Assessment of Prolonged Safety and tOLerability of in Migraine Patients in a Long-term OpeN-label Study
Phase: PHASE4
Conditions: Migraine, Migraine Disorders, Migraine Headache
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development 
Erenumab 
Clinical Trial Protocol AMG334ADE03 / NCT04084314   
Protocol Title 
Assessment of Prolonged safety and tOLerability of 
erenumab in migraine patients in a Long-term OpeN-label 
study (APOLLON) 
Document type: 
Clinical Trial Protocol 
EUDRACT number: 
2019‐002201‐22  
Version number: 
01 
Clinical trial phase: 
IV 
Release date: 
30-04-2020 (content final)
Property of Novartis Pharma GmbH Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 2.0 (01-Aug-2018) 

Novartis 
Confidential 
Page 2 
Clinical trial protocol V01 
Protocol No. CAMG334ADE03 
 
Table of contents 
Table of contents ...................................................................................................................... 2 
List of tables ............................................................................................................................. 4 
List of figures ........................................................................................................................... 5 
List of abbreviations ................................................................................................................ 6 
Glossary of terms ..................................................................................................................... 9 
Amendment 1 ................................................................................................................................ 14 
 
Introduction ............................................................................................................................ 15 
 
Background ................................................................................................................ 15 
 
Objectives and endpoints....................................................................................................... 17 
 
Study design ........................................................................................................................... 18 
 
Rationale ................................................................................................................................. 18 
 
Rationale for study design......................................................................................... 18 
 
Rationale for dose/regimen and duration of treatment ............................................ 19 
 
Risks and benefits ...................................................................................................... 20 
 
Population ............................................................................................................................... 21 
 
Inclusion criteria ........................................................................................................ 21 
 
Exclusion criteria ....................................................................................................... 22 
 
Treatment................................................................................................................................ 24 
 
Study treatment .......................................................................................................... 24 
 
Investigational drug .................................................................................. 24 
 
Additional study treatments ..................................................................... 24 
 
Treatment arms/group .............................................................................. 24 
 
Treatment duration ................................................................................... 24 
 
Concomitant therapy ................................................................................ 25 
 
Prohibited medication .............................................................................. 25 
 
Rescue medication.................................................................................... 26 
 
Subject numbering, treatment assignment, randomization ..................................... 26 
 
Subject numbering.................................................................................... 26 
 
Treatment assignment, randomization .................................................... 26 
 
Treatment blinding .................................................................................................... 26 
 
Dose escalation and dose modification .................................................................... 26 
 
Dose escalation guidelines ....................................................................... 27 
 
Dose modifications ................................................................................... 27 
 
Follow-up for toxicities............................................................................ 27 
 
Additional treatment guidance .................................................................................. 27 
 
Treatment compliance .............................................................................. 27 

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Novartis 
Confidential 
Page 5 
Clinical trial protocol V01 
Protocol No. CAMG334ADE03 
 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ............................................................................................ 46 
Table 16-1 
Liver event and laboratory trigger definitions ........................................ 58 
Table 16-2 
Follow up requirements for liver events and laboratory triggers .......... 58 
List of figures 
Figure 3-1 
Study Design ............................................................................................ 18 

Novartis 
Confidential 
Page 6 
Clinical trial protocol V01 
Protocol No. CAMG334ADE03 
 
List of abbreviations 
 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate Aminotransferase 
b.i.d. 
bis in die/twice a day 
BMI 
Body Mass Index 
BLRM 
Bayesian Logistic Regression Model 
BUN 
Blood Urea Nitrogen 
CDP 
Clinical Development Plan 
CD-ROM 
Compact Disc – Read Only Memory 
CDS 
Core Data Sheet 
CK 
Creatinine Kinase 
ClinRO 
Clinician Reported Outcomes 
CMO&PS  
Chief Medical Office and Patient Safety 
COA 
Clinical Outcome Assessment 
CO2 
carbon dioxide 
CRF 
Case Report/Record Form (paper or electronic) 
CO 
Country Organization 
CQA 
Clinical Quality Assurance 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTC 
Common Terminology Criteria 
CV 
coefficient of variation 
DBP 
Diastolic Blood Pressure 
DIN 
Drug Inducted Nephrotoxicity 
DLT 
Dose Limiting Toxicity 
DMC 
Data Monitoring Committee 
DQF 
Data Query Form 
ECG 
Electrocardiogram 
eCOA 
Electronic Clinical Outcome Assessment 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked immunosorbent assay 
EOI 
End of Infusion 
eSAE 
Electronic Serious Adverse Event 
eSource 
Electronic Source 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GGT 
Gamma-glutamyl transferase 
h 
Hour 
HbsAg 
Hepatitis B surface antigen 

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Confidential 
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Clinical trial protocol V01 
Protocol No. CAMG334ADE03 
 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HED 
Human Equivalent Dose 
HEOR 
Health Economics & Outcomes Research  
HIV 
Human Immunodeficiency Virus 
HNSTD 
Highest Non-Severely Toxic Dose 
HRQoL 
Health-Related Quality of Life 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
i.v. 
intravenous 
LDH 
lactate dehydrogenase 
LFT 
Liver function test  
LLN 
lower limit of normal 
LLOQ 
lower limit of quantification 
MedDRA 
Medical dictionary for regulatory activities  
mg 
milligram(s) 
mL 
milliliter(s) 
MRSD 
Maximum Recommended Starting Dose 
MTD 
Maximum Tolerated Dose 
Nab 
Neutralizing antibody 
NCDS 
Novartis Clinical Data Standards 
NOVDD 
Novartis Data Dictionary 
ObsRO 
Observer Reported Outcomes 
PA 
posteroanterior 
PC 
Personal Computer 
PD 
Pharmacodynamic(s) 
PerfO 
Performance Outcomes 
PIP 
Pediatric Investigation Plan 
PK 
Pharmacokinetic(s) 
p.o. 
oral(ly) 
PRO 
Patient Reported Outcomes 
PSD 
Premature Subject Discontinuation 
PT 
prothrombin time 
QD 
Once a day 
QMS 
Quality Management System 
QTcF 
QT interval corrected by Fridericia’s formula 
RAP 
Report and Analysis Plan 
RBC 
red blood cell(s) 
RDC 
Remote Data Capture 
RDE 
Recommended dose for expansion 

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Novartis 
Confidential 
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Clinical trial protocol V01 
Protocol No. CAMG334ADE03 
 
