction from baseline in MMD 
over the last 3 months (month 4, 5, and 6) of the double-blind epoch.  
The secondary analysis will contrast erenumab versus topiramate in the FAS. 


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2.6.2 
Statistical hypothesis, model, and method of analysis 
Null hypothesis: odds of achievement of at least 50% reduction from baseline in MMD are 
equal in both treatment groups.  
Alternative hypothesis: odds are not equal when comparing erenumab to topiramate 
Statistical hypothesis: H0:  
 (p1 / (1- p1)) / (p0 / (1- p0)) = 1,  
where 
pj – probability of patients achieved at least 50% reduction from baseline in the treatment 
group j 
j = 0 corresponds to topiramate group 
j = 1 corresponds to erenumab group 
The odds ratio not significantly different from one would mean that there is no evidence for a 
difference in achieving at least 50% reduction from baseline between the two treatment groups.  
Statistical hypothesis will be tested in the frame of logistic regression analysis controlling for 
the stratification factor: 
logit (probability) = treatment group + stratification factor  
Odds ratio, its 95% confidence interval and the corresponding p-value will be presented. 
Significance level will be set at 5%. By significant test results (p(odds ratio = 1) ≤ 0.05) the 
superiority of erenumab will be claimed only by the correct direction, i.e. if the erenumab 
odds are higher than topiramate odds.  
Additional to the odds ratios, estimates for the relative risk and the risk difference (with 95% 
confidence intervals and p-values) will be calculated for the secondary endpoint. Confidence 
intervals and p-values for the relative risks and risk difference should be calculated based on the 
normal distribution. 
In case of zero events in only one treatment arm add 1 patient with 0.5 events to each treatment 
arm for calculation of the relative risk. Odds ratio will not be estimated in this case. 
In case of zero events in both treatment arms no odds ratio will be estimated, the null hypothesis 
will not be tested and no difference between treatment arms can be claimed. Additionally, no 
relative risk will be calculated. 
2.6.3 
Handling of missing values/censoring/discontinuations 
All the subjects’ data collected regarding 50% response in MMD will be used in the analysis 
regardless of whether subjects discontinue study treatment or not. Subjects with missing 
response information on this endpoint will be imputed as non-response (non-responder 
imputation). 
2.6.4 
Subgroup analyses 
Not applicable. 


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2.7 
Analysis of exploratory objectives 
2.7.1 
Exploratory endpoints 
Exploratory efficacy analyses of erenumab in comparison to topiramate  is based on patients’ 
reported data assessed via eDiary, including 
 
 
• 
Patients’ quality of life assessed with SF-36v2 (The Short Form (36) Health Survey) 
• 
Headache impact on patients’ functional ability assessed by HIT-6 (Headache Impact 
Test) 
 
 
 
Objectives of the exploratory efficacy analyses are listed in the table below. 
Exploratory objective  
Efficacy endpoint   
Assessment time point 
To evaluate the effect of erenumab 
compared to topiramate on 
functional impairment 
Week 24 
 
HIT-6: 
Proportion of patients 
achieving at least a 5 
points reduction from 
baseline 
Week 24 
To evaluate the effect of erenumab 
compared to topiramate on generic 
health-related quality of life 
Week 24 
SF-36 v.2: 
Proportion of patients 
achieving at least a 5 
points increase from 
baseline in PCS- and 
MCS score 
Week 24 


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2.7.2 
Statistical hypothesis, model, and method of analysis 
Analysis of exploratory efficacy endpoints will utilize the FAS. Subjects will be analyzed 
according to their randomized treatment group. 
Methods of analysis for exploratory efficacy analyses are summarized in the table below. 
Exploratory 
Endpoint 
Model 
Terms included 
in the model 
Imputation of 
missing 
values 
Additional 


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scheduled 
visit) 
Treatment 
difference 
will be 
tested using 
a contrast 
from the 
model  
Proportion of 
patients achieving 
at least a 5 points 
reduction from 
baseline in HIT-6 
total score  
Logistic 
regression model 
- 
treatment 
group 
- 
baseline value 
- 
stratification 
factor 
 