Glossary of terms 
 
Additional treatment 
Medicinal products that may be used during the clinical trial as described in the 
protocol, but not as an investigational medicinal product (e.g. any background 
therapy) 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, 
urine, stool, etc. taken from a study subject  
Cohort 
A specific group of subjects fulfilling certain criteria and generally treated at the 
same time 
Control drug 
A  study drug (active or placebo) used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug 
Cycles 
Number and timing or recommended repetitions of therapy are usually expressed as 
number of days (e.g., q28 days) 
Dosage 
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg once a 
day, 75 mg twice a day) 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study data 
using data collection systems, such as Web-based applications, interactive voice 
response systems and clinical laboratory interfaces. EDC includes the use of 
Electronic Case Report Forms (eCRFs) which are used to capture data transcribed 
from paper source forms used at the point of care 
End of the clinical trial 
The end of the clinical trial is defined as the last visit of the last subject or at a later 
point in time as defined by the protocol  
Enrollment 
Point/time of subject entry into the study at which informed consent must be 
obtained  
eSource (DDE) 
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines source 
documents and case report forms (eCRFs) into one application, allowing for the real 
time collection of clinical trial information to sponsors and other oversight authorities, 
as appropriate 
Healthy volunteer 
A person with no known significant health problems who volunteers to be a study 
participant  
Investigational drug/ 
treatment 
The drug whose properties are being tested in the study 
Medication number 
A unique identifier on the label of medication kits 
Mis-randomized 
subjects 
Mis-randomized subjects are those who were not qualified for randomization and 
who did not take study treatment, but have been inadvertently randomized into the 
study  
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy) 
Part  
A sub-division of a study used to evaluate specific objectives or contain different 
populations. For example, one study could contain a single dose part and a multiple 
dose part, or a part in subjects with established disease and in those with newly-
diagnosed disease 
Patient 
An individual with the condition of interest for the study 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) which are 
described in the Protocol. Periods define the study phases and will be used in 
clinical trial database setup and eventually in analysis 
Perpetrator drug 
A drug which affects the pharmacokinetics of the other drug 
Personal data 
Subject information collected by the Investigator that is transferred to Novartis for 
the purpose of the clinical trial. This data includes subject identifier information, 
study information and biological samples.  

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Clinical trial protocol V01 
Protocol No. CAMG334ADE03 
 
Premature subject 
withdrawal 
Point/time when the subject exits from the study prior to the planned completion of 
all study drug administration and/or assessments; at this time all study drug 
administration is discontinued and no further assessments are planned 
Randomization number 
A unique identifier assigned to each randomized subject 
Run-in Failure 
A subject who is screened but not randomized/treated after the run-in period (where 
run-in period requires adjustment to subject’s intervention or other treatment) 
Screen Failure 
A subject who did not meet one or more criteria that were required for participation 
in the study 
Source Data/Document 
Source data refers to the initial record, document, or primary location from where 
data comes. The data source can be a database, a dataset, a spreadsheet or even 
hard-coded data, such as paper or eSource 
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size of the 
tumor, whether lymph nodes contain cancer, and whether the cancer has spread 
from the original site to other parts of the body 
Start of the clinical trial 
The start of the clinical trial is defined as the signature of the informed consent by 
the first subject. 
Study treatment 
Any single drug or combination of drugs or intervention administered to the subject 
as part of the required study procedures 
Study treatment 
discontinuation 
When the subject permanently stops taking any of the study drug(s) prior to the 
defined study treatment completion date (if any) for any reason; may or may not also 
be the point/time of study discontinuation  
Subject 
A trial participant (can be a healthy volunteer or a patient) 
Subject number 
A unique number assigned to each subject upon signing the informed consent. This 
number is the definitive, unique identifier for the subject and should be used to 
identify the subject throughout the study for all data collected, sample labels, etc. 
Treatment arm/group  
A treatment arm/group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. 
Variable 
A measured value or assessed response that is determined from specific 
assessments and used in data analysis to evaluate the drug being tested in the 
study 
Victim drug  
The drug that is affected by the drug-drug interaction 
Withdrawal of study 
consent (WoC) 
Withdrawal of consent from the study occurs only when a subject does not want to 
participate in the study any longer and does not allow any further collection of 
personal data  
 
 
 

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Clinical trial protocol V01 
Protocol No. CAMG334ADE03 
 
Amendment 1 
 
The protocol is being amended to include patients with chronic migraine and to restrict the 
transition from the trial CAMG334ADE01 to this study to 3 months.  
Further, some minor linguistic changes have been introduced to clarify certain criteria and 
procedures in the protocol. 
 
Changes to the protocol 
• Objectives were updated to include chronic migraine patients. 
• The description of the study population has been adjusted to include all female and male 
patients that are 18 years or older with a documented history of episodic (4  – 14 baseline 
migraine days) or chronic migraine (≥15 baseline headache days), who were 
successfully randomized to clinical trial CAMG334ADE01.  
• The inclusion criteria have been adjusted to define 3 months after the V199 visit as the 
latest time point at which patients can  be included in the study 
• The exclusion criteria have been updated to exclude patients that have terminated the 
trial CAMG334ADE01 due to a safety event.  
• The sample size calculation was updated considering the inclusion of chronic migraine 
patients and resulted in a sample size increase from 700 to 750 patients including up to 
70 patients with ≥ 15 monthly migraine days.Mentions of an eDiary were replaced by 
paper-based migraine diary. 
 

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Clinical trial protocol V01 
Protocol No. CAMG334ADE03 
 
 
Introduction 
 
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.  
A novel class of drugs for the prophylactic treatment of migraine is based on the discovery of 
calcitonin-gene-related peptide (CGRP) being involved in the pathogenesis of migraine. 
Currently, several monoclonal antibodies directly targeting CGRP are either under development 
or already approved. Erenumab (AMG334) as the only monoclonal antibody targeting the 
CGRP receptor itself was approved by EMA and FDA in 2018 as the first compound 
specifically developed for the prophylactic treatment of migraine patients.  
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. 
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 
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 

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Clinical trial protocol V01 
Protocol No. CAMG334ADE03 
 
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 (DGN 2018) 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 erenumab treated 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 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 a positive benefit-risk ratio for the chosen patient population with certain 
patients obtaining an additional benefit from the 140 mg dose. CGRP targeting in migraine 

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Clinical trial protocol V01 
Protocol No. CAMG334ADE03 
 
 
Study design 
This is an open-label, multi center, single arm study with flexible dosing allowing both dose 
adjustment and one drug holiday per patient.  
The study design consists of 3 parts: 
• Screening Epoch (0 - 2 weeks): required for all patients to assess initial eligibility. 
• Open-label Treatment Epoch (128 weeks): Individual patients are treated for 128 
weeks in the open-label treatment phase. During this open-label Treatment Epoch the 
erenumab dose may be adjusted from 70 mg to 140 mg or vice versa by discretion of 
the physician at any scheduled study visit. Additionally, a voluntary single treatment 
interruption (‘drug holiday’) of up to 24 weeks (approximately six months) may be 
introduced after at least 12 weeks of treatment in the open-label Treatment Epoch.  
• Follow-up Epoch (4 weeks): A Follow-Up Visit 4 weeks after the last regular study 
visit (8 weeks after last IMP application) will be required as part of routine safety 
monitoring. 
 
End of trial will occur when the last patient completes last visit (LPLV). 
 
Figure 3-1 
Study Design  
 
 
 
 
Rationale 
 
 
Rationale for study design 
Until now long-term safety and tolerability data of erenumab in a large group of patients are 
still limited. This 128-week open-label study will provide further treatment to patients still 
blinded for the randomization of the study CAMG334ADE01 (Eudract number:2019‐

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Clinical trial protocol V01 
Protocol No. CAMG334ADE03 
 
002201‐22) and will provide data about the long-term safety and tolerability of Erenumab and 
patients’ quality of life during long-term treatment. The regular assessments in a controlled trial 
allows a close observation of safety parameters during long-term treatment with erenumab.  
Furthermore, while regular reviews of treatment outcome and drug holidays are routine in 
migraine prophylaxis and also recommended in the German S1 guideline (DGN 2018), there 
are no data regarding erenumab treatment yet. Besides options to adjust the dose, an optional 
drug holiday is therefore included in this open-label study and the effects of a treatment 
interruption on safety, tolerability, efficacy and quality of life will be investigated. 
 
 
Rationale for dose/regimen and duration of treatment 
Dosing and route of administration are in accordance with the Summary of Product 
Characteristics (SmPC, version Mai 2019) either 70 mg or 140 mg erenumab at the discretion 
of the physician. Erenumab will be injected s.c. by the well trained patient at home in 28-day 
intervals.  
 
The starting dose of erenumab in the open-label trial is matched to the last dose received (either 
as erenumab verum or placebo) during the head-to-head clinical trial CAMG334ADE01 from 
which all patients are recruited. In CAMG334ADE01 patients have received either erenumab 
verum at 70/140 mg and topiramate placebo OR erenumab placebo at 70/140 mg and topiramate 
verum for 24 weeks. While patients and physicians are still blinded at study start of 
CAMG334DE03 to the identity of verum/placebo in CAMG334ADE01 the dose is known as 
70 mg erenumab/placebo were delivered in one pre-filled syringe and 140 mg 
erenumab/placebo was injected by two pre-filled syringes. Accordingly, patients who have 
received 70 mg erenumab/placebo injections as last dose in CAMG334ADE01 will also receive 
70 mg erenumab as starting dose in this open-label study. Patients who have received 140 mg 
erenumab/placebo as last dose in CAMG334ADE01 will receive 140 mg erenumab as starting 
dose in this open-label extension study. Evidently, patients who received topiramate during trial 
CAMG334ADE01 will be switched to erenumab in this study. 
 
Subsequently, physicians may adjust the erenumab dose during the open-label study at any 
planned study visit during the open-label Treatment Epoch at their discretion. Furthermore, one 
voluntary treatment interruption (‘drug holiday’) may be performed earliest 12 weeks after first 
dose in the open-label study with a duration of no more than 24 weeks before returning to the 
dosing regimen. 
A treatment duration of 128 weeks was chosen for the long-term assessment of erenumab 
treatment. In comparison in oral migraine prophylaxis trials almost 50% of patients 
discontinued the study after six months of treatment (Hepp 2014). The chosen treatment 
duration for the open-label study is therefore five times longer and thus assessed to be suitable 
to analyze the long-term tolerability and safety of erenumab treatment and sustained study 
compliance of subjects.  
 

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Clinical trial protocol V01 
Protocol No. CAMG334ADE03 
 
 
 
Risks and benefits 
Erenumab was 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 
SmPC.  
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.  
As of June 2018, the safety of erenumab in migraine prophylaxis was assessed from integrated 
safety analyses of 2537 migraine patients exposed to at least one dose of erenumab, with a 
cumulative exposure of 2310.3 subject-years (SY). Overall, the safety and tolerability profile 
of erenumab was similar between the 140 mg and 70 mg doses and comparable to placebo. 
Adverse drug reactions include injection site reactions, constipation, muscle spasms, and 
pruritus. The majority were mild or moderate in severity and rarely led to treatment 
discontinuation. To date, no important risk has been identified for erenumab. 
Overall, to date, there is no evidence from non-clinical and clinical data of risk of cardiovascular 
effects. On the theoretical basis of the mechanism of action of erenumab, CGRP receptor 
blockade might reduce compensatory vasodilation, particularly under ischemic conditions. 
Therefore, cardiovascular effects continue to be monitored. 
All biologicals, including fully human proteins, have the potential to induce immunogenicity 
leading to the development of specific anti-drug antibodies. So far, the development of 
antierenumab antibodies has only been observed with low incidence and was not associated 
with specific adverse events or a clinically relevant reduction in erenumab plasma levels. In 
most cases, subjects with a positive anti-erenumab antibody status reverted to antibody negative 
with continued follow-up. Subjects in clinical studies will continue to be monitored for the 
development of anti-erenumab antibodies and possible associated clinical sequelae. 
Plasma levels of CGRP increase with advancement of pregnancy up to the time of delivery, 
followed by a sharp decline at term and postpartum in rats and humans. Endogenous CGRP 
may play an important role in maintaining normal fetoplacental development, fetal survival, 
and vascular adaptation during pregnancy. Women who are breastfeeding, pregnant, or 
planning to become pregnant are excluded from study participation, as well as patients who are 
unwilling to comply with the protocol-specified contraception requirements. All women of 
child-bearing potential will be screened for pregnancy at each study visit. 
An external data monitoring committee was established to review the erenumab safety data for 
Phase 2b and Phase 3a studies, and based on these data, recommended continuation of the 
program. The need for a data monitoring committee (DMC) for this study was assessed, and 
deemed not necessary because erenumab was approved by FDA and EMA for migraine 
prophylaxis and the safety profile of erenumab was well characterized in 4 double-blind, 
placebo-controlled trials in over 2500 patients. The risk to patients in this trial will be minimized 

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Clinical trial protocol V01 
Protocol No. CAMG334ADE03 
 
by compliance with the eligibility criteria, close clinical monitoring, and allowance of acute 
rescue medications. 
Initial benefits for erenumab as a migraine prophylactic have been demonstrated in a Phase 2b 
trial (Amgen Study 20120178), in which 70 mg was established as the minimally effective dose 
in EM (Sun et al 2016) with a significant placebo-corrected reduction of 1.1 monthly migraine 
days compared to baseline, as well as positive results on most secondary endpoints, including 
50% responder rate. 
Three additional Phase 2/3 studies, including 2 studies in EM, have been completed with 
erenumab, which have established 70 mg and 140 mg as being effective and safe in patients 
with EM or CM, with a favorable benefit/risk profile. Positive treatment effects in general were 
observed in a robust way across typical migraine endpoints such as change in mean monthly 
migraine days, > 50% (and higher) responder rates, change in migraine-specific medication use 
and functional improvement by established PRO scales. Results were in general highly 
statistically significant and clinically meaningful. Retention rates observed in clinical trials 
were very high (~95% with active treatment after 3 months and ~90% after 6 months with only 
minimal discontinuations attributed to adverse events). This feature is important, as 
discontinuation rates are high for current migraine prophylaxis treatments, with the main drivers 
of discontinuation being either lack of efficacy or tolerability issues (Blumenfeld et al 2013). 
As such, there is a high unmet need for a therapy that is well-tolerated, has sustained response 
rates and excellent compliance. 
As of July 2018, two open-label extension studies (OLE) of erenumab in patients with chronic 
(1 year) and episodic migraine (3 years) were reported confirming sustained efficacy and a 
favorable safety and tolerability profile. Overall, given the characteristics of erenumab and the 
large experience in clinical trials, the overall benefit-risk assessment is supportive. 
 