Non-response 
imputation 
Summary 
statistics for 
observed 
data 
 
Relative 
Risk** 
 
Risk 
Difference** 
SF-36 quality of 
life: 
 
Proportion of 
patients achieving 
at least 5 points 
increase from 
baseline to week 
24 in PCS and 
MCS 
Logistic 
regression model 
- 
treatment 
group 
- 
baseline value 
- 
stratification 
factor 
 
Non-response 
imputation 
Summary 
statistics for 
observed 
data 
 
Relative 
Risk** 
 
Risk 
Difference** 


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* MMRM: unstructured covariance matrix will be used in the repeated statement 
**Calculation of the Relative Risk and Risk Difference will be based on rules described for 
primary analysis, see Statistical hypothesis, model, and method of analysis  
2.7.3 
Handling of missing values/censoring/discontinuations 
For the exploratory endpoints “Proportion of patients achieving at least a 5 points reduction 
from baseline in HIT-6 total score” and “Proportion of patients achieving at least 5 points 
increase from baseline to week 24 in PCS and MCS (SF-36v2)” missing response data will be 
imputed as non-response (non-responder imputation). 
2.8 
Safety analyses 
Safety analyses will be based on safety data set (SAF).  
All safety analyses will be performed for the Double-Blind Treatment Epoch and Follow-up 
Epoch separately and in descriptive manner.  
Missing data will not be imputed for safety endpoints. 
2.8.1 
Adverse events (AEs) 
In the frame of safety analysis the following treatment-emergent AE types will be considered: 
• 
Any AE  
• 
Study treatment related AE 
• 
AE leading to study treatment discontinuation  
• 
AE leading to dose adjustment (including study treatment discontinuation) 
• 
AE leading to pausing in uptitration  


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• 
Serious AE (SAE) 
• 
Study treatment related SAE 
• 
SAE leading to study treatment discontinuation 
• 
Death 
All adverse events tables will be summarized by treatment group. 
The Medical Dictionary for Regulatory Activities (MedDRA) version 22.1 or later will be used 
to code all adverse events (AE) to a system organ class (SOC) and a preferred term (PT).  
Overview table of the number and percentage of patients having each type of AE. 
Tables with the summary types I will be provided for all AEs listed above except for death. 
Tables with the summary types II will only be provided for AE type ‘any AE’. 
Summary type I: Tables with number and percentage of patients having particular AE 
summarized by treatment group, SOC and PT. Summaries will be provided for each AE 
type separately. 
Summary type II: Tables with number and percentage of patients having particular AE 
summarized by treatment group, SOC, PT and severity. Summaries will be provided for 
each AE type separately. 
The SOCs will be presented in the alphabetic order and PTs will be ordered within the SOCs 
by decreasing order of frequency in the erenumab treatment group. 
If a patient reported more than one adverse event with the same PT, the adverse event with the 
greatest severity will be presented. If a patient reported more than one adverse event within the 
same primary system organ class, the patient will be counted only once with the greatest severity 
at the system organ class level, where applicable. 
All AEs, deaths (see Section 2.8.2 for details), SAEs and AEs leading to permanent study drug 
discontinuation will be listed separately. 
  
2.8.1.1 
Adverse events of special interest / grouping of AEs 
Not applicable. 
2.8.2 
Deaths 
Deaths will be listed by treatment group including the start date of the study treatment, the last 
date on study treatment, the death date and the reason for death. 
2.8.3 
Laboratory data 
Summary statistics of laboratory hematology- and blood chemistry results will be presented as 
absolute value as well as change from baseline by visit, treatment and laboratory test category. 
Change from baseline will be summarized for each time point and only for patients with both 
baseline and post-baseline assessment.  
Clinically notable laboratory values will be flagged and listed by treatment group. 