 
Population 
The study population will consist of female and male patients that are 18 years or older with a 
documented history of episodic (4  – 14 baseline migraine days) or chronic migraine (≥15 
baseline headache days), who were successfully randomized to clinical trial CAMG334ADE01. 
Patients can only be enrolled to the study from two weeks after their end of study visit (V199 
at week 24) in CAMG334ADE01 until three months after their end of study visit (V199). For 
patients terminating CAMG334ADE01 earlier than planned as per protocol,the planned end of 
study date (V199) at 26 weeks after randomization to CAMG334ADE01 is applicable (see 
inclusion criteria 4 below). 
 
Inclusion criteria 
Subjects eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study 
2. Patient is capable of understanding the nature, significance and implications of the clinical 
trial.  
3. Adults ≥18 years of age upon entry into screening 

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Protocol No. CAMG334ADE03 
 
4. Earliest time point for inclusion to this open-label study is 26 weeks after randomization 
to trial CAMG334ADE01: 
a) Subjects who completed visit V199 in trial CAMG334ADE01 have to wait additional 
2 weeks for down-titration of topiramate (doses 75 and 100 mg) and total elimination 
for topiramate (equals 26 weeks after randomization)  
b) Subjects who discontinued their participation in CAMG334ADE01 before V199 have 
to wait until the planned V199 visit date and additional 2 weeks (26 weeks after 
randomization). 
5. Latest time point for inclusion to this open-label study is 3 months after visit V199 in trial 
CAMG334ADE01. For subjects who discontinued their participation in trial 
CAMG334ADE01 the theoretical V199 is applicable. 
6. Subjects who are deemed by the investigator to benefit from erenumab therapy. 
 
Exclusion criteria 
Subjects meeting any of the following criteria are not eligible for inclusion in this study. 
1. Patients who had to terminate the trial CAMG334ADE01 due to a safety event. 
2. Use of a prophylactic migraine medication within five plasma clearance half-lives, or a 
device or procedure within one month prior to the start of the Open-label Treatment 
Epoch. This exclusion criteria does not apply to erenumab or topiramate administered 
within clinical trial CAMG334ADE01  
3. Any prior exposure to (investigational) prophylactic migraine products targeting the 
CGRP pathway, other than erenumab.  
4. Use of the following for any indication one month prior to the start of the Open-label 
Treatment Epoch:  
a. Opioid- or butalbital-containing analgesics ≥4 days/month  
5. Anticipated to require any excluded medication device or procedure (e.g., occipital 
nerve stimulators, transcranial magnetic stimulation,) during the study  
6. Active chronic pain syndromes (e.g., fibromyalgia or chronic pelvic pain)  
7. 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 
8. Evidence of drug or alcohol abuse or dependence within 12 months prior to screening, 
based on medical records or patient self-report  
9. Myocardial infarction, stroke, transient ischemic attack, unstable angina, or coronary 
artery bypass surgery or other revascularization procedures within 12 months prior to 
screening  
10. History or current diagnosis of ECG abnormalities indicating significant risk of safety 
for patients participating in the study  

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Protocol No. CAMG334ADE03 
 
11. 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 
12. Pregnant or nursing (lactating) women 
13. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
while taking study treatment and for 110 days after stopping medication. Highly 
effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject 
• Use of oral (estrogen and progesterone), injected, or implanted hormonal methods 
of contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS), or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example, 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 study treatment 
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at 
least six weeks ago.  
If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the informed consent form 
(ICF) 
14. Use of any other investigational drug outside of CAMG334ADE01 since randomization 
to the CAMG334ADE01 trial. 
15. Simultaneous participation in a study that includes administration of any investigational 
drug or procedure in the indication migraine and simultaneous participation in a non-
interventional study. 
 
16. History of hypersensitivity to the study drug or its excipients including latex 

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Protocol No. CAMG334ADE03 
 
17. 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 diary 
items) to the best of the patient’s and investigator’s knowledge 
18. Patients who may be dependent on the sponsor or investigator 
19. Patient has not been committed to an institution by virtue of an order issued either by 
the judicial or the administrative authorities 
 
Treatment 
 
Study treatment 
Novartis will supply the market sourced investigational medicinal product erenumab in pre-
filled autoinjectors containing 70 mg or 140 mg erenumab.  
 
Investigational drug 
 
 
Table 6-1 Investigational drug 
Investigational Drug 
Pharmaceutical Dosage 
Form 
Route of Administration 
AMG334 70mg 
Solution  
Subcutaneous use 
AMG334 140mg 
Solution 
Subcutaneous use 
 
Additional study treatments 
No other treatment beyond investigational drug is included in this trial. 
 
Treatment arms/group 
This is a single arm study. All subjects will continue to receive the same dose of erenumab that 
was administered (either as erenumab verum or placebo) on the last visit in clinical trial 
CAMG334ADE01.  
 
Treatment duration 
The planned duration of treatment is 128 weeks for individual patients. However, each patient 
is eligible to one voluntary treatment interruption of up to 24 weeks (approximately 6 months) 
after an initial treatment duration of at least 12 weeks. After such a voluntary treatment 
interruption within the 128 weeks of the Treatment Epoch patients may return to the treatment 
schedule.  
Subjects can be discontinued from treatment earlier due to unacceptable adverse events and/or 
at the discretion of the investigator or the subject.  
 

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Protocol No. CAMG334ADE03 
 
 
Concomitant therapy 
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject was enrolled into the study must be recorded 
on the appropriate Case Report Forms. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis Medical Advisor before 
including a subject or allowing a new medication to be started. If the subject is already enrolled, 
contact Novartis to determine if the subject should continue participation in the study. 
 
 
Prohibited medication 
Only prophylactic migraine (Erenumab) monotherapy is allowed. If a subject is taking a migraine 
prophylactic for a different pre-existing condition (not for migraine prophylaxis), this will be 
allowed as long as the subject is on stable dose for at least 3 months prior to baseline visit and the 
pre-existing condition and corresponding treatment is documented in the source and eCRF. No other 
concomitant prophylactics for migraine should be used.  
Use of the treatments displayed in Table 6-2 is NOT allowed unless in the context of a different 
pre-existing condition in stable doses for at least 3 months prior to baseline visit.  
 
 
Table 6-2 Prohibited medication 
Treatment 
Prohibition period 
All prophylactic treatments targeting the 
CGRP pathway  
Any time before study start and throughout 
the study 
Valproate/Divalproex  
Any time before study start and throughout 
the study 
All oral beta blockers  
Within 5 half-lives of the start 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  
Any time before study start 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 
visit and throughout the study  
 

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Rescue medication 
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 the patient has 
been stable dose 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. 
Use of rescue medication should be noted and documented in the eCRF. Data will include the 
drug name, indication and the individual administration dates.  
Relevant non-drug therapies should also be recorded in the eCRF. 
 
Subject numbering, treatment assignment, randomization 
 
Subject numbering 
Upon signing the informed consent form for the study CAMG334AD01, each patient was 
assigned a unique identification number by the investigator using a combination of the study 
center number and patient number. The same unique patient identification numbers used in the 
study CAMG334AD01 will be retained for the identification of patients participating in the 
study CAMG334AD03. 
 
Treatment assignment, randomization 
This is a single arm study. All patients will receive Erenumab. No randomization is required. 
At study start, subjects will be assigned to the latest choice of dose (either as erenumab verum 
or placebo) in the CAMG334ADE01 trial and can be adjusted at any following visit throughout 
the Open-label Treatment Epoch.  
 
Treatment blinding 
Treatment will be open to subjects, investigator staff, persons performing the assessments, and 
the CTT. 
 
Dose escalation and dose modification 
At study start, the subjects will be assigned to the latest administered dose of CAMG334ADE01 
trial regardless of verum or placebo. Dose modification can be performed at the discretion of 
the physician at any of the following visits throughout the Open-label Treatment Epoch of the 
study according to the SmPC.  
Dose modifications include dose escalation from 70 mg to 140 mg erenumab or dose reduction 
from 140 mg to 70 mg erenumab. One voluntary treatment interruption (drug holiday) per 
patient may be conducted but earliest after 12 weeks of treatment and for up to 24 weeks during 
the open-label treatment Epoch. Afterwards, patients may return to treatment. 

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Protocol No. CAMG334ADE03 
 
 
Dose escalation guidelines 
There is no dose escalation guideline other than the SmPC. In clinical studies there was no clear 
dose-dependent safety signal combined with a comparable overall efficacy trend between 
70 mg and 140 mg erenumab. Both 70 mg and 140 mg erenumab are considered to offer an 
optimal benefit-risk ratio for patients with some patients obtaining an additional benefit from 
the 140 mg dose. 
6.4.1.1 
Starting dose 
The starting dose of erenumab in the open-label trial is matched to the last dose received (either 
as erenumab verum or placebo) during clinical trial CAMG334ADE01 from which all patients 
are recruited. In CAMG334ADE01 patients have received either erenumab verum at 70/140 mg 
and topiramate placebo OR erenumab placebo at 70/140 mg and topiramate verum. While 
patients and physicians were blinded to the identity of verum/placebo in CAMG334ADE01 the 
dose is known as 70 mg erenumab/placebo were delivered in one pre-filled syringe and 140 mg 
erenumab/placebo was injected by two pre-filled syringes. Accordingly, patients who have 
received 70 mg erenumab/placebo injections as last dose in CAMG334ADE01 will also receive 
70 mg erenumab as starting dose in this open-label study. Patients who have received 140 mg 
erenumab/placebo as last dose in CAMG334ADE01 will receive 140 mg erenumab as starting 
dose in this open-label extension study.  
As CAMG334ADE01 will still be ongoing at patient inclusion into the open-label study 
CAMG334ADE03 un-blinding cannot be performed and neither patients nor physicians will 
know at this point which medication was received during CAMG334ADE01.  
 
Dose modifications 
See Section 6.4 above. 
 
Follow-up for toxicities 
Not applicable. 
 
Additional treatment guidance 
 
Treatment compliance 
The investigator must promote compliance by instructing the subject to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the subject’s safety and 
the validity of the study. The subject must also be instructed to contact the investigator if he/she 
is unable for any reason to take the study treatment as prescribed. Compliance will be assessed 
by the investigator and/or study personnel at each visit and based on information provided by 
the subject. This information should be captured in the source document at each visit. All study 
treatment dispensed and returned must be recorded in the Drug Accountability Log. 
 
 Emergency breaking of assigned treatment code 
Not applicable as this is an open label study. 

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Preparation and dispensation 
Each study site will be supplied with study drug in in packaging.  
 
 
Handling of study treatment 
Erenumab must be received by a designated person at the study site, handled and stored safely 
and properly and kept in a secured location to which only the investigator and designated site 
personnel have access.  
Erenumab must be stored according to the instructions specified on the label and in the 
prescribing information/package insert. Clinical supplies are to be dispensed only in accordance 
with the protocol. Technical complaints are to be reported to the respective Novartis Country 
Pharma Organization (CPO) Quality Assurance. Medication labels will include storage 
conditions for the study treatment but no information about the subject except for the medication 
number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Subjects will be asked 
to return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Sponsor address provided in the investigator 
folder at each site. 
 
Instruction 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 up-titration could be, but are not limited to:  
- 
insufficient response as deemed by physician and/or patient  
- 
reduction of acute medication use not satisfactory  
- 
insufficient improvement in life quality  
 
The dose may also be reduced from 140 mg to 70 mg. Possible reasons for down-titration 
could be, but are not limited to:  
- 
complete response as deemed by physician and/or patient  
- 
suspected treatment dependent adverse events  
A dose adjustment can be performed at any scheduled study visit during the open-label 
Treatment Epoch.  

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Informed consent procedures  
Eligible subjects may only be included in the study after providing, IRB/IEC-approved 
informed consent. 
Informed consent must be obtained before conducting any study-specific procedures (e.g., all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the subject source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the prescribing information/package insert/CDS. This information will be included in 
the subject informed consent and should be discussed with the subject during the study as 
needed. Any new information regarding the safety profile of the investigational drug that is 
identified will be communicated as appropriate, for example, via an investigator notification or 
an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the subject. 
Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements. 
Male subjects must be informed that if a female partner becomes pregnant while he is enrolled 
in the study, contact with the female partner will be attempted to request her consent to collect 
pregnancy outcome information. 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
Subjects might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience. 
 
Visit schedule and assessments 
The Assessment Schedule (Table 8-1) lists all assessments and when they are performed. All 
data obtained from these assessments must be supported in the subject’s source documentation. 
Subjects should be seen for all visits/assessments as outlined in the assessment schedule (Table 
8-1) or as close to the designated day/time as possible. Missed or rescheduled visits should not 
lead to automatic discontinuation. Subjects who prematurely discontinue the study for any 
reason should be scheduled for a visit as soon as possible, at which time all of the assessments 
listed for the final visit will be performed. At this final visit, all dispensed investigational 
product should be reconciled, and the adverse event and concomitant medications recorded on 
the CRF. 
 
In table 8-1 all assessments are shown and “X” indicate when the visits are performed. 

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During visits 101 to visit 199, intervals between visits should not exceed 84 +/- 7 days. If the 
visit has to be scheduled outside this window, an approval from the sponsor has to be collected 
to ensure patient safety.