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Table 2.8.1.1-1. 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 µmol/L 
Alkaline Phosphatase 
F 
> 832 U/L 
> 832 U/L 
Alkaline Phosphatase 
M 
> 1032 U/L 
> 1032 U/L 
Hematology variables 
Neutrophils 
Both 
< 1.5 x 103 /µL 
< 1.5 x 109 /L 
2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
For the numeric ECG measurements  
• 
ECG Mean Heart Rate 
• 
PR Interval 
• 
QRS Duration 
• 
QT Interval 
• 
QTcF Interval 
• 
RR Interval 
summary statistics will be presented for baseline and week 24 separately for each treatment 
group. Descriptive summary statistics for the change from baseline to the week 24 will be 
calculated for patients with available ECG data at both time points.  
2.8.4.2 
Vital signs 
Assessed vital signs include: 
• 
systolic/diastolic blood pressure 
• 
pulse rate 
• 
 temperature 
Patient’s values on blood pressure and pulse rate will be calculated as a mean of three 
readings. Readings with missing values will be ignored. 
Descriptive summary statistics presented by type of measurement and treatment group will 
contain vital signs measurements for each study visit as well as change 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 
will be summarized descriptively by treatment group and by visit, for DBTE and for safety 
follow-up period, respectively.  


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Shift table of C-SSRS maximum severity of suicidal ideation/behavior compared to baseline 
will be provided by treatment group for DBTE and for safety follow-up period, respectively. 
No statistical testing will be performed on C-SSRS. 
2.9 
Pharmacokinetic endpoints  
Not applicable. 
2.10 
PD and PK/PD analyses 
Not applicable.  
2.11 
Patient-reported outcomes 
Patient reported outcomes assessed in the study are limited to those used for exploratory 
efficacy analyses (MMD, HIT-6, SF-36v2, 
), safety analyses (C-SSRS) and 
patient’s baseline characteristics (BDI-II). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.12 
Biomarkers 
Not applicable.  
2.13 
Other Exploratory analyses 
See Analysis of exploratory objectives. No additional exploratory variables are specified.  
2.14 
Interim analysis 
No interim analyses is planned.  
 
 
 
  


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5 
Appendix 
5.1 
Imputation rules 
No imputation will be done for missing primary and exploratory endpoints. Subjects with 
missing response information on the secondary endpoint (achievement of at least 50% reduction 
from baseline in MMD over the last 3 months (month 4, 5, and 6) of the double-blind epoch) 
will be imputed as non-response. 
5.1.1 
Study drug 
5.1.2 
Concomitant medication date imputation 
 
Incomplete day 
Incomplete start day will be imputed as MAX(date of study day 1, earliest possible start date). 
Incomplete end day will be imputed as MIN(EoS, latest possible end date). 
 
Earliest possible start/end date is calculated on the eCRF page and refers to the first day of the 
corresponding month. Latest possible start/end date is calculated on the eCRF page and refers 
to the last day of the corresponding month. 
 
Incomplete day/month 
Incomplete start day/month will be imputed as MAX(date of study day 1, 1st January of the year 
entered). 
Incomplete end day/month will be imputed as MIN(EoS, 31th December of the year entered). 
 
Incomplete day/month/year 
Incomplete day/months/year will not be imputed. 
Prior therapies date imputation 
 
Incomplete day 
Incomplete start day will be imputed as earliest possible start date. 
Incomplete end day will be imputed as MIN (date of the day prior to study day 1, latest possible 
end date). 
 
Incomplete day/month 
Incomplete start day/month will be imputed as 1st January of the year entered. 
Incomplete end day/month will be imputed as MIN(31th December of the year entered, date of 
the day prior to study day 1). 
 


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Incomplete day/month/year 
Incomplete start date will be imputed as very early date  
Incomplete end date will be imputed as a date of the day prior to study day 1. 
 
 
5.1.2.1 
Post therapies date imputation 
Not applicable. 
5.1.2.2 
Other imputations 
5.1.2.2.1 eDiary data 
Missing eDiary data in the calculation of monthly measurements about patients’ 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:  
Monthly migraine days 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 to missing. 
 
Monthly Endpoint 
Condition 
Proration Method (does not 
need to be rounded) 
Monthly 
migraine days  
 
If eDiary days in entire baseline or 
interval post baseline >=14 
(including retrospective eDiary 
days), then do proration; 
Else monthly measurement is set to 
missing 
[eDiary day 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 an 
eDiary day or headache 
day] 
 
5.2 
AEs coding/grading 
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. 
Severity of adverse events is graded by investigator (mild, moderate, severe) and reflected in 
the eCRF. 