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Table 8-1 
Assessment Schedule 
 
 
Screen 
Open-label Treatment Epoch 
During 
drug 
holiday 
First 
visit 
after 
drug 
holiday 
Follow 
up2 
Visit number1 
0 
Baseline  V101 V102 V103 V104 V105 V106 
V107 
V108 
V109 
V110 
V199 
V201 – 
V20X 
V101B 
V301 
End of week 
-2 to 0 
0 
12 
24 
36 
48 
60 
72 
84 
96 
108 
120 
128 
Every 
12 
weeks 
NA 
132 
Obtain informed 
consent 
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 
 
S 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Vital Signs4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Concomitant 
Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

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Novartis 
Confidential 
Page 37 
Clinical trial protocol V01 
Protocol No. CAMG334ADE03 
 
Assessment 
Specification 
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 increased blood pressure is recorded (systolic/diastolic) 
measurements have to be repeated at the end of the study visit for validation. 
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. 
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. 
 
Laboratory evaluations 
Table 8-3 
Laboratory Assessments 
Test 
Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, Differential 
(Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils), Platelets  
Chemistry 
Albumin, Alkaline phosphatase, ALT , AST , Gamma-glutamyl-transferase (GGT), 
Lactate dehydrogenase (LDH), Calcium, Magnesium, Phosphorus, Sodium, 
Potassium, Creatinine, Creatine kinase, Direct Bilirubin, Indirect Bilirubin, Total 
Bilirubin, Blood Urea Nitrogen (BUN)  
Coagulation 
International normalized ratio [INR]), Activated partial thromboplastin time (APTT)  
Pregnancy 
Test 
Urine pregnancy test  
Serum pregnancy test 
 
Electrocardiogram (ECG) 
Electrocardiograms (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. The Fridericia QT correction formula (QTcF) 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, patient initials, subject number, date and 
time, and filed in the study site source documents. 
For any ECGs with subject safety concerns, two additional ECGs must be performed to confirm 
the safety finding and forwarded to the central ECG laboratory for assessment. A monitoring 
or review process should be in place for clinically significant ECG findings throughout the 
study and especially at baseline before administration of study treatment. 
 

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Novartis 
Confidential 
Page 40 
Clinical trial protocol V01 
Protocol No. CAMG334ADE03 
 
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information. 
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see withdraw of informed consent section,). Where possible, they should return 
for the assessments indicated in the assessment schedule. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be made 
to contact the subject/pre-designated contact as specified in the lost to follow-up section. This 
contact should preferably be done according to the study visit schedule. 
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule. 
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact: 
• New / concomitant treatments 
• Adverse Events/Serious Adverse Events 
 
Withdrawal of informed consent 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject: 
• Does not want to participate in the study anymore, and 
• Does not allow further collection of personal data 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, 
letter) to understand the primary reason for the subject’s decision to withdraw his/her 
consent and record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data 
that would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’s samples until the time of withdrawal) according 
to applicable law. 
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will 
no longer be used, unless permitted by applicable law. They will be stored according to 
applicable legal requirements. 

Novartis 
Confidential 
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Clinical trial protocol V01 
Protocol No. CAMG334ADE03 
 
 
Lost to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" 
by documenting in the source documents steps taken to contact the subject, e.g. dates of 
telephone calls, registered letters, etc. A subject should not be considered as lost to follow-
up until due diligence has been completed or until the end of the study. 
 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time.  
Reasons for early termination: 
• Unexpected, significant, or unacceptable safety risk to subjects enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data  
• Discontinuation of study drug development 
In taking the decision to terminate, Novartis will always consider subject welfare and safety. 
Should early termination be necessary, subjects must be seen as soon as possible and treated as 
a prematurely withdrawn subject. The investigator may be informed of additional procedures 
to be followed in order to ensure that adequate consideration is given to the protection of the 
subject’s interests. The investigator or sponsor depending on local regulation will be responsible 
for informing IRBs/IECs of the early termination of the trial. 
 
Study completion and post-study treatment 
Study completion is defined as when the last subject finishes their Study Completion visit, 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the 
date of that decision. A subject will be considered to have completed the study when the 
subject has completed the last visit planned in the protocol. 
After study completion, post-trial access to erenumab will be offered to the study participants 
as needed. 
 
Safety monitoring and reporting 
 
Definition of adverse events and reporting requirements 
 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
 

Novartis 
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Clinical trial protocol V01 
Protocol No. CAMG334ADE03 
 
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events. Novartis qualified medical personnel will be readily available to 
advise on trial related medical questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the subject 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the subject during or between visits or through physical examination findings, laboratory 
test findings, or other assessments. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with 
them, accompanied by the following information (as far as possible) (if the event is serious 
refer to Section 10.1.2): 
 
1. The severity grade:mild: usually transient in nature and generally not interfering with 
normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
2. its relationship to the study treatment.  
• Yes 
• No 
3. its duration (start and end dates) or if the event is ongoing, an outcome of not recovered/not 
resolved must be reported  
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. action taken regarding with study treatment. All adverse events must be treated 
appropriately. Treatment may include one or more of the following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/withdrawn 
6. its outcome 
 
a. not recovered/not resolved; 
 
b. recovered/resolved; 
 
c. recovered/resolved with sequelae; 
 
d. fatal; or unknown. 
 
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 
 

Novartis 
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Clinical trial protocol V01 
Protocol No. CAMG334ADE03 
 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject. Adverse events (including lab abnormalities that constitute 
AEs) should be described using a diagnosis whenever possible, rather than individual 
underlying signs and symptoms. Adverse event monitoring should be continued for at least 
eight weeks following the last dose of study treatment. 
 
Once an adverse event is detected, it must be followed until its resolution or until it is judged 
to be permanent (e.g. continuing at the end of the study), and assessment must be made at 
each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the 
SmPC. 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 SmPC 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. 
 
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. 
 
 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the 
following criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the subject was at 
risk of death at the time of the reaction; it does not refer to a reaction that hypothetically 
might have caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 

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Clinical trial protocol V01 
Protocol No. CAMG334ADE03 
 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
• elective or pre-planned treatment for a pre-existing condition that is unrelated to 
the indication under study  and has not worsened since signing the informed 
consent 
• social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
subject or might require intervention to prevent one of the other outcomes listed above. 
Such events should be considered as “medically significant”. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of 
dependency or abuse (please refer to the ICH-E2D Guidelines). 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.  
Any suspected transmission via a medicinal product of an infectious agent is also 
considered a serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious 
adverse event irrespective if a clinical event has occurred.  
 
 
SAE reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject 
has provided informed consent and until completion of the Follow-Up Epoch (8 weeks 
after last IMP injection). must be reported to Novartis safety within 24 hours of learning 
of its occurrence. Detailed instructions regarding the submission process and requirements 
are to be found in the investigator folder provided to each site. 
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. 
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. 

Novartis 
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Clinical trial protocol V01 
Protocol No. CAMG334ADE03 
 
An SAE occurring at a different time interval or otherwise considered completely unrelated 
to a previously reported one must be reported separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment, a CMO & PS 
Department associate may urgently require further information from the investigator for 
health authority reporting. Novartis may need to issue an Investigator Notification (IN) to 
inform all investigators involved in any study with the same study treatment that this SAE 
has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with 
EU Guidance 2011/C 172/01 or as per national regulatory requirements in participating 
countries. 
Any SAEs experienced after completion of the Follow-Up Epoch (8 weeks after last IMP 
injection) should only be reported to Novartis Safety if the investigator suspects a causal 
relationship to study treatment. 
 
 
Pregnancy reporting 
Pregnancies 
To ensure subject safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should 
be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded and reported by the investigator to the Novartis Chief 
Medical Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded 
on the same form and should include an assessment of the possible relationship to the study 
treatment any pregnancy outcome. Any SAE experienced during pregnancy must be 
reported. 
 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded 
on the appropriate CRF 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 

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reported in the safety database irrespective of it being associated with an AE/SAE within 
24 hours of Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated 
with an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
 
 
Additional Safety Monitoring 
 
Liver safety monitoring 
To ensure subject safety and enhance reliability in determining the hepatotoxic potential 
of an investigational drug, a standardized process for identification, monitoring and 
evaluation of liver events has to be followed. 
The following two categories of abnormalities / adverse events have to be considered 
during the course of the study (irrespective of whether classified/reported as AE/SAE): 
• Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 
• Liver events, which will require close observation, follow-up monitoring and 
contributing factors are recorded on the appropriate CRFs 
Please refer to Table 16-2 in Appendix 2 for complete definitions of liver laboratory 
triggers and liver events. 
Every liver event defined in Table 16-2 should be followed up by the investigator or 
designated personnel at the trial site, as summarized below. Additional details on actions 
required in case of liver events are outlined in Table 16-2. Repeat liver chemistry tests (i.e. 
ALT, AST, TBL, PT/INR, ALP and G-GT) to confirm elevation. 
• These liver chemistry repeats will be performed using the central laboratory. If results 
will not be available from the central laboratory, then the repeats can also be performed 
at a local laboratory to monitor the safety of the subject. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with 
this event should have results recorded on the appropriate CRF. 
•  
• If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
• Discontinuation of the investigational drug (refer to the Discontinuation of study 
treatment section), if appropriate 

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• Hospitalization of the subject if appropriate 
• Causality assessment of the liver event 
• Thorough follow-up of the liver event should include  
• These investigations can include based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease 
All follow-up information and procedures performed must be recorded as appropriate in 
the eCRF. 
 
 
Data collection and database management 
 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will 
not be given access to the EDC system until they have been trained. Automatic validation 
programs check for data discrepancies in the eCRFs, allow modification and/or verification 
of the entered data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) 
(entered into eCRF) is complete, accurate, and that entry and updates are performed in a 
timely manner. The Investigator must certify that the data entered are complete and 
accurate 
After final database lock, the investigator will receive copies of the subject data for 
archiving at the investigational site. 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational 
staff for completeness and accuracy. Electronic data queries stating the nature of the 
problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff 
are required to respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using 
the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history/current medical conditions and adverse events will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. 
At the conclusion of a non-IRT study, the occurrence of any emergency code breaks will 
be determined after return of all code break reports and unused supplies to Novartis. 

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Once all the necessary actions have been completed and the database has been declared to 
be complete and accurate, it will be locked and the treatment codes will be unblinded and 
made available for data analysis. Any changes to the database after that time can only be 
made after written agreement by Novartis development management. 
 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis  
representative will review the protocol and data capture requirements (i.e. eSource DDE or 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ 
data. The field monitor will visit the site to check the completeness of subject records, the 
accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical 
Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits. Continuous remote monitoring of 
each site’s data may be performed by a centralized Novartis organization. Additionally, a 
central analytics organization may analyze data & identify risks & trends for site 
operational parameters, and provide reports to Novartis clinical teams to assist with trial 
oversight. 
The investigator must maintain source documents for each subject in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and 
medical information, laboratory data, electrocardiograms, and the results of any other tests 
or assessments. All information on CRFs must be traceable to these source documents in 
the subject’s file. The investigator must also keep the original informed consent form 
signed by the subject (a signed copy is given to the subject). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the data capture and/or data entry. Novartis monitoring standards 
require full verification for the presence of informed consent, adherence to the 
inclusion/exclusion criteria, documentation of SAEs, and of data that will be used for all 
primary variables. Additional checks of the consistency of the source data with the CRFs 
are performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the subjects will be disclosed. 
 
Data analysis and statistical methods 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
 
Analysis sets 
The Safety Set comprises all subjects who received at least one dose of study treatment in the 
open-label treatment epoch of CAMG334ADE03. 
The Full Analysis Set is equivalent to the safety set. 
 

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Subject demographics and other baseline characteristics 
 
Demographic, medical history and other baseline data including previous migraine treatments 
will be listed and summarized descriptively for all subjects.  
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.  
In addition, all relevant medical history will be summarized by system organ class and preferred 
term, for all subjects. 
 
Treatments 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented. 
A data listing and a summary of erenumab administered will be provided. Unless otherwise 
specified, patients assigned to 70 mg or 140 mg erenumab dose will be analyzed together under 
one treatment arm erenumab. The analysis by dose will be detailed in SAP as needed. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system. 
A data listing and summary of rescue medications will be provided. 
The duration of exposure to erenumab will be summarized by means of descriptive statistics 
using the safety set. Concomitant medications and significant non-drug therapies prior to and 
after the start of the study treatment will be listed and summarized according to the Anatomical 
Therapeutic Chemical (ATC) classification system. 
 
Analysis of the primary endpoint(s) 
 
Definition of primary endpoint(s)  
 
The primary aim of the study is to evaluate the long-term safety of 70 and 140 mg erenumab 
in patients with episodic or chronic migraine. The primary endpoint variable is the exposure 
adjusted incidence rate of AEs during the open-label treatment epoch per 100 subject 
years.Statistical model, hypothesis, and method of analysis 
 
The primary analyses will be conducted dividing the number of AEs by the time under treatment 
and standardizing it per 100 person-years. Exact Pearson-Clopper confidence intervals for 
single proportions will be calculated in order to evaluate the precision of the estimated 
parameter. No formal hypotheses testing will be conducted.  
 

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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. 
 
Sensitivity analyses 
Sensitivity analyses 
The primary analysis will also be conducted within the subgroups defined by sex, disease 
severity and prior treatment failure status (naïve vs. prior treatment failures). The primary 
analysis will also be repeated for all- cause treatment discontinuations (instead of AE-related). 
Supportive analyses 
 
Analysis of secondary endpoints 
To evaluate the long-term tolerability of 70 and 140 mg erenumab in patients with episodic or 
chronic migraine. 
 