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5.3 
Laboratory parameters derivations 
Not applicable. 
5.4 
Statistical models 
5.4.1 
Primary analysis 
See Analysis of the primary objective 
5.4.2 
Key secondary analysis 
See Analysis of the secondary objective 
5.5 
Rule of exclusion criteria of analysis sets  
Exclusion criteria of analysis sets are complementary to those used for corresponding analysis 
set definitions (see Analysis sets). 


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5.8 
Appendix C: Patient-reported Outcome Scoring 
rules/Forms/Instruments 
5.8.1 
BDI-II scoring 
Beck Depression Inventory II (BDI-II) consists of 21 items, each with 4 or 6 response options.  
 
Missing data 
If more than 2 items have missing values, the total BDI score will be missing. If one or two 
items are missing, their score can be imputed with the mean of the non-missing scores before 
summing. 
Items should be rescored according following rules: 
 
Item number 
Item label in the data 
set 
Original value 
Rescored value 
1 - 15, 17, 19 - 21 
 
0 
0 
 
 
1 
1 


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2 
2 
 
 
3 
3 
16 
BDI_161L 
0 
0 
18 
BDI_181L 
1 
1 
 
 
2 
1 
 
 
3 
2 
 
 
4 
2 
 
 
5 
3 
 
 
6 
3 
Scoring 
A single score is calculated by adding up the rescored values of 21 items. The range of values 
is 0 - 63.  
5.8.2 
HIT-6 scoring 
The Headache Impact Test (HIT-6) is as a global measure of adverse headache impact, which 
assesses headache severity in the previous month and change in a patient’s clinical status over 
a short period of time.  
Scoring 
HIT-6 score will be calculated by the HIT-6 license owner “Optum” and ranges from 36 to 78.  
Score categorization 
HIT-6 score can be categorized into 4 grades: 
• 
≤ 49: little or no impact (49 or less) 
• 
50 - 55: some impact 
• 
56 - 59: substantial impact 
• 
60 - 78: severe impact  
5.8.3 
SF-36v2 scoring 
SF-36v2 scores (eight subscores and two component summary scores) will be calculated by the 
SF-36v2 license owner “Optum”. 
 


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5.8.5 
C-SSRS scoring 
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire that prospectively 
assesses Suicidal Ideation and Suicidal Behavior based on following categories: 
Suicidal Ideation 
• 
Cat. 1 - Wish to be dead 
• 
Cat. 2 - Non-specific active suicidal thoughts 
• 
Cat. 3 - Active suicidal ideation with any methods (not plan) without intent or act 
• 
Cat. 4 - Active suicidal ideation with some intent to act, without specific plan 
• 
Cat. 5 - Active suicidal ideation with specific plan and intent 
Suicidal behavior 
• 
Cat. 6 - Actual attempt (non-fatal) 
• 
Cat. 7 - Interrupted attempt 
 
• 
Cat. 8 – Aborted or self-interrupted attempt  
• 
Cat. 9 - Preparatory acts or behavior 
• 
Cat. 10 - Suicide 
Any suicidal ideation is identified by answer “yes” to at least one of the 5 suicidal ideation 
categories (cat. 1-5) for specific visit. 
Any suicidal behavior is identified by answer “yes” to at least one of the 5 suicidal behavior 
categories (cat. 6-10) for specific visit. 
Any suicidal ideation or behavior is identified by answer “yes” to at least one of the 10 
categories (cat. 1-10) for specific visit. 
 
6 
Reference 
Not applicable. 


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7 
Approval signatures 
This Statistical Analysis Plan was subject to critical review and has been approved after review 
by: 
 
 
Dr. 
 
 
 
 
 
 
 
Signature 
 
Date 
 
 
 
 
 
 
 
HTA
 
Signature 
 
Date 
 
 
 
 
 
 
 
CRO
 
Signature 
 
Date