Efficacy and/or Pharmacodynamic endpoint(s) 
• 
Proportion of patients discontinuing open-label treatment epoch due to AE 
• 
Proportion of patients discontinuing open-label treatment epoch due to non-AE reasons 
 
Safety endpoints 
For all safety analyses, the safety set will be used. All listings and tables will be presented. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). 
The on-treatment period lasts from the date of first administration of study treatment to 112 
days after the date of the last actual administration of study treatment. 
Adverse events 
All information obtained on adverse events will be displayed and subject. 
The number (and percentage) of subjects with treatment emergent adverse events (events started 
after the first dose of study medication or events present prior to start of treatment but increased 
in severity based on preferred term) will be summarized in the following ways: 
• by primary system organ class and preferred term. 
• by primary system organ class, preferred term and maximum severity 
• by Standardized MedDRA Query (SMQ) and preferred term 

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Table 2: Proportion of event and precision secondary endpoint: AE-related discontinuation 
Sample size 
Proportion any AE 
Precision (+/-) 
500 
 
5% 
1.9% 
10% 
2.6% 
15% 
3.1% 
 
Among the non-AE related study discontinuations the group ‘upon patient request’ was 
particularly high at the time point of erenumab marketing authorization. 68 patients requested 
study discontinuation in the first two years of the open-label study overlapping with marketing 
authorization. In the following 12 months 8 patients requested study discontinuation. In order 
to use more realistic number as basis for the effect calculations of the proposed study patient 
discontinuation rates after marketing authorization were utilized. This number was multiplied 
by three to account for the longer duration of the first part of the study and to add an additional 
buffer for uncertainty. This means, 24 patient requests for study discontinuation in the first two 
years and 8 requests in the third year were included in the calculation. Overall, this results in a 
discontinuation rate due to any non-AE reasons of 22.2%. Table 3 shows the estimated event 
rates and precisions for this secondary endpoint. 
 
Table 3: Proportion of event and precision secondary endpoint: non AE-related discontinuation 
Sample size 
Proportion any AE 
Precision (+/-) 
500 
 
15% 
3.1% 
20% 
3.5% 
25% 
3.8% 
In conclusion a study population of at least 500 patients was found to be sufficient for the 
secondary endpoints with an adequate range in precision. 
 
 
 
Ethical considerations and administrative procedures 
 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, 
with applicable local regulations (including European Directive 2001/20/EC, US CFR 
21), and with the ethical principles laid down in the Declaration of Helsinki. 

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Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to 
subjects. Prior to study start, the investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and 
all of the instructions and procedures found in this protocol and to give access to all 
relevant data and records to Novartis  monitors, auditors, Novartis  Quality Assurance 
representatives, designated agents of Novartis , IRBs/IECs, and regulatory authorities as 
required. If an inspection of the clinical site is requested by a regulatory authority, the 
investigator must inform Novartis  immediately that this request has been made. 
 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov 
and as required in EudraCT. In addition, after study completion (defined as last patient last 
visit) and finalization of the study report the results of this trial will be submitted for 
publication and posted in a publicly accessible database of clinical trial results, such as the 
Novartis clinical trial results website and all required Health Authority websites (e.g. 
Clinicaltrials.gov, EudraCT etc.) . 
For details on the Novartis  publication policy including authorship criteria, please refer to 
the Novartis  publication policy training materials that were provided to you at the trial 
investigator meetings. 
 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written 
Standard Operating Procedures as well as applicable global/local GCP regulations and ICH 
Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control 
of the clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory 
requirements, protocols and internal SOPs, and are performed according to written 
Novartis processes 
 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of subjects should 
be administered as deemed necessary on a case by case basis. Under no circumstances 
including incidental collection is an investigator allowed to collect additional data or 
conduct any additional procedures for any purpose involving any investigational drugs 

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under the protocol, other than the purpose of the study. If despite this interdiction 
prohibition, data, information, observation would be incidentally collected, the investigator 
shall immediately disclose it to Novartis and not use it for any purpose other than the study, 
except for the appropriate monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. 
 
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 
where required prior to implementation. 
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in 
this study, even if this action represents a deviation from the protocol. In such cases, 
Novartis should be notified of this action and the IRB/IEC at the study site should be 
informed according to local regulations. 

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Novartis 
Confidential 
Page 57 
Clinical trial protocol V01 
Protocol No. CAMG334ADE03 
 
 
Appendices 
 
Laboratory values and vital signs 
Only selected lab parameters which have potential to be sensitive to erenumab exposure are 
listed. 
 
Laboratory Variable  
Gender (M/F/Both 
Standard Units 
SI Units 
LIVER FUNCTION AND RELATED VARIABLES 
SGOT (AST)  
SGOT (AST)  
SGPT (ALT)  
SGPT (ALT)  
Total bilirubin  
Alkaline Phosphatase  
Alkaline Phosphatase  
F 
M 
F 
M 
Both 
F 
M 
>93 U/L 
>111 U/L 
>90 U/L 
>123 U/L 
>3.6 mg/d L 
>832 U/L 
>1032 U/L 
>93 U/L 
>111 U/L 
>90 U/L 
>123 U/L 
>63 mmol/L 
>832 U/L 
>1032 U/L 
 

Novartis 
Confidential 
Page 58 
Clinical trial protocol V01 
Protocol No. CAMG334ADE03 
 
 
Appendix 2: Liver event and Laboratory trigger Definitions and 
Follow-up Requirements 
Table 16-1 
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 TBL: total bilirubin; ULN: upper limit of normal 
Table 16-2 
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 
• 
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
ALT or AST 
> 8 × ULN 
• 
Discontinue the study treatment 
immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 × ULN and INR > 
1.5 
• 
Discontinue the study treatment 
immediately 
• 
Hospitalize, if clinically 
appropriate 
• 
Establish causality 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 

Novartis 
Confidential 
Page 59 
Clinical trial protocol V01 
Protocol No. CAMG334ADE03 
 
Criteria 
Actions required 
Follow-up monitoring 
• 
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF 
> 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 
• 
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 × ULN accompanied 
by symptomsb 
• 
Discontinue the study treatment 
immediately 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 to ≤ 5 × ULN 
(subject is 
asymptomatic) 
• 
Repeat LFT within the next week 
• 
If elevation is confirmed, initiate 
close observation of the subject 
Investigator discretion 
Monitor LFT within 1 to 4 weeks 
ALP (isolated) 
  
  
> 2 × ULN (in the 
absence of known bone 
pathology) 
• 
Repeat LFT within 48 hours 
• 
If elevation persists, establish 
causality 
• 
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate 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 
• 
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin) 
> 1.5 to ≤ 2 × ULN 
(subject is 
asymptomatic) 
• 
Repeat LFT within the next week 
• 
If elevation is confirmed, initiate 
close observation of the subject 
Investigator discretion 
Monitor LFT within 1 to 4 weeks 
or at next visit 
Jaundice 
• 
Discontinue the study treatment 
immediately 
• 
Hospitalize the subject 
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolutionc 
(frequency at investigator 
discretion) 

Novartis 
Confidential 
Page 60 
Clinical trial protocol V01 
Protocol No. CAMG334ADE03 
 
Criteria 
Actions required 
Follow-up monitoring 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF 
Any AE potentially 
indicative of a liver 
toxicity* 
• 
Consider study treatment 
interruption or discontinuation 
• 
Hospitalization if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate 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. 
Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease.