A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Effect of AMG 334 on Exercise Time During a Treadmill Test in Subjects With Stable Angina
Phase: PHASE2
Conditions: Stable Angina
Sponsor: Amgen

16.1.1
Protocol and Amendments
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 1

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Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 2 of 63 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled A Randomized, Double-blind, 
Placebo-controlled Study to Evaluate the Effect of AMG 334 on Exercise Time During a 
Treadmill Test in Subjects With Stable Angina, dated 28 October 2016 and agree to 
abide by all provisions set forth therein.   
I agree to comply with the International Conference on Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines.  
I agree to ensure that Financial Disclosure Statements will be completed by: 
• 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
• 
my subinvestigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
at the start of the study and for up to one year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc.  
 
 
 
Signature 
 
 
Name of Investigator 
 
Date (DD Month YYYY) 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 3

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 3 of 63 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Effect of AMG 334 
on Exercise Time During a Treadmill Test in Subjects With Stable Angina 
Study Phase:  2a 
Indication:  Prevention of migraine 
Primary Objective:  To evaluate the effect of AMG 334 compared to placebo on exercise 
capacity in subjects with stable angina as measured by total exercise time (TET) during an 
exercise treadmill test (ETT). 
Secondary Objectives:  To evaluate the effect of AMG 334 compared to placebo during an ETT 
on the time to the onset of: 
• 
Exercise-induced angina 
• 
ST-segment depression 
Safety Objectives: To evaluate the safety and tolerability of AMG 334 in a population with stable 
angina. 
Hypothesis:  The primary hypothesis is that AMG 334 does not significantly decrease exercise 
capacity, as measured by change from baseline in exercise duration, compared to placebo, and 
that the true treatment difference in change from baseline in exercise durationis less than a 
90 second decrease.   
Primary Endpoint:   
• 
Change from baseline in TET 
Secondary Endpoints:   
• 
During the ETT 
• 
Time to onset of exercise-induced angina 
• 
Time to onset of ≥ 1 mm ST-segment depression  
Safety Endpoints: 
• 
Adverse events and Disease Related Events  
• 
Changes in vital signs 
Study Design:  This is a phase 2a, multicenter, randomized, double-blind, placebo-controlled 
study in subjects with stable angina.  Subjects will be randomized in a 1:1 ratio to receive either a 
single dose of AMG 334 or placebo prior to completing an ETT.  Randomization will be stratified 
by the TET average (< 7 minutes or ≥ 7 minutes) of the 2 qualifying ETTs performed during 
screening.  Treatment group will be blinded to the investigator, subjects, and the Amgen study 
team.   
Sample Size:  At least 54 subjects will be randomized 
Summary of Subject Eligibility Criteria:  The study seeks to enroll adult subjects (≥ 18 to 
≤ 85 of age at the time of screening) with a history of chronic stable angina for at least 3 months 
prior to screening, with at least 1 angina episode/month, on average over that period, with a 
history of ischemic heart disease.  Subjects will experience at least 1 angina episode and are 
receiving stable doses of cardiac medications (eg, beta blockers, calcium channel blockers, etc.) 
for at least 30 days prior to randomization and that are not expected to change during the study.   
For a full list of eligibility criteria, please refer to Section 4.  
Investigational Product:  The investigational products used in this study include AMG 334 and 
placebo.  
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 4

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Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 5 of 63 
CONFIDENTIAL 
 
 
change from baseline in exercise duration for each treatment group and the 90% CIs will be 
reported. 
The secondary efficacy endpoints are time to onset of ≥ 1 mm ST-segment depression and time 
to exercise-induced angina.  For each endpoint, Kaplan-Meier estimates of the event-free survival 
time will be computed and graphically displayed.  A stratified (< 7 or ≥ 7 minute randomization 
strata) log-rank test statistic will be calculated to compare the two treatment groups at a 
significance level of 0.10. 
The SAS will be used to analyze safety endpoints based on the actual treatment received.  The 
Medical Dictionary for Regulatory Activities (MedDRA) will be used to code all adverse events.  
Subject incidence of all treatment-emergent adverse events will be tabulated by treatment 
groups.  Tables of fatal adverse events, serious adverse events, adverse events leading to 
withdrawal from investigational product, adverse events of special interest if any, and Disease 
Related Events also will be provided.  Subject incidence of Disease Related Events and fatal 
Disease Related Events will be tabulated by system organ class and preferred term.  The 
analyses of selected safety laboratory endpoints will include summary statistics over time by 
treatment group.  Shift tables of the worst on-study safety laboratory toxicity based on grade 
relative to baseline will be tabulated by treatment group.  The analyses of vital signs will include 
summary statistics over time by treatment group. 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen, Inc. 
Data Element Standards 
Version/Date:  
Version 5/20 March 2015   
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 6

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 6 of 63 
CONFIDENTIAL 
 
 
Study Design and Treatment Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Written Informed Consent 
Screening Period 
Eligible Subjects Randomized 1:1 
(N = 54)
Placebo Intravenous (IV) 
(N = 27) 
AMG 334 140 mg IV   
(N = 27) 
End of Study 
Week 12
Screening Period 
Up to 6 Weeks 
On-Study Period 
~12 Weeks 
• Single administration of investigational 
product on Day 1 
• Exercise Treadmill Test (ETTr) on Day 1 
• Follow-up visits at week 2, 4, 8  
 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 7

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 7 of 63 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
AJCC 
American Joint Committee on Cancer 
CEC 
Clinical Events Committee 
CGRP 
Calcitonin Gene-Related Peptide 
CI 
Confidence Interval 
CK-MB 
Creatine kinase – myocardial band 
Cmax 
maximum concentration 
CRF 
Case Report Form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
Diastolic blood pressure 
DILI 
Drug Induced Liver Injury  
DMC 
Data Monitoring Committee 
DRE 
Disease Related Event 
EAS 
Efficacy Analysis Set 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
Electronic Source Data 
(eSource)  
source data captured initially into a permanent electronic record 
used for the reconstruction and evaluation of a trial. 
End of Study (end of trial) defined as when the last subject is assessed or participates in 
study procedures for evaluation in the study (ie, study week 12) 
End of Study (primary 
completion) 
defined as when the last subject completes the on study ETT (ETTr) 
which is conducted after randomization and administration of 
investigational product on Day 1 
End of Study for 
Individual Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject 
EOS 
End Of Study 
ET 
Early Termination 
ETT 
Exercise Treadmill Test 
ETTr 
Exercise Treadmill Test post-randomization 
EU 
European Union 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
Interactive Voice 
Response System (IVRS) 
telecommunication technology that is linked to a central computer in 
real time as an interface to collect and process information  
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 8

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 8 of 63 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
Interactive Web 
Response System 
(IWRS) 
web based technology that is linked to a central computer in real 
time as an interface to collect and process information  
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IUS 
intrauterine hormonal-releasing system 
IV 
Intravenous(ly) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial Infarction 
NYHA 
New York Heart Association 
PK 
pharmacokinetic 
POR 
Proof of Receipts 
Q4W 
every 4 weeks 
SAS 
Safety Analysis Set 
SBP 
Systolic blood pressure 
SC 
subcutaneously 
Source Data 
information from an original record or certified copy of the original 
record containing subject information for use in clinical research.  
The information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained 
in source documents (original records or certified copies).  (ICH 
Guideline [E6]).  Examples of source data include Subject 
identification, Randomization identification, and Stratification Value. 
Study Day 1 
defined as the first day that investigational product is administered to 
the subject 
TIA 
Transient ischemic attack 
TET 
Total Exercise Time 
ULN 
Upper Limit of Normal 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 9

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 9 of 63 
CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................. 3 
Study Design and Treatment Schema .............................................................................. 6 
Study Glossary .................................................................................................................. 7 
1. 
OBJECTIVES ......................................................................................................... 13 
1.1 
Primary ....................................................................................................... 13 
1.2 
Secondary .................................................................................................. 13 
1.3 
Safety Objectives ........................................................................................ 13 
2. 
BACKGROUND AND RATIONALE ........................................................................ 13 
2.1 
AMG 334 Development Rationale .............................................................. 13 
2.2 
Study Rationale .......................................................................................... 13 
2.3 
Amgen Investigational Product Background ............................................... 14 
2.4 
AMG 334 Clinical Safety Summary ............................................................ 15 
2.5 
Risk Assessment ........................................................................................ 15 
2.6 
Clinical Hypothesis ..................................................................................... 16 
3. 
EXPERIMENTAL PLAN ......................................................................................... 16 
3.1 
Study Design .............................................................................................. 16 
3.2 
Number of Sites .......................................................................................... 16 
3.3 
Number of Subjects .................................................................................... 16 
3.4 
Replacement of Subjects ............................................................................ 16 
3.5 
Estimated Study Duration ........................................................................... 17 
3.5.1 
Study Duration for Subjects ........................................................ 17 
3.5.2 
End of Study ............................................................................... 17 
4. 
SUBJECT ELIGIBILITY .......................................................................................... 17 
4.1 
Inclusion and Exclusion Criteria ................................................................. 17 
4.1.1 
Inclusion Criteria ......................................................................... 17 
4.1.2 
Exclusion Criteria ........................................................................ 18 
4.1.2.1 
General .................................................................... 18 
4.1.2.2 
Reproductive ............................................................ 19 
4.1.2.3 
Psychiatric and Neurologic ...................................... 19 
4.1.2.4 
Psychosocial ............................................................ 20 
4.1.2.5 
Cardiovascular ......................................................... 20 
5. 
SUBJECT ENROLLMENT ..................................................................................... 20 
5.1 
Randomization/Treatment Assignment ...................................................... 21 
5.2 
Site Personnel Access to Individual Treatment Assignments .................... 22 
6. 
TREATMENT PROCEDURES ............................................................................... 22 
6.1 
Classification of Products ........................................................................... 22 
 
 
 
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6.2 
Investigational Product ............................................................................... 22 
6.2.1 
Amgen Investigational Product AMG 334 and Placebo .............. 22 
6.2.1.1 
Dosage, Administration, and Schedule .................... 22 
6.2.1.2 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 23 
6.3 
Concomitant Therapy ................................................................................. 23 
6.4 
Product Complaints .................................................................................... 23 
6.5 
Excluded Treatments, Medical Devices, and/or Procedures 
During Study Period ................................................................................... 24 
7. 
STUDY PROCEDURES ......................................................................................... 24 
7.1 
Schedule of Assessments .......................................................................... 24 
7.2 
General Study Procedures ......................................................................... 27 
7.2.1 
Screening ................................................................................... 27 
7.2.2 
On-Study Period ......................................................................... 27 
7.2.3 
End of Study Visit (Week 12/Early Termination Visit) ................. 27 
7.3 
Description of Study Procedures ................................................................ 27 
7.3.1 
Informed Consent ....................................................................... 27 
7.3.2 
Physical Examination, Height, and Weight ................................. 27 
7.3.2.1 
Physical Measurements ........................................... 28 
7.3.3 
Targeted Medical/Surgical History .............................................. 28 
7.3.4 
Columbia-Suicide Severity Rating Scale (C-SSRS) ................... 28 
7.3.5 
Blood Pressure/Heart Rate ......................................................... 28 
7.3.6 
Concomitant Medications ........................................................... 29 
7.3.7 
Exercise Treadmill Test .............................................................. 29 
7.3.8 
Exercise Treadmill Test Scheduling ........................................... 30 
7.3.8.1 
Screening ................................................................. 30 
7.3.8.2 
On-Study .................................................................. 31 
7.3.9 
Monitoring During Exercise Treadmill Test ................................. 31 
7.3.9.1 
Blood Pressure ........................................................ 31 
7.3.9.2 
Electrocardiograph ................................................... 32 
7.3.9.3 
ST-Segment Depression .......................................... 32 
7.3.10 
Adverse Events and Disease Related Events ............................ 34 
7.3.11 
Collection of Events for Adjudication .......................................... 34 
7.3.12 
Laboratory Assessments ............................................................ 34 
7.3.13 
Pharmacokinetic Sampling ......................................................... 35 
7.3.14 
Angina Diary ............................................................................... 35 
7.4 
Biomarkers ................................................................................................. 35 
7.5 
Sample Storage and Destruction ................................................................ 36 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 36 
8.1 
Subjects’ Decision to Withdraw .................................................................. 36 
 
 
 
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8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 37 
8.3 
Reasons for Removal From Treatment or Study ........................................ 37 
8.3.1 
Reasons for Removal From Treatment ...................................... 37 
8.3.2 
Reasons for Removal From Study ............................................. 37 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 37 
9.1 
Definition of Safety Events ......................................................................... 37 
9.1.1 
Disease Related Events ............................................................. 37 
9.1.2 
Adverse Events .......................................................................... 38 
9.1.3 
Serious Adverse Events ............................................................. 39 
9.2 
Safety Event Reporting Procedures ........................................................... 39 
9.2.1 
Reporting Procedures for Disease Related Events .................... 39 
9.2.2 
Adverse Events .......................................................................... 40 
9.2.2.1 
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria ............................ 40 
9.2.2.2 
Reporting Procedures for Serious Adverse 
Events ...................................................................... 41 
9.2.2.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 41 
9.2.2.4 
Serious Adverse Events That are not to be 
Reported in an Expedited Manner ........................... 42 
9.3 
Pregnancy and Lactation Reporting ........................................................... 43 
10. 
STATISTICAL CONSIDERATIONS ....................................................................... 43 
10.1 
Study Endpoints, Analysis Sets, and Covariates ........................................ 43 
10.1.1 
Study Endpoints ......................................................................... 43 
10.1.1.1 
Primary Endpoint ..................................................... 43 
10.1.1.2 
Secondary Endpoints ............................................... 43 
10.1.1.3 
Safety Endpoints ...................................................... 44 
10.1.2 
Analysis Sets .............................................................................. 44 
10.2 
Sample Size Considerations ...................................................................... 44 
10.3 
Access to Individual Subject Treatment Assignments by Amgen 
or Designees .............................................................................................. 44 
10.4 
Planned Analyses ....................................................................................... 45 
10.4.1 
Primary Analysis ......................................................................... 45 
10.4.2 
Final Analysis ............................................................................. 45 
10.5 
Planned Methods of Analysis ..................................................................... 45 
10.5.1 
General Considerations .............................................................. 45 
10.5.2 
Data Monitoring Committee (DMC) ............................................ 46 
10.5.3 
Primary Efficacy Endpoint .......................................................... 46 
10.5.4 
Secondary Efficacy Endpoints .................................................... 46 
10.5.5 
Safety Endpoints ........................................................................ 47 
11. 
REGULATORY OBLIGATIONS ............................................................................. 47 
 
 
 
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11.1 
Informed Consent ....................................................................................... 47 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 48 
11.3 
Subject Confidentiality ................................................................................ 49 
11.4 
Investigator Signatory Obligations .............................................................. 49 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................... 49 
12.1 
Protocol Amendments and Study Termination ........................................... 49 
12.2 
Study Documentation and Archive ............................................................. 50 
12.3 
Study Monitoring and Data Collection ........................................................ 51 
12.4 
Investigator Responsibilities for Data Collection ........................................ 52 
12.5 
Language.................................................................................................... 52 
12.6 
Publication Policy ....................................................................................... 52 
12.7 
Compensation ............................................................................................ 53 
13. 
REFERENCES ....................................................................................................... 54 
14. 
APPENDICES ........................................................................................................ 56 
List of Tables 
Table 1.  Schedule of Assessments
 
 ................................................................................ 25
Table 2.  Exercise Treadmill Test Scheduling
 
 ................................................................. 31
Table 3.  Analyte Listing
 
 .................................................................................................. 35
List of Appendices 
Appendix A.  Additional Safety Assessment Information
 
 ................................................ 57
Appendix B.  Sample Serious Adverse Event Report Form
 
 ............................................ 59
Appendix C.  Pregnancy and Lactation Notification Worksheets
 
 .................................... 62
 
 
 
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1. 
OBJECTIVES 
1.1 
Primary 
To evaluate the effect of AMG 334 compared to placebo on exercise capacity in subjects 
with stable angina as measured by total exercise time (TET) during an exercise treadmill 
test (ETT). 
1.2 
Secondary 
To evaluate the effect of AMG 334 compared to placebo during an ETT on the time to 
the onset of: 
• 
Exercise-induced angina 
• 
ST-segment depression 
1.3 
Safety Objectives 
To evaluate the safety and tolerability of AMG 334 in a population with stable angina. 
2. 
BACKGROUND AND RATIONALE 
2.1 
AMG 334 Development Rationale 
Calcitonin gene-related peptide (CGRP) is a potent vasodilator and nociceptive 
modulator peptide.  It belongs to the calcitonin family of peptides and is widely 
expressed in the peripheral and central nervous system.  Several lines of evidence 
indicate CGRP is involved in the initiation and progression of migraine pain:  1) it is 
expressed in the trigeminal system, which is implicated in the pathophysiology of 
migraines; 2) CGRP levels are elevated in migraineurs during an attack (Bellamy et al, 
2006; Ashina et al, 2000; Gallai et al, 1995; Goadsby et al, 1990; Goadsby et al, 1988); 
3) acute migraine therapies such as triptans restore CGRP levels to normal after 
treatment (Juhasz et al, 2005); 4) CGRP infusion triggers the onset of migraine 
headaches in migraine sufferers (Petersen et al, 2004; Lassen et al, 2002), and 
5) CGRP antagonists have demonstrated efficacy in acute migraine reversal 
(Connor et al, 2009; Hewitt et al, 2009; Ho et al, 2008a; Ho et al, 2008b).   
2.2 
Study Rationale 
During myocardial ischemia, cardiac sensory nerves release neuropeptides, including 
CGRP, substance P, neurokinin A, and other neurokinins that produce compensatory 
coronary vasodilation and negative inotropic and chronotropic effects, potentially 
mitigating the extent and severity of the ischemic response (Burley et al, 2007).  The 
release of CGRP during myocardial ischemia suggests that CGRP blockade may 
 
 
 
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interfere with homeostatic cardio protective mechanisms that occur in the setting of 
acute ischemia. 
The hypothesis that blockade of CGRP-receptors does not reduce exercise capacity was 
tested in an ETT with telcagepant, an orally-administered CGRP receptor antagonist 
previously under development for the treatment of acute migraine 
(Chaitman et al, 2012).   
The ETT is an established methodology for detecting the physiologic effect of vasoactive 
agents such as antianginal drugs and has also been used in safety studies to assess the 
potential of vasoactive drugs to reduce exercise time.  The effects of supra-therapeutic 
doses of telcagepant on TET were assessed in a double-blind, randomized, 
placebo-controlled, two-period, crossover study in 60 subjects with stable angina and 
reproducible exercise-induced angina.  No significant between-treatment differences 
were found in TET, maximum exercise heart rate, or time to > 1-mm ST-segment 
depression.  The results of this study suggest that CGRP blockade does not exacerbate 
myocardial ischemia.   
2.3 
Amgen Investigational Product Background 
AMG 334 is a human monoclonal antagonist antibody that interacts with the extracellular 
domains of the CGRP receptor complex blocking the action of CGRP.  AMG 334 
dose-dependently inhibited CGRP-induced skin vasodilation measured by laser Doppler 
in healthy human volunteers, confirming its in vivo potency in blocking this pathway.  
AMG 334 is being developed for the prevention of migraines based on the observed long 
serum half-life in humans, the strong rationale for CGRP involvement in migraine 
pathophysiology, and the clinical data demonstrating CGRP antagonists are effective in 
acute migraine reversal as well as the prophylaxis of migraine. 
The present study will evaluate the hypothesis that AMG 334 does not decrease 
exercise capacity, as measured by TET during an ETT, in subjects with documented 
cardiovascular disease and stable angina.  Additional endpoints to be measured in this 
study include time to onset of exercise-induced angina, and time to onset of ≥ 1mm 
ST-depression during the ETT, incidence of adverse events and Disease Related 
Events, and changes in vital signs.  In addition, the safety and tolerability of AMG 334 in 
a stable angina population will also be evaluated.  Due to the variability of TET, the study 
design will be double-blind and placebo-controlled.  It is expected that AMG 334 
administered subcutaneously (SC) once monthly in doses of 70 to 140 mg will be 
effective in migraine prophylaxis.  A dose of 140 mg of AMG 334 administered 
 
 
 
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intravenously (IV) will be evaluated in this study to ensure adequate coverage of the 
expected exposure with the intended clinical doses.  Pharmacokinetic (PK) simulation 
indicates that 140 mg administered SC every 4 weeks (Q4W) will result in a mean 
steady-state maximum concentration (Cmax) of approximately 25,000 ng/mL in serum.  
Greater serum concentrations (mean > 28,000 ng/mL) were observed during the first 
2 days following a single 140 mg IV dose, which was well tolerated (Study 2010267; 
Amgen data on file). 
2.4 
AMG 334 Clinical Safety Summary 
As of 10 August 2015, approximately 1,039 subjects have received AMG 334 since the 
beginning of the clinical development program.  Across phase 1 studies, 152 subjects 
(healthy subjects, subjects with hot flash and migraineurs) have received AMG 334 at 
doses up to 280 mg SC and 140 mg IV.  In the phase 1 studies, 24-hour continuous 
ambulatory blood pressure (BP) monitoring demonstrated no change in BP circadian 
rhythm and no increase in BP with increasing doses of AMG 334. 
Across ongoing phase 2 clinical studies, approximately 887 subjects have received more 
than 1 dose of investigational product (IP), including a total of 472 subjects in the 
double-blind phase of the episodic migraine study (Study 20120178).  In both the 
double-blind and open-label treatment portions of the phase 2 episodic migraine study 
(Study 20120178), concomitant use of triptan-based migraine medications was reported 
in 64.8% of subjects.  In this study, BP was assessed at each visit.  There was no 
clinically significant difference in either systolic or diastolic BP at any dose group of 
AMG 334 compared with placebo.  Moreover, there was no difference in the frequency 
of the adverse event of blood pressure increase between placebo and any dose of 
AMG 334.  To date, AMG 334 has demonstrated a favorable safety and tolerability 
profile that supports further development.  Refer to the AMG 334 Investigator’s Brochure 
for details. 
2.5 
Risk Assessment 
There is no direct benefit for individual subjects participating in this study, however there 
is a potential indirect benefit to participants in this study since they will undergo 
cardiovascular evaluation and assessments, including ETT, which may provide their 
treating physician with more detailed information that may improve their care.  This study 
will test the hypothesis that AMG 334 does not significantly decrease exercise capacity 
in the study population, and, as such, would be supportive of the safe use of AMG 334 
as migraine prophylaxis in subjects with, or at risk of, cardiovascular disease. 
 
 
 
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To date, no evidence of a cardiovascular safety signal has been observed in preclinical, 
or phase 1, 2, and 3 studies of several investigational products interfering with the 
CGRP signaling pathway.  This body of evidence includes dedicated cardiovascular 
studies with hemodynamic monitoring. 
All subjects participating in the clinical study will be monitored closely for any 
cardiovascular abnormalities with vital signs assessments, electrocardiograms (ECGs), 
and physical examinations conducted at screening and before, during, and after the ETT 
procedures. 
2.6 
Clinical Hypothesis 
The primary hypothesis is that AMG 334 does not significantly decrease exercise 
capacity, as measured by change from baseline in TET, compared to placebo and that 
the true treatment difference in change from baseline in exercise duration is less than a 
90 second decrease.   
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a phase 2a, multicenter, randomized, double-blind, placebo-controlled study in 
subjects with stable angina.  At least 54 subjects will be randomized in a 1:1 ratio to 
receive either a single dose of AMG 334 or placebo prior to completing an ETT.  
Randomization will be stratified by the TET average (< 7 minutes or ≥ 7 minutes) of the 
2 qualifying ETTs performed during screening.  Treatment group will be blinded to the 
investigator, subjects, and the Amgen study team.   
The overall study design is described by a study schema at the end of the 
protocol synopsis section. 
The study endpoints are defined in Section 10.1.1. 
3.2 
Number of Sites 
This is a multicenter study that will be conducted at approximately 40 sites. 
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”. 
At least 54 subjects will be enrolled in this study (27 subjects in the placebo group and 
27 in the AMG 334 group).  Refer to Section 10.2 for sample size considerations. 
3.4 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
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3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
The estimated study duration for an individual subject is approximately 18 weeks, 
consisting of the following: 
• 
Up to 6-week screening period 
• 
12-week on-study period 
3.5.2 
End of Study 
Primary Completion:  The date on which the last subject completes the on-study ETT 
post-randomization (ETTr) which is conducted after randomization and administration of 
investigational product on Day 1. 
Final completion
4. 
SUBJECT ELIGIBILITY 
:  The end of study ([EOS], end of trial) is defined as the time when the 
last subject is assessed or participates in study procedures for evaluation in the study 
(ie, study week 12). 
Before any study-specific activities/procedure, the appropriate written informed consent 
form must be obtained (see Section 11.1).   
4.1 
Inclusion and Exclusion Criteria 
4.1.1 
Inclusion Criteria  
101 
Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures. 
102 
Age ≥ 18 to ≤ 85 at the time of screening. 
103 
History of chronic stable angina for at least 3 months prior to screening, with at 
least 1 angina episode/month, on average over that period. 
104 
Ischemic heart disease documented by any one or more of the following: 
a. A history of myocardial infarction (MI) with elevated Creatine 
kinase - myocardial band (CK-MB), troponin I or T, or the presence of 
electrocardiogram (ECG) changes consistent with an MI, or 
b. Coronary angiography demonstrating at least 1 major epicardial coronary 
artery (eg, left anterior descending, left circumflex, or right coronary artery) 
with a stenosis of at least 50% diameter or greater but excluding > 50% or 
flow-limiting stenosis of the left main coronary artery unless revascularized by 
coronary artery bypass grafting, or 
c. Revascularization procedure (eg, cardiac bypass graft, angioplasty) 
≥ 3 months prior to screening 
 
 
 
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105 
Receiving stable doses of cardiac medications (eg, beta blockers, calcium 
channel blockers, antianginals, etc.) for at least 30 days prior to randomization 
and that are not expected to change during the study 
106 
Completes 2 qualifying ETTs during screening period (as described for 
Screening in Section 7.3.7 and Section 7.3.8).  The following ETT qualifications 
are required: 
a. Limitation of exercise due to symptoms related to myocardial ischemia 
(such as angina pectoris, chest pain/discomfort, dyspnea, shortness 
of breath), or ≥ 3 mm ST-segment depression   
b. ≥ 1.0 mm ischemic ST-segment depression during exercise 
performance   
c. Exercise duration of ≥ 3 to ≤ 12 minutes, and  
d. ≤ 1 minute difference or within 20% duration (using the longest 
duration qualifying ETT) in TET between the 2 qualifying ETTs 
e. ECG tracings from screening ETTs are acceptable to the core ECG 
laboratory 
4.1.2 
Exclusion Criteria 
4.1.2.1 
General 
201 
Currently participating in another investigational device or drug study, or less 
than 30 days since ending treatment on another investigational device or drug 
studies.  Other investigational procedures while participating in this study are not 
allowed. 
202 
Current or prior malignancy within 5 years of randomization, with the exception of 
non-melanoma skin cancers, cervical or breast ductal carcinoma in situ, and 
adenocarcinoma of the prostate Stage I or IIa (defined as T1, T2a or T2b, N0, M0 
with documented serum PSA <20 ng/mL and Gleason score ≤7) per the 
American Joint Committee on Cancer (AJCC) primary tumor, regional lymph 
nodes, and distant metastasis system. 
203 
Subject has known sensitivity to any of the components of the investigational 
product  
204 
Subject likely to not be available to complete all protocol required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject and investigator’s knowledge 
205 
History or evidence of any other clinically significant disorder, condition or 
disease that, in the opinion of the investigator or Amgen physician, if consulted, 
would pose a risk to subject safety or interfere with the study evaluation, 
procedures, or completion. 
 
 
 
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4.1.2.2 
Reproductive 
206 
Females of reproductive potential who are not willing to use acceptable 
method(s) of effective birth control during treatment with AMG 334 and for an 
additional 12 weeks after receiving a single dose of AMG 334 
• 
Acceptable methods of effective contraception  include: true sexual 
abstinence when this is in line with the preferred and usual lifestyle of the 
subject [periodic abstinence (eg, calendar, ovulation, symptothermal, 
post-ovulation methods), declaration of abstinence for the duration of the 
study, and withdrawal are not acceptable methods of contraception], or 
use of hormonal birth control methods (oral, implantable, injectable, 
transdermal, intravaginal), intrauterine devices (IUDs), intrauterine 
hormonal-releasing system (IUS), surgical contraceptive methods 
(vasectomy with medical assessment of the surgical success of this 
procedure or bilateral tubal ligation), or two (2) barrier methods (one by 
each partner and at least one of the barrier methods must include 
spermicide (unless spermicide is not approved in the country or 
region) - the male must use a condom and the female must choose either 
a diaphragm OR cervical cap, OR contraceptive sponge  (a male and 
female condom cannot be used together due to the risk of tearing).  
• 
Female subjects not of childbearing potential are defined as:  Any female 
who is has had a hysterectomy, OR bilateral salpingectomy, OR bilateral 
oophorectomy, OR are post-menopausal.  Post-menopausal women are 
those who fit into one of the following categories: 
o Age ≥ 55 years with cessation of menses for 12 or more 
months, OR 
o Age < 55 years but no spontaneous menses for at least 
2 years, OR 
o Age < 55 years and spontaneous menses within the past 
1 year, but currently amenorrheic (eg, spontaneous or 
secondary to hysterectomy), AND with postmenopausal 
gonadotropin levels (luteinizing hormone and 
follicle-stimulating hormone levels > 40 IU/L) or 
postmenopausal estradiol levels (< 5 ng/dL) or according to 
the definition of "postmenopausal range" for the laboratory 
involved. 
207 
Females who are pregnant, planning to become pregnant, or breastfeeding 
during treatment with AMG 334 and for an additional 12 weeks after receiving a 
single dose of AMG 334 
208 
Subject with a positive pregnancy test at screening 
4.1.2.3 
Psychiatric and Neurologic 
209 
Within the 6 months prior to or during screening, report of suicidal ideation with 
intent, with or without a plan, or suicidal behavior as evidenced by a 
Columbia-Suicide Severity Rating Scale (C-SSRS) score of 4 or 5 and any 
behavior during screening 
 
 
 
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210 
Any psychiatric or neurologic conditions that may interfere with the conduct of the 
study 
4.1.2.4 
Psychosocial 
211 
History of alcohol abuse or dependence within 12 months prior to study 
enrollment, or inability to refrain from alcohol use within 8 hours prior to a 
scheduled ETT 
212 
Inability to refrain from use of caffeine or nicotine products within 2 hours prior to 
a scheduled ETT 
213 
Unable to refrain from unaccustomed strenuous physical activity from the date of 
consent through their completion of the trial 
4.1.2.5 
Cardiovascular 
214 
History of cardiovascular conditions (including but not limited to severe aortic or 
mitral stenosis, heart failure New York Heart Association (NYHA) class 3 or 4, 
Brugada or long QT syndrome) that may interfere with the conduct or 
interpretation of the study or may constitute a safety risk per the investigator 
215 
Systolic blood pressure (SBP) > 160 mmHg or diastolic blood pressure (DBP) 
> 90 mmHg (determined by the mean of 3 consecutive measurements at least 
5 minutes apart during screening) 
216 
Within the 3 months prior to or during screening 
a. Unstable angina or acute coronary syndrome 
b. Transient ischemic attack (TIA) or stroke 
c. Revascularization procedure  
d. Instability in ST-segment depression between screening ETTs, as 
assessed by the core ECG laboratory.  
217 
ECG findings that preclude analysis of the ETT, including but not limited to: 
a. Any right or left bundle branch block  
b. Pacemaker  
c. Resting ST-segment depression ≥ 1.0 mm 
d. Left ventricular hypertrophy with repolarization changes 
e. Wolf-Parkinson White  
218 
Digitalis or Implantable defibrillator use 
5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent, and all other subject 
information and/or recruitment material, if applicable (see Section 11.2).  All subjects 
 
 
 
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must personally sign and date the informed consent form before commencement of 
study-specific activities/procedures.   
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment case report form (CRF). 
Each subject who enters into the screening period for the study (up to 6 weeks) receives 
a unique subject identification number before any study-related activities/procedures are 
performed.  The subject identification number will be assigned by the Interactive Voice 
Response System (IVRS)/Interactive Web Response System (IWRS).  This number will 
be used to identify the subject throughout the clinical study and must be used on all 
study documentation related to that subject.  A subject may be rescreened once if there 
are exclusionary medical conditions (such as elevated blood pressure or abnormal 
laboratory findings) that may resolve and allow for rescreening.  Subjects may also be 
rescreened once if in the opinion of the investigator the reason for initial screen failure 
has been resolved or is no longer applicable (eg, due to a protocol amendment).  
Subjects may not be rescreened if unable to perform at least two ETTs with TET within 
one minute (or within 20% duration, using the longest duration qualifying ETT) of each 
other.  If for any other reason a subject should fail screening as a result of 
technical difficulties while conducting the ETTs during screening these cases 
should be reviewed, and it will be at Amgen discretion whether re-screening will 
be permitted.  The subject identification number must remain constant throughout the 
entire clinical study; it must not be changed after initial assignment, including if a subject 
is rescreened.  The randomization number will be different from the subject identification 
number. 
5.1 
Randomization/Treatment Assignment 
Randomization must occur on day 1 pre-dose and after the completion of procedures 
associated with the end of the screening phase. 
Subjects will be randomized in a 1:1 allocation ratio to a single dose of AMG 334 or 
placebo prior to completing an ETT with approximately 27 subjects assigned to each 
treatment group.  Randomization will be stratified by the TET average (< 7 minutes or 
≥ 7 minutes) of the 2 qualifying ETTs performed during screening.  The randomization 
will be performed by IVRS/IWRS.  Treatment groups will be blinded to the investigator, 
subjects, and the Amgen study team. 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 22

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Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 23 of 63 
CONFIDENTIAL 
 
 
6.2.1.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
The dosage of investigational product is fixed for all subjects and cannot be adjusted. 
The investigator may discontinue investigational product administration for any subject 
who experiences a severe or life-threatening adverse event reported by the investigator 
to be related to investigational product.  Refer to Section 9 for details regarding adverse 
event reporting. 
Subjects who  are randomized but do not receive investigational product or receive 
partial dose are to  remain on study and follow all other study procedures until the 
end of the -study .  If subjects refuse to complete all remaining study visits, they should 
complete the early termination (ET) visit.  
End of investigational product and early discontinuation from investigational product are 
to be registered in the IVRS/IWRS. 
6.3 
Concomitant Therapy 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.5. 
Concomitant therapies are to be collected from informed consent through the EOS.  The 
therapy name, indication, dose, unit, frequency, start date, and stop date are to be 
recorded on each subject’s CRF or Diary. 
6.4 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material.  
This includes any drug(s) or device(s) provisioned and/or repackaged /modified by 
Amgen.  Drug(s) or device(s) includes investigational product.   
Any product complaint(s) associated with an investigational product(s) or 
non-investigational product(s) or device(s) supplied by Amgen are to be reported 
according to the instructions provided in the IPIM. 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 24

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 24 of 63 
CONFIDENTIAL 
 
 
6.5 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
Subjects are prohibited from participating in other interventional studies (eg, studies 
which require medical device use or drug therapy or with protocol required procedures) 
while participating in this study. 
The following are excluded prior to ETT: 
• 
alcohol within 8 hours  
• 
sublingual nitroglycerin within 4 hours  
• 
caffeine and nicotine products within 2 hours  
Any cardiac medications taken on a regular schedule (eg, beta blockers, calcium 
channel blockers, antianginals, etc.) should remain stable and not interrupted throughout 
the study, unless determined otherwise by the investigator or local regulatory guidance. 
7. 
STUDY PROCEDURES 
Screening assessments and study procedures outlined in this section and in Table 1 can 
only be performed after obtaining a signed informed consent.  This includes any 
discontinuation of the subject’s medication for the purpose of participation in this study. 
It is very important to attempt to perform study procedures and obtain samples at the 
precise timepoints stipulated below.  When it is not possible to perform the study visit at 
the exact timepoint, the visit may be performed within the acceptable visit window as 
defined in the visit-specific section below. 
With the exception of the screening and re-screen visits, all study procedures for a visit 
should be completed on the same day.  Any missed visits, tests not done, or 
examinations that are not conducted must be reported as such on the CRFs.  
Subsequent study visits should resume on the original schedule.  Missed assessments 
at prior visits should not be duplicated at subsequent visits.  
Refer to the applicable supplemental laboratory manuals for detailed collection and 
handling procedures. 
7.1 
Schedule of Assessments  
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 25

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 25 of 63 
CONFIDENTIAL 
 
 
Table 1.  Schedule of Assessments 
Procedure 
Screening Period (up to 6 weeks) 
On-Study Period (12 weeks) 
EOS/ET 
Screening Visits 
On-Study Visitsj 
Visit 1a 
Visit 2 a 
Visit 3 
Visit 4l 
Day 1 
Week 2i 
Week 4 
Week 8 
Week 12 
Pre-doseb 
Post-dose 
General and Safety Assessments 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Physical Examination, including weight 
X 
 
 
 
 
 
 
 
 
X 
Targeted Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Randomizationc 
 
 
 
 
X 
 
 
 
 
 
Columbia-Suicide Severity Rating Scale 
X 
 
 
 
X 
 
 
X 
X 
X 
ETTd 
 
Xd 
Xd 
Xd 
 
X 
 
 
 
 
Blood Pressure, Heart Ratee 
X 
 
 
 
X 
X 
 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
Record Continuously 
X 
Serious Adverse Events 
X 
Record Continuously 
X 
Adverse Events and Disease Related Events 
 
 
 
 
 
X 
Record Continuously 
X 
Collection of Events for Adjudication 
 
 
 
 
 
X 
Record Continuously 
X 
Angina diaryf 
X 
Record Continuously 
X 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
Hematology, Chemistry  
(central laboratory) 
X 
 
 
 
X 
 
 
 
 
X 
Hepatitis Sample Collection 
X 
 
 
 
 
 
 
 
 
 
Urine pregnancy testg 
(females of reproductive potential) 
X 
 
 
 
X 
 
 
 
 
X 
Pharmacokinetic Sampling 
 
 
 
 
 
Xh 
 
 
 
 
Biomarker Sampling 
 
 
 
 
X 
 
 
 
 
 
Urine drug screenk 
X 
 
 
 
 
 
 
 
 
 
Dosing 
 
 
 
 
 
 
 
 
 
 
AMG 334 or Placebo 
 
 
 
 
 
X 
 
 
 
 
Footnotes defined on next page 
 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 26

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 26 of 63 
CONFIDENTIAL 
 
 
ECG = electrocardiogram; EOS = end of study; ET = early termination; ETT = Exercise Treadmill Test; PK = pharmacokinetic.  
a Visits 1 and 2 in the Screening period may be combined.  In the case where visits 1 and 2 are combined, all visit 1 assessments must be completed prior 
to the ETT for visit 2.  The laboratory assessment results do not need to be reviewed prior to the ETT for visit 2, but must be reviewed prior to subsequent 
ETT (or before randomization). 
b Pre-dose assessments should be conducted on day 1 prior to randomization. 
c Week 1 begins on the date of randomization.  Study day 1 is defined as the date investigational product is received.  
d During the screening period, two ETTs are required > 48 hours and ≤ 14 days apart that meet inclusion criteria, and they will be reviewed by a core ECG laboratory to 
confirm eligibility.  No more than 3 ETTs can be performed during the screening period.  Each ETT should occur within 14 days of each other and the total screening 
period for ETTs should not exceed 28 days. 
e Blood pressure and heart rate should be assessed at all visits following the standard procedure.  During ETT visits, the standard procedure will be conducted prior to 
the ETT; blood pressure assessments will also be conducted following the monitoring procedure described for the ETT. 
f Angina diary will be completed by subjects beginning on the day of Visit 1 and through the EOS/ET visit to  record angina episodes not occurring during ETTs.  
g Results of pre-dose pregnancy test must be reviewed prior to administration of investigational product on day 1.  
h PK sample to be drawn on day 1 after completion of exercise treadmill test post-randomization (ETTr). 
i Visit at week 2 can be done via telephone contact. 
j Study visit windows are ± 1 week.  
kUrine drug screen may also be performed as needed throughout the study per investigator judgment. 
l Optional Visit 4 to be performed if ETT3 is required for eligibility determination. 
 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 27

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 27 of 63 
CONFIDENTIAL 
 
 
7.2 
General Study Procedures 
The procedures performed at each study visit are outlined above in Table 1.  Details 
regarding each type of procedure are provided in subsequent sub-sections.   
Refer to the applicable supplemental central laboratory, IVRS/IWRS, and study manuals 
for detailed collection and handling procedures.   
7.2.1 
Screening 
Informed consent must be obtained before completing any other screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  After signing the written 
informed consent, the site will register the subject in IVRS/IWRS and screen the subject 
in order to assess eligibility for participation.  The screening window is up to 6 weeks.  If 
a subject has not met all eligibility criteria at the end of the 6-week window, the subject 
will be registered as a screen fail.  Screen fail subjects may be eligible for re-screening 
once. 
7.2.2 
On-Study Period 
The following procedures will be completed during the 12 week on-study period at the 
times designated in the Schedule of Assessments (Table 1).  Prior to enrollment, subject 
eligibility must be confirmed with screening procedures.  Subjects satisfying eligibility 
requirements will be enrolled.  The date of the first dose of AMG 334 or placebo is 
defined as day 1.  All subsequent study visits will be scheduled based on the day 1 date. 
AMG 334 or placebo is to be administered after all pre-dose assessments have been 
completed on day 1.   
7.2.3 
End of Study Visit (Week 12/Early Termination Visit) 
Subjects who complete the on-study period or who discontinue investigational product 
would complete the EOS/ET visit 12 weeks after the last dose of investigational product 
(refer to Table 1).   
7.3 
Description of Study Procedures 
7.3.1 
Informed Consent 
All subjects must sign and personally date the IRB/IEC approved informed consent 
before any study specific procedures are performed. 
7.3.2 
Physical Examination, Height, and Weight 
A physical examination will be performed at the initial screening visit (Visit 1) and 
abnormal findings collected on the medical history CRF.  Breast, genital, and rectal 
examinations are not required unless specific evaluation is warranted.  The physical 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 28

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 28 of 63 
CONFIDENTIAL 
 
 
examination at the EOS/ET visit will consist of a follow-up examination to monitor for any 
changes from the screening physical examination.  Any clinically significant changes in 
the physical examination per the investigator’s opinion should be recorded in the Event 
CRF.  All screening physical examinations are to be conducted per the site’s standard of 
care. 
7.3.2.1 
Physical Measurements 
Height (in centimeters) should be measured with the subject’s shoes removed.  
Weight (in kilograms) should be measured with the subject wearing light clothing and 
with shoes removed. 
7.3.3 
Targeted Medical/Surgical History 
The investigator or designee will collect a targeted subject’s relevant medical and 
surgical history and will be reviewed prior to randomization for the purposes of eligibility.  
The investigator or designee will collect medical and surgical history, including 
information on the subject’s current conditions.  The information will be recorded in the 
medical history CRF for subjects enrolled into the study on study day 1. 
7.3.4 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a clinician rating of suicidal behavior and ideation.  The C-SSRS 
consists of a maximum of 20 items which define 5 subtypes of suicidal ideation and 
behavior in addition to self-injurious behavior with no suicidal intent.  The C-SSRS will be 
administered to assess possible suicide ideation and behavior.  Reports of suicidal 
ideation with intent to act (severity of 4 or 5) and reports of actual, aborted, or interrupted 
suicide attempts or behavior preparatory for making an attempt indicate subjects at high 
risk for suicide.  If such reports are identified, the investigator is to appropriately manage 
the subject in accordance with standard of care.   
7.3.5 
Blood Pressure/Heart Rate 
The systolic and diastolic BP and heart rate is to be collected at the timepoints outlined 
in the schedule of assessments (refer to Table 1).   
Blood pressure will be measured in the following manner: 
• 
Subjects should be sitting quietly and comfortably, with both feet on the floor, for 
at least 5 minutes.  The upper arm should be bare without constrictive clothing 
and supported at heart level. 
• 
Caffeine, exercise, and nicotine use should be avoided for at least 30 minutes 
prior to measurement. 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 29

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 29 of 63 
CONFIDENTIAL 
 
 
• 
An appropriately-sized cuff (cuff bladder encircling at least 80% of the arm) 
should be used to ensure accuracy.  At least two measurements (separated by at 
least 5 minutes) should be made and the average recorded.  If there is a high 
value, it is acceptable to wait approximately 30 minutes before the next two blood 
pressure measurements are taken for the purpose of averaging and recording in 
the CRF. 
• 
Blood pressure will initially be recorded in both of the subject’s arms unless a 
concomitant condition favors the use of a particular arm.  The arm with the higher 
systolic reading at initial screening should then be used for blood pressure 
determinations throughout the study. 
• 
Neither the subject nor the observer (measurer) should talk during measurement. 
The position selected for a subject (ie, sitting) should be the same that is used 
throughout the study and documented on the Vital Signs CRF. 
7.3.6 
Concomitant Medications   
All concomitant medications (eg, cardiovascular, psychiatric, central nervous system, 
endocrine, pain medications), prescribed at the time the subject signs the informed 
consent will be recorded in the CRF through the completion of the EOS/ET visit .  
For cardiovascular medications the name of the medication, dose, route, frequency, and 
dates of administration will be collected. 
For other medications the name of the medication, start and stop dates will be collected. 
7.3.7 
Exercise Treadmill Test  
The ETT will be conducted using the standard Bruce protocol.  A motor-driven treadmill 
should be utilized under uniform conditions, optimally by the same technician and 
supervising physician for each ETT.  The subject should wear comfortable clothing and 
shoes suitable for exercise (eg, no boots or flip flops) for all ETTs.  On the day of the 
treadmill test subjects may consume a light breakfast > 2 hours prior to the ETT.  
Subjects should not use sublingual nitroglycerin ≤ 4 hours prior to the test.  All ETTs for 
a given subject should be performed in approximately the same conditions (time, 
temperature, food intake and caffeine and nicotine consumption before the exercise test) 
with the same investigator who should supervise the ETT performance in the same way 
throughout the study.  Subjects may touch the treadmill bars or handles lightly to assist 
with balance, however they must not be allowed to hold onto or lean on the treadmill 
bars or handles during the ETT.  The appropriate site staff should examine all ECG 
tracings and ETT records to ensure subject safety.   
Additional details regarding the ETT procedures, including provision of data to the core 
ECG laboratory, may be found in the ETT manual. 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 30

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 30 of 63 
CONFIDENTIAL 
 
 
7.3.8 
Exercise Treadmill Test Scheduling 
7.3.8.1 
Screening   
During screening 2 ETTs will be conducted (ETT 1 and ETT 2) to determine the 
subject’s eligibility for the study.  ETT 2 will be conducted after acknowledgement of 
acceptability of ETT1 has been received from the core ECG laboratory, within > 48 hours 
and ≤ 14 days after ETT 1.  Both ETTs must be scheduled between 0600 and 
1300 (eg, must begin no earlier than 0600 and no later than 1300 [see Table 2]).  In 
addition, ETT 2 should begin within ± 2 hours of the recorded time at which ETT 1 began 
(eg, when ETT 1 begins at 0700, ETT 2 must begin no earlier than 0600 and no later 
than 0900).   
If the TET in ETT 1 and ETT 2 differs by > 1 minute or > 20% duration, using the longest 
duration qualifying ETT, an additional screening ETT (ETT 3) must be conducted; ETT 3 
should occur within > 48 hours and ≤ 14 days after ETT 2 and begin within ± 2 hours of 
the recorded time at which the ETT 2 began.  No more than 3 screening ETTs can be 
conducted.  Each ETT should occur within 14 days of each other and the total screening 
period for ETTs should not exceed 28 days.   
Subjects may enroll in the trial if there is ≤ 1 minute difference and ≤ 20% duration 
difference in the TET between the 2 qualifying ETTs performed during screening.  The 
qualifying ETTs should have associated ECGs that have been deemed acceptable by 
the core ECG laboratory before a subject can be randomized. 
For further guidance please refer to the EET study manual that outlines site 
requirements for conduct, tracing requirements, scheduling, and shipping 
procedures for all ETTs to be performed by a subject. 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 31

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 31 of 63 
CONFIDENTIAL 
 
 
Table 2.  Exercise Treadmill Test Scheduling 
If initial1 ETT begins at: 
Follow- upa ETT must begin between: 
0600 
0600 - 0800 
0630 
0600 - 0830 
0700 
0600 - 0900 
0730 
0600 - 0930 
0800 
0600 - 1000 
0830 
0630 - 1030 
0900 
0700 - 1100 
0930 
0730 - 1130 
1000 
0800 - 1200 
1030 
0830 - 1230 
1100 
0900 - 1300 
1130 
0930 - 1300 
1200 
1000 - 1300 
1230 
1030 -1300 
1300 
1100 -1300 
ETT = exercise treadmill test 
a Initial ETT refers to the first of 2 qualifying ETTs (ETT1 or 2), follow-up ETT refers to the second qualifying 
ETT (ETT 2 or 3) 
7.3.8.2 
On-Study 
Eligible subjects will have 1 additional ETT (ETTr) conducted after randomization and 
administration of investigational product on Day 1.  The ETTr must be scheduled 
between 0600 and 1300 (eg, must begin no earlier than 0600 and no later than 1300) 
and should begin within ± 2 hours of the recorded time at which the last qualifying ETT 
began.  
7.3.9 
Monitoring During Exercise Treadmill Test 
7.3.9.1 
Blood Pressure 
In addition to the standard blood pressure assessments conducted at each visit, during 
all ETTs blood pressure should be recorded as follows: 
• 
Prior to the ETT  
o In a standing position after 2 minutes of standing 
• 
Within 30 seconds prior to each change in stage and at peak exercise 
during the ETT, in a standing position 
• 
At the end of the ETT in a sitting position 
• 
During recovery in a sitting position, every minute for 5 minutes after the 
end of the ETT, then every 5 minutes, as needed, until values return to 
near baseline values, per the judgment of the investigator. 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 32

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 32 of 63 
CONFIDENTIAL 
 
 
7.3.9.2 
Electrocardiograph 
Site staff should visually monitor the subject’s ECG during the ETT.  The subject’s heart 
rate and rhythm should be monitored in addition to identification of ischemic changes 
that may occur during the ETT.  All ECG tracings should be examined and copies 
retained in the subject’s source notes. 
A 12-lead exercise ECG should be collected as follows during all ETTs: 
• 
Prior to the ETT  
o In a sitting position at rest after at least 3 minutes 
o In a standing position after at least 2 minutes of standing 
• 
Every minute 
• 
At the end of each exercise stage, in an upright position 
• 
At peak exercise during the ETT, in an upright position 
• 
Immediately post-exercise, in a standing position 
• 
At 1, 3 and 5 minutes post-exercise, during recovery, in a sitting position, 
and every 5 minutes thereafter if needed, until heart rate and blood 
pressure return to baseline or near-baseline values, as judged by the 
investigator. 
If ST-segment changes occur, a printout will be run every 30 seconds until resolution.  
Additional exercise ECGs will be obtained per the recovery period schedule as 
appropriate. 
7.3.9.3 
ST-Segment Depression 
ST-segment depression must occur during exercise performance.  The depth of the 
ST-segment depression is measured at 60 msec after the J-point.   
Definition 
A ≥ 1 mm ST-segment depression is defined as: 
• 
Horizontal or down-sloping ST depression  
o If the ST level at baseline is above the isoelectric line, the 
isoelectric line is the reference point for measurements 
o If the ST level at baseline is below the isoelectric line, the baseline 
ST level is the reference point for measurements 
o Examples: 
 
If the standing at-rest value is +0.2, then a 1 mm 
ST-segment depression would be reached when the 
subject’s ST value is -1.0 mm 
 
If the standing at-rest value is -0.2, then a 1 mm segment 
depression would be reached when the subject’s ST value 
equals -1.2 mm 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 33

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 33 of 63 
CONFIDENTIAL 
 
 
The measurement of ST-segment depression during exercise should be based on the 
average of at least 3 consecutive ST-segments.  Any computer-generated determination 
of ST-segment depression should be verified by review of the ECGs to confirm that they 
meet criteria for ischemic ST-segment depression.  ST-segment deviation should be 
visually monitored throughout the ETT.  Frequent 12-lead ECGs (ie, every 30 seconds) 
must be recorded until resolution of the ST-segment depression. 
Measurement 
The ECG tracings are to be properly labeled, with one copy maintained in the subject’s 
source records and one copy provided to the core ECG laboratory, per the instructions 
provided in the ETT Manual.  Analysis of the ETT parameters will be performed by the 
core ECG laboratory. 
For each ETT, identify a single primary reason for stopping the test.  During the on-study 
ETT , terminate the ETT as soon as the subject experiences symptom-limited exercise 
(defined below), or if asymptomatic ST-segment depression ≥ 3 mm is observed.  The 
exercise duration is the time required for the subject to reach the exercise-limiting 
degree of symptoms and no further, thus site staff are not to push, coach or encourage 
subjects to tolerate symptoms during the ETT which would typically cause them to stop 
exercise during the course of their usual daily activities. 
Criteria for Stopping 
The following symptoms are reasons for stopping the ETT: 
• 
Unacceptable angina (a condition for which the ETT must be interrupted 
because of excessive chest pain, rather than because of exercise 
limitation) 
• 
Shortness of breath or fatigue  
• 
Arrhythmia (eg, sustained ventricular tachycardia, ventricular triplets, high 
degree of ventricular ectopy, heart block, bradyarrythmia) 
• 
Excessive elevation of blood pressure (eg, systolic pressure > 230 mmHg 
or diastolic pressure > 115 mmHg) 
• 
Technical difficulties in monitoring ECG or SBP 
• 
Fall in systolic blood pressure during exercise of > 10 mmHg 
• 
Feeling of dizziness or faintness 
• 
Intolerable musculoskeletal pain or discomfort 
• 
ST-segment elevation > 1 mm in leads without diagnostic Q waves (other 
than V1 or aVR) 
• 
ST-segment depression ≥ 3 mm or marked axis shift 
 
 
 
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The primary reason for ETT discontinuation should be documented in the CRF.  
7.3.10 
Adverse Events and Disease Related Events 
Serious adverse events that occur in a subject after signing the informed consent 
through the EOS will be recorded in the CRF.  All adverse events and Disease Related 
Events that occur after randomization through the EOS will be recorded in the event 
CRF. 
Exercise induced chest pain should not be reported as an adverse event provided that it 
is consistent with the subject’s previous pattern or level of angina. 
Disease Related Events 
7.3.11 
Collection of Events for Adjudication 
Cardiovascular and cerebrovascular events will be collected from the date of 
randomization through the end of the study (12 weeks after last dose of IP) and 
adjudicated in a blinded fashion by an independent clinical events committee (CEC).  
Data for the specified events will be collected on the event CRF for adjudication and 
transferred to the CEC for analysis per Amgen instructions.   
7.3.12 
Laboratory Assessments 
All screening and on-study laboratory samples will be processed and sent to the central 
laboratory, unless otherwise noted.  The results of this testing will be maintained in the 
source documents at the site.  The central laboratory will provide a study manual that 
outlines handling, labeling, and shipping procedures for all samples.  Please refer to the 
central laboratory manual for the complete listing of analytes run by the central 
laboratory.  Blood samples will be obtained by venipuncture before investigational 
product administration, and PK sampling will be done postdose after ETTr.  The date 
and time of sample collection will be recorded in the source documents at the site.  
Specific analytes for serum chemistry, hematology, and other testing to be conducted on 
blood and urine samples are below (Table 3).  Although not specifically listed, additional 
components, abnormal, and/or atypical cells will also be reported if present. 
 
 
 
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Table 3.  Analyte Listing 
Sodium 
Chemistry 
Potassium 
Chloride  
Bicarbonate 
Total protein 
Albumin 
Calcium 
Adjusted calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
AST (SGOT) 
ALT (SGPT) 
WBC 
Hematology 
RBC 
Hemoglobin 
Hematocrit 
Platelets 
WBC Differential 
• 
Bands/stabs 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Neutrophils 
 
Hepatitis B surface antigen  
Other Labs 
Hepatitis B core antibody 
Hepatitis C virus antibody 
 
PK 
Cardiac biomarkers 
• 
Troponin-I 
• 
CK 
• 
CK-MB 
Urine drug screen 
Urine pregnancy test (local) 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
CK = creatine kinase; CK-MB = creatine kinase MB isoenzyme; RBC = red blood cell; SGOT = serum 
glutamic-oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase; WBC = white blood cell 
7.3.13 
Pharmacokinetic Sampling 
The PK sample drawn on day 1 will be collected after the completion of ETTr.  The PK 
samples will be analyzed only for those subjects assigned to an AMG 334 treatment 
group.   
Approximately 5 mL of blood will be collected on day 1 (refer to Table 1).  Please refer to 
the central laboratory manual for instructions on sample collection, processing, and 
shipping of PK samples. 
7.3.14 
Angina Diary 
Angina diary will be completed by subjects beginning on the day of Visit 1 and through 
the EOS/ET visit to record angina episodes not occurring during ETTs (refer to Table 1). 
7.4 
Biomarkers  
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention.  Biomarker development can be useful in developing markers to identify 
disease subtypes, guide therapy, and/or predict disease severity. 
 
 
 
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Amgen may attempt to develop test(s) designed to identify subjects most likely to 
respond positively or negatively to AMG 334 products. 
Blood samples are to be collected at the following time points: day 1 pre-dose for all 
subjects to enable testing of baseline cardiac markers (eg, troponin) or other safety 
measures, if needed. 
7.5 
Sample Storage and Destruction  
Any sample collected according to the Schedule of Assessments (Table 1) can be 
analyzed for any of the tests outlined in the protocol and for any tests necessary to 
minimize risks to study subjects.  This includes testing to ensure analytical methods 
produce reliable and valid data throughout the course of the study.  This can also 
include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.   
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects (or a legally acceptable representative) can decline to receive investigational 
product and/or other protocol-required therapies or procedures at any time during the 
study but continue participation in the study.  If this occurs, the investigator is to discuss 
with the subject the appropriate processes for discontinuation from investigational 
product or other protocol-required therapies and must discuss with the subject the 
options for continuation of the Schedule of Assessments (Table 1) and collection of data, 
including endpoints and adverse events.  The investigator must document the change to 
the Schedule of Assessments (Table 1).   
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publically available 
 
 
 
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data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.   
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product and/or other protocol-required therapies, protocol procedures, or the study as a 
whole at any time prior to study completion.    
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or by a separate protocol or as provided for by the local country’s regulatory 
mechanism, based on parameters consistent with Section 12.1. 
8.3 
Reasons for Removal From Treatment or Study 
8.3.1 
Reasons for Removal From Treatment 
Reasons for removal from protocol-required investigational products or procedural 
assessments include any of the following: 
• 
subject request   
• 
safety concern (eg, due to an adverse event, ineligibility determined, protocol 
deviation, non-compliance, pregnancy) 
• 
death 
• 
lost to follow-up 
• 
decision by Sponsor (other than subject request, safety concern, lost to follow-up) 
8.3.2 
Reasons for Removal From Study 
• 
Reasons for removal of a subject from the study are: 
• 
decision by sponsor  
• 
withdrawal of consent from study 
• 
death 
• 
lost to follow-up 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
Disease Related Events 
Disease Related Events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease.  Such events do not meet the definition 
of an adverse event unless assessed to be more severe than expected for the subject’s 
baseline condition.  Disease-related events for the purposes of this study include angina 
pectoris and related symptoms such as chest pain and shortness of breath (refer to 
 
 
 
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Section 7.3.10).  Angina pectoris and related symptoms do not meet the definition of an 
adverse event unless assessed to be more severe than expected relative to the 
subject’s baseline condition (refer to Section 9.1.3). 
Disease Related Events and/or Disease Related Outcomes that do not qualify as 
Serious Adverse Events:  
• 
An event which is part of the normal course of disease under study (eg, disease 
progression in oncology or hospitalization due to disease progression) is to be 
reported as a Disease Related Event.  
• 
Death due to the disease under study is to be recorded on the Event CRF. 
If the outcome of the underlying disease is worse than that which would normally be 
expected for the subject, or if the investigator believes there is a causal relationship 
between the investigational products/study treatment protocol required therapies and 
disease worsening, this must be reported as an adverse event or serious adverse event. 
9.1.2 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease 
(eg, diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected, and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study or involves 
an intervention such as elective cosmetic surgery or a medical procedure while on study, 
is not considered an adverse event.   
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study.   
 
 
 
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9.1.3 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria (unless it meets the definition of a Disease Related Events as 
defined in Section 9.1.1): 
• 
fatal 
• 
life threatening (places the subject at immediate risk of death) 
• 
requires in-patient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
congenital anomaly/birth defect 
• 
other medically important serious event 
A disease related event is to be reported as a serious adverse event if: 
the subject’s pre-existing condition becomes worse than what the investigator would 
consider typical for a patient with the same underlying condition, or 
if the investigator believes a causal relationship exists between the investigational 
medicinal product(s)/protocol-required therapies and the event, 
and the event meets at least 1 of the serious criteria above 
An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).   
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, drug induced liver injury 
([DILI] see Appendix A for drug-induced liver injury reporting criteria), or events that 
necessitate an emergency room visit, outpatient surgery, or urgent intervention. 
9.2 
Safety Event Reporting Procedures  
9.2.1 
Reporting Procedures for Disease Related Events 
The investigator is responsible for ensuring that all Disease Related Events observed by 
the investigator are reported by the subject that occur after the first dose of 
investigational medicinal products/study treatment/protocol-required therapies through 
the end of study period (12 weeks after the last dose of IP), are reported using the Event 
CRF.  Additionally, the investigator is required to report a fatal Disease Related Event on 
the Event CRF.   
 
 
 
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Events assessed by the investigator to be related to the investigational medicinal 
products/study treatment/protocol-required therapies, and determined to be serious, 
require reporting of the event on the Event CRF.  
9.2.2 
Adverse Events 
9.2.2.1 
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of investigational 
products through the end of study period (12 weeks after the last dose of IP) are 
reported using the Event CRF. 
The investigator must assign the following adverse event attributes: 
• 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
• 
Dates of onset and resolution (if resolved), 
• 
Severity  
• 
Assessment of relatedness to investigational product(s) and/or any study-mandated 
activity or procedure, and 
• 
Action taken. 
The adverse event grading scale used will be the Common Terminology Criteria for 
Adverse Events (CTCAE).  The grading scale used in this study is described in 
Appendix A. 
The investigator must assess whether the adverse event is possibly related to the 
investigational products.  This relationship is indicated by a “yes” or “no” response to the 
question:  Is there a reasonable possibility that the event may have been caused by the 
investigational medicinal products?   
The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity (eg, administration of investigational product, protocol-required 
therapies, device(s) and/or procedure (including any screening procedure(s).  This 
relationship is indicated by a “yes” or “no” response to the question:  “Is there a 
reasonable possibility that the event may have been caused by a study activity 
(eg, administration of investigational product, protocol-required therapies, device(s)), 
and/or procedure”?  
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record as a single event with the worst severity on the Adverse Event 
Summary CRF. 
 
 
 
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The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the investigator's judgment) are not to be 
recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. 
The investigator is expected to follow reported adverse events until stabilization or 
reversibility. 
9.2.2.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through the end of the study period (12 weeks after the last dose of 
investigational product) are recorded in the subject’s medical record and are submitted 
to Amgen, including serious adverse events that are reported to the Event Adjudication 
Committee for adjudication.  All serious adverse events must be submitted to Amgen 
within 24 hours following the investigator’s knowledge of the event via the Event CRF.  
9.2.2.3 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after EOS.  However, these serious adverse 
events can be reported to Amgen.  In some countries (eg, European Union [EU] member 
states), investigators are required to report serious adverse events that they become 
aware of after EOS.  If serious adverse events are reported, the investigator is to report 
them to Amgen within 24 hours following the investigator’s knowledge of the event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases for the purposes of expedited 
reporting.  
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event Contingency Report Form within 24 hours of the investigator’s 
knowledge of the event.  See Appendix B for a sample of the Serious Adverse Event 
Worksheet/electronic Serious Adverse Event Contingency Report Form.  For EDC 
 
 
 
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studies where the first notification of a Serious Adverse Event is reported to Amgen via 
the electronic Serious Adverse Event Contingency Report Form, the data must be 
entered into the EDC system when the system is again available. 
The investigator must assess whether the serious adverse event is possibly related to 
any study-mandated activity or procedure.  This relationship is indicated by a “yes” or 
“no” response to the question:  “Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure”?  
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility.  
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  The investigator 
may be asked to provide additional follow-up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the Event CRF. 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities.  Investigators 
will receive notification of related serious adverse events reports sent to regulatory 
authorities in accordance with local requirements.   
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and good 
clinical practice.  
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local procedures and statutes. 
9.2.2.4 
Serious Adverse Events That are not to be Reported in an Expedited 
Manner 
A serious adverse event of stable angina will not be reported in an expedited manner as 
this is anticipated to occur in the study population at some frequency independent of the 
 
 
 
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protocol-required therapies.  The Data Monitoring Committee (DMC) will monitor these 
events on an ongoing basis.  As there are no identified risks for AMG 334, all adverse 
events are considered ‘unexpected’ for regulatory reporting purposes. 
9.3 
Pregnancy and Lactation Reporting 
If a pregnancy occurs in a female subject, or female partner of a male subject, following 
exposure to protocol-required therapies report the pregnancy to Amgen as specified 
below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur through 12 weeks after a single dose of 
investigational product.   
The pregnancy should be reported to Amgen’s Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C).  Amgen Global Patient Safety will 
follow-up with the investigator regarding additional information that may be requested.  
If a lactation case occurs following a female subject’s exposure to protocol-required 
therapies, report the lactation case to Amgen as specified below.  
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur through 12 weeks after a single dose of investigational 
product.   
Any lactation case should be reported to Amgen’s Global Patient Safety within 24 hours 
of the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up with 
the investigator regarding additional information that may be requested.  
10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoint 
• 
Change from baseline in TET 
10.1.1.2 
Secondary Endpoints 
• 
During the ETT 
o Time to onset of exercise-induced angina 
o Time to onset of ≥ 1 mm ST-segment depression  
 
 
 
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10.1.1.3 
Safety Endpoints 
• 
Adverse events and Disease Related Events 
• 
Changes in vital signs 
10.1.2 
Analysis Sets 
The full analysis set (FAS) includes all subjects who were randomized in the study. 
The efficacy analysis set (EAS) includes subjects in the FAS, who received  
investigational product and completed the ETTr.  In the EAS, subjects will be analyzed 
according to the randomized treatment, regardless of the treatment received. 
The safety analysis set (SAS) includes all subjects in the FAS who received 
investigational product.  In the SAS, subjects will be analyzed based on actual treatment 
received. 
10.2 
Sample Size Considerations 
The primary endpoint is the change from baseline in TET.  Assuming between-subject 
standard deviation for change from baseline in exercise duration of 130 seconds 
(Chaitman et al., 2004), with a planned study size of at least 27 subjects in each group 
and a difference in change from baseline in exercise duration of 0 seconds between 
AMG 334 group and placebo group, there is an 80% probability (power) that the lower 
bound of the 90% confidence interval (CI) will exceed -90 seconds.  A margin larger 
than - 60 seconds between groups was required to accommodate the 60 second 
or 20% difference allowed in qualifying TETs for each subject.  Because of this 
within-subject TET variation, a maximum TET difference of 90 seconds between 
the AMG 334 group and placebo group was considered reasonable in this study.  
As such, a margin of - 90 secs was selected, which corresponds to the margin 
used in a previous study testing a comparable hypothesis (Patterson, et. al 2005).  
Twenty-nine subjects are needed in each group if considering 5% dropout. 
When approximately 45 subjects have been enrolled, Amgen may conduct a blinded 
sample re-estimation and choose to alter the sample size based on the blinded 
variance in the pooled treatment groups. 
10.3 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
Blinded individuals will not have access to unblinded information until the study is 
formally unblinded.  Unblinding and potentially unblinding information should not be 
distributed to the study team, investigators or subjects prior to the study being unblinded  
 
 
 
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except as specified (eg, Section 5.2 and Section 9.2.2.3).  With the exception of site 
staff and subjects, the study will be unblinded at the time of the primary analysis.  
Complete unblinding of the study will occur at the final analysis. 
Staff from Clinical Supply Chain, Biological Sample Management, PK and Drug 
Metabolism, Clinical Immunology, Clinical Pharmacology, Department of Molecular 
Sciences & Computational Biology, and Global Biostatistics Sciences departments who 
are responsible for tracking, assaying, or analyzing biological samples or checking the 
accuracy of randomization during the conduct of this study are considered unblinded to 
the treatment assignments in this study.  These individuals will not have access to 
subject level clinical data apart from the samples they are assaying and analyzing during 
the course of the study. 
10.4 
Planned Analyses 
10.4.1 
Primary Analysis 
The primary analysis of the primary and secondary endpoints will be performed after 
all subjects have completed the ETTr. 
10.4.2 
Final Analysis  
The final analysis for the study will be performed after all subjects have completed the 
study. 
10.5 
Planned Methods of Analysis  
10.5.1 
General Considerations 
The primary objective of this study is to evaluate the effect of AMG 334 compared to 
placebo on exercise capacity in subjects with stable angina as measured by TET during 
an ETT. 
The FAS will be used to tabulate demographic data, baseline disease characteristics, 
and subject disposition.  The EAS will include all FAS subjects who received 
investigational product and completed the ETTr and will be used to analyze the primary 
and secondary endpoints (including the change from baseline in TET, time to onset of 
≥ 1 mm ST-segment depression, and time to onset of exercise-induced angina).  The 
SAS include all FAS subjects who received investigational product and will be used to 
analyze safety endpoints. 
Summary statistics by each treatment group will be tabulated at each visit.  For 
continuous endpoints, the descriptive statistics include: number of subjects, mean, 
 
 
 
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median, standard deviation, standard error, lower and upper quartiles, minimum, and 
maximum.  For categorical endpoints, frequency, and percentage will be given. 
Missing data will not be imputed. 
Baseline value for exercise duration is the average value of the last two measurements 
in the screening period. 
10.5.2 
Data Monitoring Committee (DMC) 
An independent DMC has been established to oversee the safety of study participants 
for several AMG 334 Migraine programs, including this study.  The DMC will be 
composed of members with relevant expertise (cardiology, neurology, and statistics).  
DMC meetings are held approximately every 3 months and ad hoc meetings may be 
requested at any time by either the DMC or the sponsor.  Safety data, including adverse 
events and laboratory data, will be reviewed frequently throughout the study, and the 
DMC will advise the study sponsor on findings that may impact the conduct of the study, 
including a recommendation to terminate the study.  All serious unexpected serious 
adverse reactions will be promptly shared with the DMC. 
10.5.3 
Primary Efficacy Endpoint 
The primary endpoint is the change from baseline in exercise duration as measured by 
TET during the ETT.  The primary hypothesis is that AMG 334 does not significantly 
decrease exercise capacity, as measured by change in TET  compared to placebo, and 
that the true treatment difference in change from baseline in exercise duration is less 
than a 90 second decrease.   
In the primary analysis, the primary endpoint will be analyzed using an analysis of 
variance model with terms for treatment group and randomization strata (< 7 or 
≥ 7 minutes).  A two-sided 90% CI for the mean difference in change from baseline in 
exercise duration will be calculated .  If the lower bound of the CI of the difference is 
more than -90 seconds, then the hypothesis that AMG 334 does not decrease exercise 
duration will be supported.  The mean change from baseline in exercise duration for 
each treatment group and the 90% CIs will be reported. 
10.5.4 
Secondary Efficacy Endpoints 
For the secondary endpoints of time to onset of ≥ 1 mm ST-segment depression and 
time to exercise-induced angina Kaplan-Meier estimates of the event-free survival time 
will be computed and graphically displayed for each endpoint.  For each endpoint, a 
 
 
 
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stratified (< 7 or ≥ 7 minute randomization strata) log-rank test statistic will be calculated 
to compare the two treatment groups at a significance level of 0.10. 
10.5.5 
Safety Endpoints 
The SAS will be used to analyze safety endpoints based on the actual treatment 
received. 
The Medical Dictionary for Regulatory Activities (MedDRA) will be used to code all 
adverse events. 
Subject incidence of all treatment-emergent adverse events will be tabulated by 
treatment groups.  Tables of fatal adverse events, serious adverse events, leading to 
withdrawal from investigational product, adverse events of special interest if any, and 
Disease Related Events also will be provided. 
Subject incidence of Disease Related Events and fatal Disease Related Events will be 
tabulated by system organ class and preferred term. 
The analyses of selected safety laboratory endpoints will include summary statistics over 
time by treatment group.  Shift tables of the worst on-study safety laboratory toxicity 
based on grade relative to baseline will be tabulated by treatment group.   
The analyses of vital signs will include summary statistics over time by treatment group. 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the template are to 
be communicated formally in writing from the Amgen Clinical Study Manager to the 
investigator.  The written informed consent document is to be prepared in the 
language(s) of the potential subject population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol-specific screening procedures or any investigational product(s) is/are 
administered.   
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
 
 
 
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notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 
The acquisition of the informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent is to be signed and personally dated by the subject 
and by the person who conducted the informed consent discussion.  The original signed 
informed consent is to be retained in accordance with institutional policy, and a copy of 
the signed consent form is to be provided to the subject. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent to attest that informed consent 
was freely given and understood. 
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed informed consent, other written subject information, 
and any proposed advertising material must be submitted to the IRB/IEC for written 
approval.  A copy of the written approval of the protocol and informed consent must be 
received by Amgen before recruitment of subjects into the study and shipment of Amgen 
investigational product. 
The investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent.  The 
investigator is to notify the IRB/IEC of deviations from the protocol or serious adverse 
events occurring at the site and other adverse event reports received from Amgen, in 
accordance with local procedures. 
The investigator is responsible for obtaining annual IRB/IEC approval IRBs only/renewal 
IRBs and IECs throughout the duration of the study.  Copies of the investigator’s reports 
and the IRB/IEC continuance of approval must be sent to Amgen. 
 
 
 
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11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen.   
• 
Subjects are to be identified by a unique subject identification number.   
• 
Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations.   
• 
On the CRF demographics page, in addition to the unique subject identification 
number, include the age at time of enrollment.   
• 
For serious adverse events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with 
local laws and regulations), and date of birth (in accordance with local laws and 
regulations). 
• 
Documents that are not submitted to Amgen (eg, signed informed consent s) are to 
be kept in confidence by the investigator, except as described below. 
In compliance with Federal regulations/International Conference on Harmonisation (ICH) 
Good Clinical Practice (GCP) Guidelines, it is required that the investigator and 
institution permit authorized representatives of the company, of the regulatory agency(s), 
and the IRB/IEC direct access to review the subject’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, 
analyzing, verifying, and reproducing any records and reports that are important to the 
evaluation of the study.  The investigator is obligated to inform and obtain the consent of 
the subject to permit such individuals to have access to his/her study-related records, 
including personal information. 
11.4 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of 
multi-center studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
• 
a recognized expert in the therapeutic area 
• 
an investigator who provided significant contributions to either the design or 
interpretation of the study 
• 
an investigator contributing a high number of eligible subjects 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
If Amgen amends the protocol, we will notify investigators of any amendments to the 
protocol.  The IRB/IEC must be informed of all amendments and give approval.  The 
investigator must send a copy of the approval letter from the IRB/IEC to Amgen. 
 
 
 
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Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
investigator reserve the right to terminate the investigator’s participation in the study 
according to the study contract.  The investigator is to notify the IRB/IEC in writing of the 
study’s completion or ET and send a copy of the notification to Amgen.   
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
12.2 
Study Documentation and Archive 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
CRF entries may be considered source data if the CRF is the site of the original 
recording (ie, there is no other written or electronic record of data).  In this study, CRF 
C-SSRS and angina diary can be used as source documents.  
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.   
Elements to include: 
• 
Subject files containing completed CRFs, informed consents, and subject 
identification list 
• 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
• 
Investigational product-related correspondence including Proof of Receipts (POR), 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable. 
 
 
 
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In addition, all original source documents supporting entries in the CRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Amgen Clinical Monitor is responsible for verifying the CRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical 
research.  The Clinical Monitor is to have access to subject medical records and other 
study-related records needed to verify the entries on the CRFs. 
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function (or 
designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy storage 
areas, laboratories) and review of study-related records will occur to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 
Data capture for this study is planned to be electronic: 
• 
All source documentation supporting entries into the CRFs must be maintained 
and readily available. 
• 
Updates to CRFs will be automatically documented through the software’s “audit 
trail”. 
• 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During 
this review, subject data are checked for consistency, omissions, and any 
apparent discrepancies.  In addition, the data are reviewed for adherence to the 
protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries are created in the EDC system 
database for site resolution and subsequently closed by the EDC system or by 
an Amgen reviewer. 
 
 
 
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• 
The investigator signs only the Investigator Verification Form for this EDC study 
or the investigator applies an electronic signature in the EDC system if the study 
is set up to accept an electronic signature.  This signature indicates that 
investigator inspected or reviewed the data on the CRF, the data queries, and 
agrees with the content. 
Amgen (or designee) will perform self-evident corrections to obvious data errors in the 
clinical trial database, as documented in the Study Specific Self Evident Corrections 
Plan.  Examples of obvious data errors that may be corrected by Amgen (or designee) 
include deletion of obvious duplicate data (eg, same results sent twice with the same 
date with different visit-week 4 and ET) and clarifying “other, specify” if data are provided 
(eg, race, physical examination).  Each investigative site will be provided a list of the 
types of corrections applied to study data at the initiation of the trial and at study 
closeout.   
12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 1), the investigator can search publically available 
records (where permitted) to ascertain survival status.  This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible.   
12.5 
Language 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.   
12.6 
Publication Policy 
To coordinate dissemination of data from this study, Amgen encourages the formation of 
a publication committee consisting of several investigators and appropriate Amgen staff, 
the governance and responsibilities of which are set forth in a Publication Charter.  The 
committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff as appropriate as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Recommendations for the Conduct, Reporting, Editing, and Publication 
 
 
 
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of Scholarly Work in Medical Journals (International Committee of Medical Journal 
Editors, 2013, updated 2014), which states: 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published; (4) agreement to be accountable for all aspects of the work 
in ensuring that questions related to the accuracy or integrity of any part of the work 
are appropriately investigated and resolved.  Authors should meet conditions 1, 2, 3, 
and 4. 
• 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 
• 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
• 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
• 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
Additional information on the current guidelines for publications can be found at the 
following location:  http://www.icmje.org/. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
12.7 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Clinical Trial Agreement that is available as a separate 
document. 
 
 
 
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13. 
REFERENCES 
Amgen. AMG 334 Investigator Brochure, version 5.0. 
Ashina M, Bendtsen L, Jensen R, Schifter S, Olesen J. Evidence for increased plasma 
levels of calcitonin gene-related peptide in migraine outside of attacks. Pain. 
2000;86:133-138. 
Bellamy JL, Cady RK, Durham PL. Salivary levels of CGRP and VIP in rhinosinusitis and 
migraine patients. Headache. 2006;46:24-33. 
Burley DS, Hamid SA, Baxter GF. Cardioprotective actions of peptide hormones in 
myocardial ischemia. Heart Fail. Rev. 2007;12:279–291. 
Chaitman B, Ho A, Behm M, et al. A randomized, placebo-controlled study of the effects 
of telcagepant on exercise time in patients with stable angina.  Clin Pharmacol Ther. 
2012;91(3):459-466. 
Chaitman B, Pepine C, Parker J, et al. Effects of ranolazine with atenolol, amlodipine, or 
diltiazem on exercise tolerance and angina frequency in patients with severe chronic 
angina, a randomized controlled trial. JAMA. 2004;291(3):309-316. 
Connor KM, Shapiro RE, Diener HC, et al. Randomized, controlled trial of telcagepant 
for the acute treatment of migraine. Neurology. 2009;73(12):970-977. 
Gallai V, Sarchielli P, Floridi A, et al. Vasoactive peptide levels in the plasma of young 
migraine patients with and without aura assessed both interictally and ictally. 
Cephalalgia. 1995;15:384-390. 
Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral 
circulation of humans during migraine headache. Ann Neurol. 1990;28:183-187. 
Goadsby PJ, Edvinsson L, Ekman R. Release of vasoactive peptides in the 
extracerebral circulation of humans and the cat during activation of the trigeminovascular 
system. Ann Neurol. 1988;23:193-196. 
Ho TW, Ferrari MD, Dodick DW, et al. Efficacy and tolerability of MK-0974 (telcagepant), 
a new oral antagonist of calcitonin gene-related peptide receptor, compared with 
zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial. 
Lancet. 2008a;372:2115-2123. 
Ho TW, Mannix LK, Fan X, et al; MK-0974 Protocol 004 study group. Randomized 
controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of 
migraine. Neurology. 2008b;70(16):1304-1312. 
Hewitt D, Aurora S, Dodick D, et al. Efficacy and tolerability of the CGRP receptor 
antagonist MK-3207 for the acute treatment of migraine: a single attack randomized 
double-blind placebo-controlled adaptive dose ranging trial. Abstract for the 14th 
Congress of the International Headache Society. 2009; LBOR3. 
International Committee of Medical Journal Editors, Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals:  Writing and Editing for Biomedical 
Publication.  2013. http://www.icmje.org/. 
Juhasz G, Zsombok T, Jakab B, Nemeth J, Szolcsanyi J, Bagdy G. Sumatriptan causes 
parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and 
migraine headache during nitroglycerin induced migraine attack. Cephalalgia. 
2005;25(3):179-183. 
 
 
 
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Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J. CGRP may 
play a causative role in migraine. Cephalalgia. 2002;22:54-61. 
Patterson D, Kloner R, Effron M, et al.  The effect of tadalafil on the time to 
exercise-induced myocardial ischaemia in subjects with coronary artery disease. 
Br J Clin Pharmacol. 2005, 60:459-468. 
Petersen KA, Birk S, Doods H, Edvinsson L, Olesen J. Inhibitory effect of BIBN4096BS 
on cephalic vasodilatation induced by CGRP or transcranial electrical stimulation in the 
rat. Br J Pharmacol. 2004;143:1074-1075. 
 
 
 
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14. 
APPENDICES 
 
 
 
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Appendix A.  Additional Safety Assessment Information 
The Common Terminology Criteria for Adverse Events Version 4 (CTCAE v4) is 
available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm] 
Drug-induced Liver Injury Reporting & Additional Assessments  
Reporting 
• 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
• 
The appropriate CRF (eg, Event CRF) that captures information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities is to be completed 
and sent to the Amgen.  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.1.3. 
All subjects in whom investigational product(s) or is/are withheld (either permanently or 
conditionally) due to potential DILI or who experience AST or ALT elevations > 3 x ULN 
are to undergo a period of “close observation” until abnormalities return to normal or to 
the subject’s baseline levels.  Assessments that are to be performed during this period 
include:  
Additional Clinical Assessments and Observation 
• 
Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours  
• 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
• 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL: 
− 
Obtain complete blood count (CBC) with differential to assess for eosinophilia 
− 
Obtain serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti 
Smooth Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to 
assess for autoimmune hepatitis 
− 
Obtain serum acetaminophen (paracetamol) levels 
 
 
 
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− 
Obtain a more detailed history of:  
• 
Prior and/or concurrent diseases or illness 
• 
Exposure to environmental and/or industrial chemical agents  
• 
Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
• 
Prior and/or concurrent use of alcohol, recreational drugs and special diets 
• 
Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
− 
Obtain viral serologies 
− 
Obtain CPK, haptoglobin, LDH, and peripheral blood smear 
− 
Perform appropriate liver imaging if clinically indicated 
• 
Obtain appropriate blood sampling for pharmacokinetic analysis if this has not 
already been collected  
• 
Obtain hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist) 
• 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal.  The “close observation period” is to 
continue for a minimum of 4 weeks after discontinuation of all investigational 
product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding CRFs. 
 
 
 
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Appendix B.  Sample Serious Adverse Event Report Form 
 
 
 
 
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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 
 
 
 
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Date:  06 August 2015 
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Template Date:  15 December 2014 
Version 4.0 
Amendment 1 
Protocol Title:  A Randomized, Double-blind, Placebo-controlled Study to Evaluate 
the Effect of AMG 334 on Exercise Time During a Treadmill Test in Subjects With 
Stable Angina 
 
Amgen Protocol Number 20140254 
 
Version 1.0; Date 
Amendment 1 Date: 
12 June 2015 
06 August 2015 
Rationale: 
The rationale for this amendment is to clarify language throughout the protocol and to 
remove references to the storage of future research samples. 
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Description of Changes: 
Section:  Global 
Change:  Removed “adverse” from disease related “adverse” events. Correcting 
typographical and formatting errors. 
Section:  Title Page 
Replace:   
Header: Date: 24 November 2014 
With:  
Header: Date: 06 August 2015 
Replace: 
Version 1.0; Date: 
12 June 2015 
With: 
Version 1.0; Date: 
Amendment 1; Date: 
12 June 2015 
06 August 2015 
Section:  Investigator’s Agreement 
Replace: 
I have read the attached protocol entitled A Randomized, Double-blind, 
Placebo-controlled Study to Evaluate the Effect of AMG 334 on Exercise Time During a 
Treadmill Test in Subjects With Stable Angina, dated 02 June 2015 and agree to abide 
by all provisions set forth therein.   
With:  
I have read the attached protocol entitled A Randomized, Double-blind, 
Placebo-controlled Study to Evaluate the Effect of AMG 334 on Exercise Time During a 
Treadmill Test in Subjects With Stable Angina, dated 06 August 2015 and agree to 
abide by all provisions set forth therein.   
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Section:  Study Glossary 
Replace: 
End of Study (primary 
completion) 
defined as when the last subject completes the on study ETT (ETTr) 
which is conducted after randomization and administration of study 
drug on Day 1 
With: 
End of Study (primary 
completion) 
defined as when the last subject completes the on study ETT (ETTr) 
which is conducted after randomization and administration of 
investigational product on Day 1 
Section:  Protocol Synopsis – Statistical Considerations 
Replace: 
In the primary analysis, the primary endpoint will be analyzed using an analysis of 
variance model with terms for treatment group and baseline exercise duration.  A 
two-sided 90% confidence interval (CI) for the mean difference in change from baseline 
in exercise duration will be calculated.  If the lower bound of the CI of the difference is 
more than -60 seconds, then the hypothesis that AMG 334 does not decrease exercise 
duration will be supported.  The mean change from baseline in exercise duration for 
each treatment group and the 90% CIs will be reported. 
With: 
In the primary analysis, the primary endpoint will be analyzed using an analysis of 
variance model with terms for treatment group and randomization strata  
(< 7 or ≥ 7 minutes).  A two-sided 90% confidence interval (CI) for the mean difference 
in change from baseline in exercise duration will be calculated.  If the lower bound of the 
CI of the difference is more than -60 seconds, then the hypothesis that AMG 334 does 
not decrease exercise duration will be supported.  The mean change from baseline in 
exercise duration for each treatment group and the 90% CIs will be reported. 
Section:  3.5.2 End of Study 
Replace: 
Primary Completion:  the date on which the last subject completes the on-study ETT 
(ETTr) which is conducted after randomization and administration of study drug on 
Day 1. 
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Product:  AMG 334 
Protocol Number:  20140254 
Date:  06 August 2015 
Page 4 of 15 
CONFIDENTIAL 
 
 
With: 
Primary Completion
Section:  4.1.2.2 Reproductive 
:  the date on which the last subject completes the on-study ETT 
(ETTr) which is conducted after randomization and administration of investigational 
product on Day 1. 
Replace: 
206 
Females of reproductive potential who are not willing to use acceptable 
method(s) of effective birth control during treatment with AMG 334 and for an 
additional 12 weeks after receiving a single dose of AMG 334 
Acceptable methods of effective contraception  include: true sexual 
abstinence when this is in line with the preferred and usual lifestyle of 
the subject [periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence for 
the duration of the study, and withdrawal are not acceptable methods 
of contraception], or use of hormonal birth control methods (oral, 
implantable, injectable, transdermal, intravaginal), intrauterine devices 
(IUDs), intrauterine hormonal-releasing system (IUS), or two (2) 
barrier methods (one by each partner and at least one of the barrier 
methods must include spermicide (unless spermicide is not approved 
in the country or region) - the male must use a condom and the 
female must choose either a diaphragm OR cervical cap, OR 
contraceptive sponge  (a male and female condom cannot be used 
together due to the risk of tearing). 
Female subjects not of childbearing potential are defined as:  Any 
female who is has had a hysterectomy, OR bilateral salpingectomy, 
OR bilateral oophorectomy, OR are post-menopausal.  Post-
menopausal women are those who fit into one of the following 
categories: 
o Age 55 years with cessation of menses for 12 or 
more months, OR 
With: 
206 
Females of reproductive potential who are not willing to use acceptable 
method(s) of effective birth control during treatment with AMG 334 and for an 
additional 12 weeks after receiving a single dose of AMG 334 
 
Acceptable methods of effective contraception  include: true 
sexual abstinence when this is in line with the preferred and usual 
lifestyle of the subject [periodic abstinence (eg, calendar, 
ovulation, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of the study, and withdrawal are not 
acceptable methods of contraception], or use of hormonal birth 
control methods (oral, implantable, injectable, transdermal, 
intravaginal), intrauterine devices (IUDs), intrauterine 
hormonal-releasing system (IUS), surgical contraceptive 
methods (vasectomy with medical assessment of the surgical 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 68

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Product:  AMG 334 
Protocol Number:  20140254 
Date:  06 August 2015 
Page 7 of 15 
CONFIDENTIAL 
 
 
Section:  7.3.12 Laboratory Assessments 
Replace: 
Table 1.  Analyte Listing 
Sodium 
Chemistry 
Potassium 
Chloride Bicarbonate 
Total protein 
Albumin 
Calcium 
Adjusted calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
AST (SGOT) 
ALT (SGPT) 
Specific gravity 
Urinalysis 
pH 
Blood 
Protein 
Glucose 
Bilirubin 
Microscopic (Reflex 
testing if > trace) 
Pregnancy 
WBC 
Hematology 
RBC 
RBC morphology 
Absolute neutrophil 
count 
Hemoglobin 
Hematocrit 
Platelets 
WBC Differential 
• 
Bands/stabs 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Neutrophils 
• 
Monocytes 
Hepatitis B surface 
antigen and Hepatitis 
B core antibody 
Other Labs 
Hepatitis C virus 
antibody 
Tuberculosis Testingb 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 71

 
 
 
Product:  AMG 334 
Protocol Number:  20140254 
Date:  06 August 2015 
Page 8 of 15 
CONFIDENTIAL 
 
 
With: 
Table 2.  Analyte Listing 
Sodium 
Chemistry 
Potassium 
Chloride  
Bicarbonate 
Total protein 
Albumin 
Calcium 
Adjusted calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
AST (SGOT) 
ALT (SGPT) 
Specific gravity 
Urinalysis 
pH 
Blood 
Protein 
Glucose 
Bilirubin 
Microscopic (Reflex 
testing if > trace) 
Pregnancy 
WBC 
Hematology 
RBC 
 
Hemoglobin 
Hematocrit 
Platelets 
WBC Differential 
• 
Bands/stabs 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Neutrophils 
• 
Monocytes 
Hepatitis B surface 
antigen  
Other Labs 
Hepatitis B core 
antibody 
Hepatitis C virus 
antibody 
PK 
Cardiac biomarkers 
• 
Troponin-I 
• 
CK 
• 
CK-MB 
Urine drug screen 
Urine pregnancy 
test (local) 
Section:  7.5 Sample Storage and Destruction 
Replace: 
Any sample collected according to the Schedule of Assessments (Table 1) can be 
analyzed for any of the tests outlined in the protocol and for any tests necessary to 
minimize risks to study subjects.  This includes testing to ensure analytical methods 
produce reliable and valid data throughout the course of the study.  This can also 
include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.  
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
coronary artery disease, the dose response and/or prediction of response to AMG 334, 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 72

 
 
 
Product:  AMG 334 
Protocol Number:  20140254 
Date:  06 August 2015 
Page 9 of 15 
CONFIDENTIAL 
 
 
characterize antibody response, and characterize aspects of the molecule 
(eg, mechanism of action/target, metabolites).  Results from these analyses are to be 
documented and maintained, but are not necessarily reported as part of this study.  
Samples can be retained for up to 20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of biomarker development, or other exploratory studies are 
not placed in the subject’s medical record and are not to be made available to the 
subject, members of the family, the personal physician, or other third parties, except as 
specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
samples and any other components from the cells can be located and destroyed.  
Samples will be destroyed once all protocol-defined procedures are completed.  
However, information collected from samples prior to the request for destruction, will be 
retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  Refer to 
Section 11.3 regarding subject confidentiality.  
With: 
Any sample collected according to the Schedule of Assessments (Table 1) can be 
analyzed for any of the tests outlined in the protocol and for any tests necessary to 
minimize risks to study subjects.  This includes testing to ensure analytical methods 
produce reliable and valid data throughout the course of the study.  This can also 
include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability.  
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 73

 
 
 
Product:  AMG 334 
Protocol Number:  20140254 
Date:  06 August 2015 
Page 10 of 15 
CONFIDENTIAL 
 
 
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.  
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
coronary artery disease, the dose response and/or prediction of response to AMG 334, 
characterize antibody response, and characterize aspects of the molecule 
(eg, mechanism of action/target, metabolites).  Results from these analyses are to be 
documented and maintained, but are not necessarily reported as part of this study.  
Samples can be retained for up to 20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of biomarker development, or other exploratory studies are 
not placed in the subject’s medical record and are not to be made available to the 
subject, members of the family, the personal physician, or other third parties, except as 
specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
samples and any other components from the cells can be located and destroyed.  
Samples will be destroyed once all protocol-defined procedures are completed.  
However, information collected from samples prior to the request for destruction, will be 
retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  Refer to 
Section 11.3 regarding subject confidentiality.  
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 74

 
 
 
Product:  AMG 334 
Protocol Number:  20140254 
Date:  06 August 2015 
Page 11 of 15 
CONFIDENTIAL 
 
 
Section:  10.5.3 Primary Efficacy Endpoint 
Replace: 
In the primary analysis, the primary endpoint will be analyzed using an analysis of 
variance model with terms for treatment group and baseline exercise duration.  A 
two-sided 90% CI for the mean difference in change from baseline in exercise duration 
will be calculated.  If the lower bound of the CI of the difference is more  
than -60 seconds, then the hypothesis that AMG 334 does not decrease exercise 
duration will be supported.  The mean change from baseline in exercise duration for 
each treatment group and the 90% CIs will be reported. 
With: 
In the primary analysis, the primary endpoint will be analyzed using an analysis of 
variance model with terms for treatment group and randomization strata  
(< 7 or ≥ 7 minutes).  A two-sided 90% CI for the mean difference in change from 
baseline in exercise duration will be calculated.  If the lower bound of the CI of the 
difference is more than -60 seconds, then the hypothesis that AMG 334 does not 
decrease exercise duration will be supported.  The mean change from baseline in 
exercise duration for each treatment group and the 90% CIs will be reported. 
Section:  Appendix C. Pregnancy and Lactation Notification Worksheets 
Replace: 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 75

 
 
 
Product:  AMG 334 
Protocol Number:  20140254 
Date:  06 August 2015 
Page 12 of 15 
CONFIDENTIAL 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 76

 
 
 
Product:  AMG 334 
Protocol Number:  20140254 
Date:  06 August 2015 
Page 13 of 15 
CONFIDENTIAL 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 77

 
 
 
Product:  AMG 334 
Protocol Number:  20140254 
Date:  06 August 2015 
Page 14 of 15 
CONFIDENTIAL 
 
 
With: 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 78

 
 
 
Product:  AMG 334 
Protocol Number:  20140254 
Date:  06 August 2015 
Page 15 of 15 
CONFIDENTIAL 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 79

 
 
 
Product:  AMG 334 
Protocol Number:  20140254 
Date:  17 November 2015 
Page 1 of 19 
CONFIDENTIAL 
 
 
Template Date:  15 December 2014 
Version 4.0 
Amendment 2 
Title:  A Randomized, Double-blind, Placebo-controlled Study to Evaluate the 
Effect of AMG 334 on Exercise Time During a Treadmill Test in Subjects With 
Stable Angina 
 
Amgen Protocol Number 20140254 
 
Version 1.0 Date: 
Amendment 1 Date: 
Amendment 2 Date: 
12 June 2015 
06 August 2015 
17 November 2015 
Rationale: 
The rationale for this amendment is to add:  a 12-lead electrocardiogram to be 
conducted 4 hours after the completion of the Exercise Treadmill Test on day 1; an 
assessment of anti-AMG 334 antibodies at day 1, week 4, and end of study; a summary 
of clinical safety data to the Background and Rationale; and to clarify language 
throughout the protocol. 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 80

 
 
 
Product:  AMG 334 
Protocol Number:  20140254 
Date:  17 November 2015 
Page 2 of 19 
CONFIDENTIAL 
 
 
Description of Changes: 
Section:  Global 
Change:  Administration, typographical and formatting changes were made throughout 
the protocol.   
Section:  Title Page 
Replace:   
Header: Date: 06 August 2015 
With:  
Header: Date: 17 November 2015 
Replace: 
Version 1.0 Date: 
Amendment 1 Date: 
12 June 2015 
06 August 2015 
With: 
Version 1.0 Date: 
Amendment 1 Date: 
Amendment 2 Date: 
12 June 2015 
06 August 2015 
17 November 2015 
Section:  Investigator’s Agreement 
Replace: 
I have read the attached protocol entitled A Randomized, Double-blind, Placebo-
controlled Study to Evaluate the Effect of AMG 334 on Exercise Time During a Treadmill 
Test in Subjects With Stable Angina, dated 06 August 2015 and agree to abide by all 
provisions set forth therein.   
With: 
I have read the attached protocol entitled A Randomized, Double-blind, Placebo-
controlled Study to Evaluate the Effect of AMG 334 on Exercise Time During a Treadmill 
Test in Subjects With Stable Angina, dated 17 November 2015 and agree to abide by all 
provisions set forth therein.   
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 81

 
 
 
Product:  AMG 334 
Protocol Number:  20140254 
Date:  17 November 2015 
Page 3 of 19 
CONFIDENTIAL 
 
 
Section:  Protocol Synopsis – Summary of Subject Eligibility Criteria 
Replace: 
For a full list of eligibility criteria, please refer to Section 4.1.1 through 4.2.2. 
With: 
For a full list of eligibility criteria, please refer to Section 4. 
Section:  Protocol Synopsis – Amgen Investigational Product Dosage and Administration 
Replace: 
See Section 6.2.1 for further details. 
With: 
See Section 6.2.1.1 for further details. 
Section:  Protocol Synopsis – Procedures 
Replace: 
After signing the informed consent form, adverse events and serious adverse events will 
be collected, and subjects will enter the screening phase (up to 6 weeks).  Screening 
evaluations will include targeted medical and medication history, physical exam, vital 
signs, Columbia-Suicide Severity Rating Scale (C-SSRS) assessment, and ETT.  Blood 
samples will be collected for pharmacokinetics (PK), biomarker, hematology, chemistry, 
and for all females (except those at least 2 years post-menopausal or surgically sterile) a 
urine pregnancy test.  At the day 1 pre-dose visit, eligible subjects will be enrolled and 
randomized into the 12-week double-blind on-study period and will receive 
investigational product.  Following investigational product administration, an ETT (ETTr) 
will be conducted.  Safety follow-up visits will occur every 2-4 weeks after the last dose 
of investigational product.  Subjects will record episodes of angina and antianginal 
medication use in an angina diary beginning on the day of screening Visit 1 and through 
the End of Study (EOS)/Early Termination (ET) visit to record angina episodes not 
occurring during ETT.   
With: 
After signing the informed consent form, adverse events and serious adverse events will 
be collected, and subjects will enter the screening phase (up to 6 weeks).  Screening 
evaluations will include targeted medical and medication history, physical examination, 
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CONFIDENTIAL 
 
 
vital signs, Columbia-Suicide Severity Rating Scale (C-SSRS) assessment, and ETT.  
Blood samples will be collected for pharmacokinetics (PK), biomarker analysis, 
hematology, chemistry, and for all females (except those at least 2 years post-
menopausal or surgically sterile) a urine pregnancy test.  At the day 1 pre-dose visit, 
eligible subjects will be enrolled and randomized into the 12-week double-blind on-study 
period and will receive investigational product.  Following investigational product 
administration, an ETT (exercise treadmill test post-randomization [ETTr]) will be 
conducted.  Safety follow-up visits will occur every 2-4 weeks after the last dose of 
investigational product.  Subjects will record episodes of angina and antianginal 
medication use in an angina diary beginning on the day of screening visit 1 and through 
the End of Study (EOS)/Early Termination (ET) visit to record angina episodes not 
occurring during ETT.   
Section:  Protocol Synopsis – Statistical Considerations: 
Replace: 
The SAS will be used to analyze safety endpoints based on the actual treatment 
received.  The Medical Dictionary for Regulatory Activities (MedDRA) will be used to 
code all adverse events.  Subject incidence of all treatment-emergent adverse events 
will be tabulated by treatment groups.  Tables of fatal adverse events, serious adverse 
events, adverse events leading to withdrawal from investigational product, treatment-
related adverse events, serious treatment-related adverse events, adverse events of 
special interest if any, and Disease Related Events also will be provided.  Subject 
incidence of Disease Related Events and fatal Disease Related Events will be tabulated 
by system organ class and preferred term.  The analyses of selected safety laboratory 
endpoints will include summary statistics over time by treatment group.  Shift tables of 
the worst on-study safety laboratory toxicity based on grade relative to baseline will be 
tabulated by treatment group.  Tabulations of grades ≥ 3 laboratory toxicities will be 
provided.  The analyses of vital signs will include summary statistics over time by 
treatment group. 
With: 
The SAS will be used to analyze safety endpoints based on the actual treatment 
received.  The Medical Dictionary for Regulatory Activities (MedDRA) will be used to 
code all adverse events.  Subject incidence of all treatment-emergent adverse events 
will be tabulated by treatment groups.  Tables of fatal adverse events, serious adverse 
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Date: 
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Product:  AMG 334 
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CONFIDENTIAL 
 
 
events, adverse events leading to withdrawal from investigational product, treatment-
related adverse events, serious treatment-related adverse events, adverse events of 
special interest if any, and Disease Related Events also will be provided.  Subject 
incidence of Disease Related Events and fatal Disease Related Events will be tabulated 
by system organ class and preferred term.  The analyses of selected safety laboratory 
endpoints will include summary statistics over time by treatment group.  Shift tables of 
the worst on-study safety laboratory toxicity based on grade relative to baseline will be 
tabulated by treatment group.  Tabulations of grades ≥ 3 laboratory toxicities will be 
provided.  The analyses of vital signs will include summary statistics over time by 
treatment group. 
Section:  2.4 AMG 334 Clinical Safety Summary 
Add: 
As of August 10, 2015, approximately 1,039 subjects have received AMG 334 since 
the beginning of the clinical development program.  Across phase 1 studies, 
152 subjects (healthy subjects, subjects with hot flash and migraineurs) have 
received AMG 334 at doses up to 280 mg SC and 140 mg IV.  In the phase 1 
studies, 24-hour continuous ambulatory blood pressure (BP) monitoring 
demonstrated no change in BP circadian rhythm and no increase in BP with 
increasing doses of AMG 334.   
Across ongoing phase 2 clinical studies approximately 887 subjects have 
received >1 dose of investigational product, including a total of 472 subjects in the 
double-blind phase of the episodic migraine study (Study 20120178).  In both the 
double-blind and open-label treatment portions of the phase 2 episodic migraine 
study (Study 20120178) concomitant use of triptan-based migraine medications 
was reported in 64.8% of subjects.  In this study, blood pressure was assessed at 
each visit.  There was no clinically significant difference in either systolic or 
diastolic blood pressure at any dose group of AMG 334 compared with placebo.  
Moreover, there was no difference in the frequency of the adverse event of blood 
pressure increase between placebo and any dose of AMG 334.  To date, AMG 334 
has demonstrated a favorable safety and tolerability profile that supports further 
development.  Refer to the AMG 334 Investigator’s Brochure for details. 
Product: 
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CONFIDENTIAL 
 
 
Section:  2.5 Risk Assessment 
Add: 
There is no direct benefit for individual subjects participating in this study, 
however there is a potential indirect benefit to participants in this study since they 
will undergo cardiovascular evaluation and assessments, including ETT, which 
may provide their treating physician with more detailed information that may 
improve their care.  This study will test the hypothesis that AMG 334 does not 
significantly decrease exercise capacity in the study population, and, as such, 
would be supportive of the safe use of AMG334 as migraine prophylaxis in 
subjects with, or at risk of, cardiovascular disease. 
To date, no evidence of a cardiovascular safety signal has been observed in 
preclinical, or phase 1, 2, and 3 studies of several investigational products 
interfering with the CGRP signaling pathway.  This body of evidence includes 
dedicated cardiovascular studies with hemodynamic monitoring. 
All subjects participating in the clinical study will be monitored closely for any 
cardiovascular abnormalities with vital signs assessments, ECGs, and physical 
examinations conducted at screening and before, during, and after the ETT 
procedures. 
Section:  3.2 Number of Sites 
Replace: 
This is a multicenter study that will be conducted at approximately 30 sites. 
With: 
This is a multicenter study that will be conducted at approximately 40 sites. 
Section:  4.1.2.2 Reproductive 
Replace: 
206. 
Females of reproductive potential who are not willing to use acceptable 
method(s) of effective birth control during treatment with AMG 334 and for an 
additional 12 weeks after receiving a single dose of AMG 334 
• 
Acceptable methods of effective contraception include: true sexual abstinence 
when this is in line with the preferred and usual lifestyle of the subject [periodic 
abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence for the duration of the study, and withdrawal are not 
acceptable methods of contraception], or use of hormonal birth control methods 
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Product:  AMG 334 
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CONFIDENTIAL 
 
 
(oral, implantable, injectable, transdermal, intravaginal), intrauterine devices 
(IUDs), intrauterine hormonal-releasing system (IUS), surgical contraceptive 
methods (vasectomy with medical assessment of the surgical success of this 
procedure or bilateral tubal ligation), or two (2) barrier methods (one by each 
partner and at least one of the barrier methods must include spermicide (unless 
spermicide is not approved in the country or region) - the male must use a 
condom and the female must choose either a diaphragm OR cervical cap, OR 
contraceptive sponge  (a male and female condom cannot be used together due 
to the risk of tearing). 
With: 
206. 
Females of reproductive potential who are not willing to use highly effective 
methods of birth control during treatment with AMG 334 and for an additional 
12 weeks after receiving a single dose of AMG 334 
• 
Highly effective methods of contraception as per Clinical Trial Facilitation 
Group recommendations include:  
• Combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation: 
o oral 
o intravaginal 
o transdermal 
• Progestogen-only hormonal contraception associated with inhibition 
of ovulation: 
o oral 
o injectable 
o implantable 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner (with medical assessment of the surgical 
success of this procedure) 
• Sexual abstinence 
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Date: 
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Product:  AMG 334 
Protocol Number:  20140254 
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CONFIDENTIAL
Section:  5.2 Site Personnel Access to Individual Treatment Assignments 
Replace: 
A subject’s treatment assignment should only be unblinded when knowledge of the 
treatment is essential for the further management of the subject on this study.  
Unblinding at the study site for any other reason will be considered a protocol deviation.  
The investigator is strongly encouraged to contact the Amgen Clinical Study Manager 
before unblinding any subject’s treatment assignment, but must do so within 1 working 
day after the event.   
With: 
A subject’s treatment assignment should only be unblinded when knowledge of the 
treatment is essential for the further management of the subject in this study (eg, in 
situations of emergency).  Unblinding at the study site for any other reason will be 
considered a protocol deviation.  The investigator is strongly encouraged to contact the 
Amgen Clinical Study Manager before unblinding any subject’s treatment assignment, 
but must do so within 1 working day after the event.   
Section:  7.1 Schedule of Assessments 
Replace: 
Product: 
Date: 
AMG 334
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CONFIDENTIAL
Table 1.  Schedule of Assessments 
Procedure 
Screening Period (up to 6 weeks) 
On-Study Period (12 weeks) 
EOS/ET 
Screening Visitsi
On-Study Visitsi
Visit 1 
Visit 2 
Visit 3 
Visit 4k 
Day 1 
Pre-dosea 
Day 1 Post-
dose 
Week 2h 
Week 4 
Week 8 
Week 12 
General and Safety Assessments 
Informed Consent 
X 
Physical Examination, including weight 
X 
X 
Targeted Medical/Surgical History 
X 
Height 
X 
Randomizationb
X 
Columbia-Suicide Severity Rating Scale 
X 
X 
X 
X 
X 
ETTc 
Xc 
Xc 
Xc 
X 
Blood Pressure, Heart Rated 
X 
X 
X 
X 
X 
X 
ECG 
X 
Concomitant Medications 
X 
Record Continuously 
X 
Serious Adverse Events 
X 
Record Continuously 
X 
Adverse Events and Disease Related Events 
X 
Record Continuously 
X 
Angina diarye 
Record Continuously 
Laboratory Assessments 
Hematology, Chemistry  
(central laboratory) 
X 
X 
X 
Urine pregnancy testf  
(females of reproductive potential) 
X 
X 
X 
Pharmacokinetic Sampling 
Xg 
Biomarker Sampling 
X 
Urine drug screenj 
X 
Dosing 
AMG 334 or Placebo 
X 
Footnotes defined on next page 
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Product:  AMG 334 
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CONFIDENTIAL
ECG = electrocardiogram; EOS = end of study; ET = early termination; ETT = Exercise Treadmill Test; PK = pharmacokinetic.  
a Pre-dose assessments should be conducted on day 1 prior to randomization. 
b Week 1 begins on the date of randomization.  Study day 1 is defined as the date investigational product is received.  
c During the screening period, two consecutive ETTs are required > 48 hours and ≤ 14 days apart that meet inclusion criteria and were reviewed by a core ECG 
laboratory to confirm eligibility. 
d Blood pressure and heart rate should be assessed at all visits following the standard procedure.  During ETT visits, the standard procedure will be conducted prior to 
the ETT; blood pressure assessments will also be conducted following the monitoring procedure described for the ETT. 
e Angina diary will be completed by subjects beginning on the day of Visit 1 and through the EOS/ET visit to  record angina episodes not occurring during ETTs   
through EOS.  
f Results of pre-dose pregnancy test must be reviewed prior to administration of investigational product on day 1.  
g PK sample to be drawn on day 1 after completion of exercise treadmill test post-randomization (ETTr). 
h Visit at week 2 can be done via telephone contact. 
i Study visit windows are ± 1 week.  
j Urine drug screen may also be performed as needed throughout the study per investigator judgment. 
k Optional Visit 4 to be performed if ETT3 is required for eligibility determination. 
With: 
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Date: 
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Protocol Number:  20140254 
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CONFIDENTIAL
Table 1.  Schedule of Assessments 
Procedure 
Screening Period (up to 6 weeks) 
On-Study Period (12 weeks) 
EOS/ET 
Screening Visitsk
On-Study Visitsk
Visit 1 
Visit 2 
Visit 3 
Visit 4m 
Day 1 
Pre-dosea 
Day 1 Post-
dose 
Week 2j 
Week 4 
Week 8 
Week 12 
General and Safety Assessments 
Informed Consent 
X 
Physical Examination, including weight 
X 
X 
Targeted Medical/Surgical History 
X 
Height 
X 
Randomizationb
X 
Columbia-Suicide Severity Rating Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ETTc 
Xc 
Xc 
Xc 
X 
Blood Pressure, Heart Rated 
X 
X 
X 
X 
X 
X 
ECG 
X 
X 
X 
X 
Xe 
X 
Concomitant Medications 
X 
Record Continuously 
X 
Serious Adverse Events 
X 
Record Continuously 
X 
Adverse Events and Disease Related Events 
X 
Record Continuously 
X 
Angina diaryf 
Record Continuously 
Laboratory Assessments 
Hematology, Chemistry  
(central laboratory) 
X 
X 
X 
Urine pregnancy testg  
(females of reproductive potential) 
X 
X 
X 
Pharmacokinetic Sampling 
Xh 
Biomarker Sampling 
X 
Xi 
Anti-AMG 334 antibodies 
X 
X 
X 
Urine drug screenl 
X 
Dosing 
AMG 334 or Placebo 
X 
Footnotes defined on next page 
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Date: 
AMG 334
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Product:  AMG 334 
Protocol Number:  20140254 
Date:  17 November 2015 
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CONFIDENTIAL
ECG = electrocardiogram; EOS = end of study; ET = early termination; ETT = Exercise Treadmill Test; PK = pharmacokinetic.  
a Pre-dose assessments should be conducted on day 1 prior to randomization. 
b Week 1 begins on the date of randomization.  Day 1 is defined as the date investigational product is received.  
c During the screening period, 2 consecutive ETTs are required > 48 hours and ≤ 14 days apart that meet inclusion criteria and will be reviewed by a core ECG 
laboratory to confirm eligibility. 
d Blood pressure and heart rate should be assessed at all visits following the standard procedure.  During ETT visits, the standard procedure will be conducted prior to 
the ETT; blood pressure assessments will also be conducted following the monitoring procedure described for the ETT 
e ECG will be performed 4 hours after the end of the ETT. 
f Angina diary will be completed by subjects beginning on the day of visit 1 and through the EOS/ET visit to record angina episodes not occurring during ETTs through 
EOS.  
g Results of pre-dose pregnancy test must be reviewed prior to administration of investigational product on day 1.  
h PK sample to be drawn on day 1 after completion of exercise treadmill test post-randomization (ETTr). 
i Biomarker sampling for troponin I measurement will be performed 4 hours after the end of the ETT. 
j Visit at week 2 can be done via telephone contact. 
k Study visit windows are ± 1 week.  
l Urine drug screen may also be performed as needed throughout the study per investigator judgment. 
m Optional visit 4 to be performed if ETT 3 is required for eligibility determination. 
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CONFIDENTIAL
Section:  7.3.4 Columbia-Suicide Severity Rating Scale (C-SSRS) 
Replace: 
The C-SSRS is a clinician rating of suicidal behavior and ideation.  The C-SSRS 
consists of a maximum of 20 items.   
With: 
The C-SSRS is a clinician rating of suicidal behavior and ideation.  The C-SSRS 
consists of a maximum of 20 items which define 5 subtypes of suicidal ideation and 
behavior in addition to self-injurious behavior with no suicidal intent.  The C-SSRS 
will be administered to study subjects at each study visit to assess possible 
suicide ideation and behavior.  Reports of suicidal ideation with intent to act 
(severity of 4 or 5) and reports of actual, aborted, or interrupted suicide attempts 
or a behavior preparatory for making an attempt indicate subjects at high risk for 
suicide.  If such reports are identified, the investigator is to appropriately manage 
the subject in accordance with standard of care. 
Section:  7.3.7 Exercise Treadmill Test 
Replace: 
The appropriate site staff should examine all ECG tracings and ETT records to ensure 
subject safety.   
Subjects may touch the treadmill bars or handles lightly to assist with balance, however 
they must not be allowed to hold onto or lean on the treadmill bars or handles during the 
ETT.  The appropriate site staff should examine all ECG tracings and ETT records to 
ensure subject safety.   
Additional details regarding the ETT procedures, including provision of data to the core 
ECG laboratory, may be found in the ETT manual. 
With: 
Subjects may touch the treadmill bars or handles lightly to assist with balance, however 
they must not be allowed to hold onto or lean on the treadmill bars or handles during the 
ETT.  The appropriate site staff should examine all ECG tracings and ETT records to 
ensure subject safety.  The appropriate site staff should examine all ECG tracings and 
ETT records to ensure subject safety.   
Product: 
Date: 
AMG 334
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Date:  17 November 2015 
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CONFIDENTIAL
Appropriate measures of emergency assistance (including cardiopulmonary 
resuscitation, access to intensive care unit, and specialized interventions such as 
coronary catheterization) must be available. 
Additional details regarding the ETT procedures, including provision of data to the core 
ECG laboratory, may be found in the ETT manual. 
Section:  7.3.9.1 Blood Pressure 
Replace: 
•
Prior to the ETT
o
In a standing position after 2 minutes of standing
•
Within 30 seconds prior to each change in stage and at peak exercise
during the ETT, in a standing position
•
At the end of the ETT in a sitting position
•
During recovery in a sitting position, every minute for 5 minutes after the
end of the ETT, then every 5 minutes, as needed, until values return to
near baseline values, per the judgment of the investigator.
With: 
•
Prior to the ETT
o
In a standing position after 2 minutes of standing
•
Within 30 seconds prior to each change in stage and at peak exercise
during the ETT, in a standing position
•
At the end of the ETT in a sitting position
•
During recovery in a sitting position, every minute for 5 minutes after the
end of the ETT, then every 5 minutes, as needed, until values return to
near baseline values, per the judgment of the investigator
•
Maximum SBP during the ETT will be recorded.
Section:  7.3.9.2 Electrocardiograph 
Replace: 
If ST-segment changes occur, run a printout every 30 seconds until resolution.  
Additional exercise ECGs will be obtained per the recovery period schedule as 
appropriate.   
With: 
If ST-segment changes occur, run a printout will be run every 30 seconds until 
resolution.  Additional exercise ECGs will be obtained per the recovery period schedule 
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CONFIDENTIAL 
 
 
as appropriate.  Maximum heart rate and maximum ST-segment depression during 
ETT will be recorded. 
After the ETTr, all subjects will be followed up at the site for at least 4 hours.  At 
the end of the 4-hour follow-up period, the following procedures will be 
performed: 
• 
12-lead rest ECG in a sitting position 
• 
Blood pressure measurement in a sitting position 
• 
Blood sampling for measurement of troponin I  
Subjects can be kept at the site for longer than 4 hours at the discretion of the 
investigator. 
Section:  7.3.12 Laboratory Assessments 
Replace:  
Table 2.  Analyte Listing 
Chemistry 
Sodium 
Potassium 
Chloride  
Bicarbonate 
Total protein 
Albumin 
Calcium 
Adjusted calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
AST (SGOT) 
ALT (SGPT) 
• 
Bands/stabs 
Hematology 
WBC 
RBC 
 
Hemoglobin 
Hematocrit 
Platelets 
WBC Differential 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Neutrophils 
 
• 
Troponin I 
Other Labs 
Hepatitis B surface antigen  
Hepatitis B core antibody 
Hepatitis C virus antibody 
 
PK 
Cardiac biomarkers 
• 
CK 
• 
CK-MB 
Urine drug screen 
Urine pregnancy test (local) 
With: 
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CONFIDENTIAL 
 
 
Table 3.  Analyte Listing 
Chemistry 
Sodium 
Potassium 
Chloride  
Bicarbonate 
Total protein 
Albumin 
Calcium 
Adjusted calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
AST (SGOT) 
ALT (SGPT) 
• 
Bands/stabs 
Hematology 
WBC 
RBC 
 
Hemoglobin 
Hematocrit 
Platelets 
WBC Differential 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Neutrophils 
 
• 
Troponin I 
Other Labs 
Hepatitis B surface antigen  
Hepatitis B core antibody 
Hepatitis C virus antibody 
 
PK 
Cardiac biomarkers 
• 
CK 
• 
CK-MB 
Urine drug screen 
Urine pregnancy test (local) 
Section:  7.3.15 Anti-AMG 334 Antibody Analysis 
Add: 
Blood samples will be collected for the measurement of anti-AMG 334 binding 
antibodies at the following time points: before dose on day 1, week 4 and EOS, 
and at additional time points as needed (see Table 1).  Samples testing positive for 
binding antibodies will also be tested for neutralizing antibodies and may be 
further characterized for quantity/titer, isotype, affinity and/or presence of immune 
complexes.  Additional blood samples may be obtained to rule out anti-AMG 334 
antibodies during the study.  Subjects who test positive for neutralizing 
antibodies to AMG 334 at the final scheduled study visit will be asked to return for 
additional follow-up testing.  This testing should occur approximately every 3 
months starting from when the site has been notified of the positive result, until: 
(1) neutralizing antibodies are no longer detectable or (2) the subject has been 
followed for a period of at least 1 year (± 4 weeks).  More frequent testing (eg, 
every month), or testing for a longer period of time may be requested in the event 
of safety-related concerns.  Follow-up testing will not be required where it is 
established that the subject did not receive AMG 334.  Subjects who test positive 
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CONFIDENTIAL 
 
 
for binding, non-neutralizing antibodies and have clinical sequelae that are 
considered potentially related to an anti-AMG 334 antibody response may also be 
asked to return for additional follow-up testing. 
Section:  7.4 Biomarkers 
Replace: 
Blood samples are to be collected at the following time points: day 1 pre-dose for all 
subjects to enable testing of baseline cardiac markers (eg, troponin) or other safety 
measures, if needed. 
With: 
Blood samples are to be collected at day 1 post-ETT (4 hours) for all subjects to enable 
testing of troponin I or other safety measures, if needed. 
Section:  9.2.2.4 Serious Adverse Events That are not to be Reported in an Expedited 
Manner 
Replace: 
A serious adverse event of stable angina will not be reported in an expedited manner as 
this is anticipated to occur in the study population at some frequency independent of the 
protocol-required therapies.  The Data Monitoring Committee (DMC) will monitor these 
events on an ongoing basis. 
With: 
A serious adverse event of stable angina will not be reported in an expedited manner as 
this is anticipated to occur in the study population at some frequency independent of the 
protocol-required therapies.  The Data Monitoring Committee (DMC) will monitor these 
events on an ongoing basis.  As there are no identified risks for AMG 334, all 
adverse events will be considered ‘unexpected’ for regulatory reporting purposes. 
Section:  10.5.2 Data Monitoring Committee (DMC) 
Replace: 
A DMC will review and make recommendations regarding the safety of the study 
participants throughout the study.  The DMC will be composed of members with relevant 
expertise.  Safety data will be reviewed and the DMC will advise the study sponsor on 
findings that may impact the conduct of the study. 
With: 
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CONFIDENTIAL 
 
 
An independent DMC has been established to oversee the safety of study 
participants for several AMG 334 Migraine programs, including this study.  The 
DMC will be composed of members with relevant expertise (cardiology, neurology, 
and statistics).  DMC meetings are held approximately every 3 months and ad hoc 
meetings may be requested at any time by either the DMC or the Sponsor.  Safety 
data including adverse events and laboratory data, will be reviewed frequently 
throughout the study, and the DMC will advise the study sponsor on findings that 
may impact the conduct of the study, including a recommendation to terminate 
the study.  All serious unexpected serious adverse reactions will be promptly 
shared with the DMC.   
Section:  10.5.5 Safety Endpoints 
Replace: 
Subject incidence of all treatment-emergent adverse events will be tabulated by 
treatment groups.  Tables of fatal adverse events, serious adverse events, leading to 
withdrawal from investigational product, treatment-related adverse events, serious 
treatment-related adverse events, adverse events of special interest if any, and Disease 
Related Events also will be provided. 
Subject incidence of Disease Related Events and fatal Disease Related Events will be 
tabulated by system organ class and preferred term. 
The analyses of selected safety laboratory endpoints will include summary statistics over 
time by treatment group.  Shift tables of the worst on-study safety laboratory toxicity 
based on grade relative to baseline will be tabulated by treatment group.  Tabulations of 
grades ≥ 3 laboratory toxicities will be provided. 
The analyses of vital signs will include summary statistics over time by treatment group.   
With: 
Subject incidence of all treatment-emergent adverse events will be tabulated by 
treatment groups.  Tables of fatal adverse events, serious adverse events leading to 
withdrawal from investigational product, treatment-related adverse events, serious 
treatment-related adverse events, adverse events of special interest if any, and Disease 
Related Events also will be provided. 
Subject incidence of Disease Related Events and fatal Disease Related Events will be 
tabulated by system organ class and preferred term. 
Product: 
Date: 
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Product:  AMG 334 
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CONFIDENTIAL 
 
 
The analyses of selected safety laboratory endpoints will include summary statistics over 
time by treatment group.  Shift tables of the worst on-study safety laboratory toxicity 
based on grade relative to baseline will be tabulated by treatment group.  Tabulations of 
grades ≥ 3 laboratory toxicities will be provided. 
The analyses of vital signs will include summary statistics over time by treatment group.  
Specifically, change from baseline in maximum SBP, maximum heart rate and 
maximum ST-segment depression (mm) on day 1 post dose will be summarized by 
treatment group. 
The incidence and percentage of subjects who develop anti-AMG 334 antibodies 
(binding and if positive, neutralizing) at any time will be tabulated by treatment 
group. 
Section:  13 References 
Added:  
Amgen. AMG 334 Investigator Brochure, version 5.0. 
Section:  Appendix A. Additional Safety Assessment Information 
Replace: 
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.2.2.2. 
With: 
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.1.3. 
Product: 
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Date:  27 January 2016 
Page 1 of 20 
 
CONFIDENTIAL 
 
 
Amendment 3 
Protocol Title:  A Randomized, Double-blind, Placebo-controlled Study to Evaluate 
the Effect of AMG 334 on Exercise Time During a Treadmill Test in Subjects With 
Stable Angina 
 
Amgen Protocol Number 20140254 
 
Amendment 3 Date: 
27 January 2016 
 
 
Rationale: 
This protocol is being amended to: 
• 
Increase the number of study centers 
• 
Support decreasing the screen failure rate by: 
o allowing for the use of 2 out of 3 screening exercise treadmill tests (ETTs) 
to qualify patients for enrollment 
o removing the restriction for antianginal medication on the morning of the 
ETT 
• 
Clarify the background safety information of AMG 334 use in patients with 
migraine. 
• 
Clarify the definition of the Columbia-Suicidality Severity Scale (C-SSRS) 
• 
Clarify adverse event, drug related event and serious adverse event reporting 
instructions 
• 
Align with changes made to the updated standard Amgen protocol template 
 
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CONFIDENTIAL 
 
 
Description of Changes: 
Section: 
Global 
Change: 
Version dates updated throughout document from 06 August 2015 to 
27 January 2016 
Section: 
Global 
Change: 
Typographic, grammatical, and formatting errors were corrected 
throughout the protocol. 
Section: 
Global 
Change: 
Corrected abbreviations throughout the protocol (defined on first use, 
definition removed on subsequent uses). 
Section: 
Title Page 
Replace: 
Version 1.0; Date: 
12 June 2015 
Amendment 1; Date: 
06 August 2015 
With: 
Version 1.0 Date: 
12 June 2015 
Amendment 1 Date: 
06 August 2015 
Amendment 2 Date: 
17 November 2015 (European Union, Voluntary 
Harmonization Procedure countries only) 
Amendment 3 Date: 
27 January 2016 
Section: 
Protocol Synopsis, Study Design 
Replace: 
This is a phase 2a, multicenter, randomized, double-blind, placebo-controlled study in 
subjects with stable angina.  Subjects will be randomized in a 1:1 ratio to receive either a 
single dose of AMG 334 or placebo prior to completing an ETT.  Randomization will be 
stratified by the TET average of the 2 final screening ETT (< 7 minutes or ≥ 7 minutes).  
Treatment group will be blinded to the investigator, subjects, and the Amgen study team.   
With: 
This is a phase 2a, multicenter, randomized, double-blind, placebo-controlled study in 
subjects with stable angina.  Subjects will be randomized in a 1:1 ratio to receive either a 
single dose of AMG 334 or placebo prior to completing an ETT.  Randomization will be 
stratified by the TET average (< 7 minutes or ≥ 7 minutes) of the 2 qualifying ETTs 
performed during screening.  Treatment group will be blinded to the investigator, 
subjects, and the Amgen study team.   
Section: 
Protocol Synopsis, Summary of Subject Eligibility Criteria 
Replace: 
Subject will experience at least 1 angina episode and are receiving stable doses of 
cardiac medications (eg, beta blockers, calcium channel blockers, etc.) for at least 
30 days prior to randomization and that are not expected to change during the study. 
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CONFIDENTIAL 
 
 
For a full list of eligibility criteria, please refer to Section 4.1.1 through Section 4.1.2.  
With: 
Subjects will experience at least 1 angina episode and are receiving stable doses of 
cardiac medications (eg, beta blockers, calcium channel blockers, etc.) for at least 
30 days prior to randomization and that are not expected to change during the study.   
For a full list of eligibility criteria, please refer to Section 4. 
Section: 
Protocol Synopsis, Amgen Investigational Product Dosage and 
Administration 
Replace: 
See Section 6.2.1 for further details.  
With: 
See Section 6.2.1.1 for further details.  
Section: 
Protocol Synopsis, Procedures 
Replace: 
After signing the informed consent form, adverse events and serious adverse events will 
be collected, and subjects will enter the screening phase (up to 6 weeks).  Screening 
evaluations will include targeted medical and medication history, physical exam, vital 
signs, Columbia-Suicide Severity Rating Scale (C-SSRS) assessment, and ETT.  Blood 
samples will be collected for pharmacokinetics (PK), biomarker, hematology, chemistry, 
and for all females (except those at least 2 years post-menopausal or surgically sterile) a 
urine pregnancy test.  At the day 1 pre-dose visit, eligible subjects will be enrolled and 
randomized into the 12-week double-blind on-study period and will receive 
investigational product.  Following investigational product administration, an ETT (ETTr) 
will be conducted. 
With: 
After signing the informed consent form (ICF) subjects will enter the screening phase 
(up to 6 weeks), serious adverse events will be collected throughout the study 
including the screening phase, while adverse events and disease related events 
will start being collected post randomization/post first dose.  Screening evaluations 
will include targeted medical and medication history, physical examination, vital signs, 
Columbia-Suicide Severity Rating Scale (C-SSRS) assessment, and exercise treadmill 
test (ETT).  Blood samples will be collected for biomarker analysis, hematology, 
chemistry, and for all females (except females not of childbearing potential, see 
definition in Exclusion Criteria Section 4.1.2.2) a urine pregnancy test.  At the day 1 
pre-dose visit, eligible subjects will be enrolled and randomized into the 12-week 
double-blind on-study period and will receive investigational product.  Following 
investigational product administration, an exercise treadmill test post-randomization 
(ETTr) will be conducted, and pharmacokinetics (PK) sampling will be performed. 
Section:   
Protocol Synopsis, Statistical Considerations, 8th paragraph 
Delete: 
The SAS will be used to analyze safety endpoints based on the actual treatment 
received.  The Medical Dictionary for Regulatory Activities (MedDRA) will be used to 
code all adverse events.  Subject incidence of all treatment emergent adverse events 
will be tabulated by treatment groups.  Tables of fatal adverse events, serious adverse 
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CONFIDENTIAL 
 
 
events, adverse events leading to withdrawal from investigational product, treatment-
related adverse events, serious treatment related adverse events, adverse events of 
special interest if any, and Disease Related Events also will be provided.  Subject 
incidence of Disease Related Events and fatal Disease Related Events will be tabulated 
by system organ class and preferred term.  The analyses of selected safety laboratory 
endpoints will include summary statistics over time by treatment group.  Shift tables of 
the worst on-study safety laboratory toxicity based on grade relative to baseline will be 
tabulated by treatment group.  Tabulations of grades ≥ 3 laboratory toxicities will be 
provided.  The analyses of vital signs will include summary statistics over time by 
treatment group. 
Section:   
Study Glossary 
Add: 
Abbreviation or Term 
Definition/Explanation 
AE 
Adverse Event 
DRE 
Disease Related Event 
SAE 
Serious Adverse Event 
Section:  
2.4 
AMG 334 Clinical Safety Summary (new section) 
Add: 
2.4 
AMG 334 Clinical Safety Summary 
As of 10 August 2015, approximately 1,039 subjects have received AMG 334 since 
the beginning of the clinical development program.  Across phase 1 studies, 
152 subjects (healthy subjects, subjects with hot flash and migraineurs) have 
received AMG 334 at doses up to 280 mg SC and 140 mg IV.  In the phase 1 
studies, 24-hour continuous ambulatory blood pressure (BP) monitoring 
demonstrated no change in BP circadian rhythm and no increase in BP with 
increasing doses of AMG 334. 
Across ongoing phase 2 clinical studies, approximately 887 subjects have 
received more than 1 dose of investigational product (IP), including a total of 
472 subjects in the double-blind phase of the episodic migraine study 
(Study 20120178).  In both the double-blind and open-label treatment portions of 
the phase 2 episodic migraine study (Study 20120178), concomitant use of 
triptan-based migraine medications was reported in 64.8% of subjects.  In this 
study, BP was assessed at each visit.  There was no clinically significant 
difference in either systolic or diastolic BP at any dose group of AMG 334 
compared with placebo.  Moreover, there was no difference in the frequency of the 
adverse event of blood pressure increase between placebo and any dose of 
AMG 334.  To date, AMG 334 has demonstrated a favorable safety and tolerability 
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CONFIDENTIAL 
 
 
profile that supports further development.  Refer to the AMG 334 Investigator’s 
Brochure for details. 
Section: 
2.5 
Risk Assessment (new section) 
Add: 
2.5 
Risk Assessment 
There is no direct benefit for individual subjects participating in this study, 
however there is a potential indirect benefit to participants in this study since they 
will undergo cardiovascular evaluation and assessments, including ETT, which 
may provide their treating physician with more detailed information that may 
improve their care.  This study will test the hypothesis that AMG 334 does not 
significantly decrease exercise capacity in the study population, and, as such, 
would be supportive of the safe use of AMG 334 as migraine prophylaxis in 
subjects with, or at risk of, cardiovascular disease. 
To date, no evidence of a cardiovascular safety signal has been observed in 
preclinical, or phase 1, 2, and 3 studies of several investigational products 
interfering with the CGRP signaling pathway.  This body of evidence includes 
dedicated cardiovascular studies with hemodynamic monitoring. 
All subjects participating in the clinical study will be monitored closely for any 
cardiovascular abnormalities with vital signs assessments, electrocardiograms 
(ECGs), and physical examinations conducted at screening and before, during, 
and after the ETT procedures. 
Section:  
3.1 
Study Design, 1st paragraph 
Replace: 
This is a phase 2a, multicenter, randomized, double-blind, placebo-controlled study in 
subjects with stable angina.  Approximately 120 subjects will be randomized in a 
1:1 ratio to receive either a single dose of AMG 334 or placebo prior to completing an 
ETT.  Randomization will be stratified by the TET average of the 2 final screening ETT 
(< 7 minutes or ≥ 7 minutes).  Treatment group will be blinded to the investigator, 
subjects, and the Amgen study team.   
With: 
This is a phase 2a, multicenter, randomized, double-blind, placebo-controlled study in 
subjects with stable angina.  Approximately 120 subjects will be randomized in a 
1:1 ratio to receive either a single dose of AMG 334 or placebo prior to completing an 
ETT.  Randomization will be stratified by the TET average (< 7 minutes or ≥ 7 minutes) 
of the 2 qualifying ETTs performed during screening.  Treatment group will be 
blinded to the investigator, subjects, and the Amgen study team.   
Section:  
3.2 
Number of Sites 
Replace: 
This is a multicenter study that will be conducted at approximately 30 sites. 
With: 
This is a multicenter study that will be conducted at approximately 40 sites. 
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CONFIDENTIAL 
 
 
Section:  
3.5.2 End of Study, 2nd paragraph 
Replace: 
The end of study ([EOS]), end of trial) is defined as the time when the last subject is 
assessed or receives an intervention for evaluation in the study (ie, study week 12). 
With: 
Final completion:  The end of study ([EOS], end of trial) is defined as the time when the 
last subject is assessed or receives an intervention for evaluation in the study (ie, study 
week 12). 
Section:  
4.1.1 Inclusion Criteria 
Delete: 
101 
Subject has provided informed consent/assent prior to initiation of any 
study-specific activities/procedures. 
Section:  
4.1.1 Inclusion Criteria 
Replace: 
106 
Completes 2 consecutive ETTs during screening, performed > 48 hours and 
≤ 14 days apart using a standard Bruce ETT protocol, with: 
a. 
Limitation of exercise due to symptoms of angina or ≥ 3 mm 
ST-segment depression   
b. 
≥ 1.0 mm ischemic ST-segment depression   
c. 
Exercise duration of ≥ 3 to ≤ 12 minutes , and  
d. 
≤ 1 minute difference or within 20% duration (using the longest 
duration qualifying ETT) in TET between the 2 qualifying tests 
e. 
ECG tracings from screening ETTs are acceptable to the core 
ECG laboratory 
With: 
106 
Completes 2 qualifying ETTs during screening period (as described for 
Screening in Section 7.3.8).  The following ETT qualifications are required: 
a. Limitation of exercise due to symptoms related to myocardial 
ischemia (such as angina pectoris, chest pain/discomfort, 
dyspnea, shortness of breath), or ≥ 3 mm ST-segment depression   
b. ≥ 1.0 mm ischemic ST-segment depression during exercise 
performance   
c. Exercise duration of ≥ 3 to ≤ 12 minutes , and  
d. ≤ 1 minute difference or within 20% duration (using the longest 
duration qualifying ETT) in TET between the 2 qualifying ETTs 
e. ECG tracings from screening ETTs are acceptable to the core ECG 
laboratory 
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CONFIDENTIAL 
 
 
Section:   
4.1.2.5 Exclusion Criteria, Cardiovascular 
Replace: 
217 
ECG findings that preclude analysis of the ETT, including but not limited to: 
a. Left bundle branch block  
b. Pacemaker  
c. Resting ST-segment depression ≥ 1.0 mm 
d. Left ventricular hypertrophy with repolarization changes 
e. Wolf-Parkinson White  
With: 
217 
ECG findings that preclude analysis of the ETT, including but not limited to: 
a. Any right or left bundle branch block  
b. Pacemaker  
c. Resting ST-segment depression ≥ 1.0 mm 
d. Left ventricular hypertrophy with repolarization changes 
e. Wolf-Parkinson White  
Section:   
5 
Subject Enrollment, 3rd paragraph 
Replace:  
Each subject who enters into the screening period for the study (up to 6 weeks) receives 
a unique subject identification number before any study-related activities/procedures are 
performed.  The subject identification number will be assigned by the Interactive Voice 
Response System (IVRS)/Interactive Web Response System (IWRS).  This number will 
be used to identify the subject throughout the clinical study and must be used on all 
study documentation related to that subject.  A subject may be rescreened once if there 
are exclusionary medical conditions, such as elevated blood pressure or abnormal 
laboratory findings that may resolve and allow for rescreening.  Subjects may not be 
rescreened if unable to perform two ETT with TET within one minute of each other. 
With:  
Each subject who enters into the screening period for the study (up to 6 weeks) receives 
a unique subject identification number before any study-related activities/procedures are 
performed.  The subject identification number will be assigned by the Interactive Voice 
Response System (IVRS)/Interactive Web Response System (IWRS).  This number will 
be used to identify the subject throughout the clinical study and must be used on all 
study documentation related to that subject.  A subject may be rescreened once if there 
are exclusionary medical conditions (such as elevated blood pressure or abnormal 
laboratory findings) that may resolve and allow for rescreening.  Subjects may also be 
rescreened once if in the opinion of the investigator the reason for initial screen 
failure has been resolved or is no longer applicable (eg, due to a protocol 
amendment).  Subjects may not be rescreened if unable to perform at least two ETTs 
with TET within one minute (or within 20% duration, using the longest duration 
qualifying ETT) of each other. 
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CONFIDENTIAL 
 
 
Section:   
5.1 
Randomization/Treatment Assignment, 2nd paragraph 
Replace:  
Subjects will be randomized in a 1:1 allocation ratio to a single dose of AMG 334 or 
placebo prior to completing an ETT with approximately 60 subjects assigned to each 
treatment group.  Randomization will be stratified by the TET average of the 2 final 
screening ETT (< 7 minutes or ≥ 7 minutes).  The randomization will be performed by 
IVRS/IWRS.  Treatment groups will be blinded to the investigator, subjects, and the 
Amgen study team. 
With:  
Subjects will be randomized in a 1:1 allocation ratio to a single dose of AMG 334 or 
placebo prior to completing an ETT with approximately 60 subjects assigned to each 
treatment group.  Randomization will be stratified by the TET average (< 7 minutes or 
≥ 7 minutes) of the 2 qualifying ETTs performed during screening.  The 
randomization will be performed by IVRS/IWRS.  Treatment groups will be blinded to the 
investigator, subjects, and the Amgen study team. 
Section:   
5.2 
Site Personnel Access to Individual Treatment Assignments 
Add:  
A subject’s treatment assignment should only be unblinded when knowledge of the 
treatment is essential for the further management of the subject on this study (eg, in 
situations of emergency).  Unblinding at the study site for any other reason will be 
considered a protocol deviation.  The investigator is strongly encouraged to contact the 
Amgen Clinical Study Manager before unblinding any subject’s treatment assignment, 
but must do so within 1 working day after the event.   
Section:   
6.5 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period, 2nd paragraph 
Replace:  
The following are excluded prior to ETT: 
• 
alcohol within 8 hours  
• 
sublingual nitroglycerin within 4 hours  
• 
caffeine and nicotine products within 2 hours  
• 
antianginal medications on the morning (within 4 hours) 
Any cardiac medications (eg, beta blockers, calcium channel blockers, antianginals, etc.) 
should remain stable throughout the study. 
With:  
The following are excluded prior to ETT: 
• 
alcohol within 8 hours  
• 
sublingual nitroglycerin within 4 hours  
• 
caffeine and nicotine products within 2 hours  
Any cardiac medications taken on a regular schedule (eg, beta blockers, calcium 
channel blockers, antianginals, etc.) should remain stable and not interrupted 
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CONFIDENTIAL 
 
 
throughout the study, unless determined otherwise by the investigator or local 
regulatory guidance. 
Section:   
7 
Study Procedures, 2nd paragraph 
Delete:  
With the exception of the screening and re-screen visits, all study procedures for a visit 
should be completed on the same day.  Any missed visits, tests not done, or 
examinations that are not conducted must be reported as such on the electronic CRFs.  
Subsequent study visits should resume on the original schedule.  Missed assessments 
at prior visits should not be duplicated at subsequent visits.  
 
 
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CONFIDENTIAL
Section:  
Section 7.1, Table 1 Schedule of Assessments 
Add: 
Procedure 
Screening Period (up to 6 weeks) 
On-Study Period (12 weeks) 
EOS/ET 
Screening Visitsi 
On-Study Visitsi
Visit 1 
Visit 2 
Visit 3 
Visit 4k 
Day 1 
Pre-dosea 
Day 1 Post-
dose 
Week 2h 
Week 4 
Week 8 
Week 12 
Serious Adverse Events 
X 
Record Continuously 
X 
Adverse Events and Disease Related Events 
X 
Record Continuously 
X 
Collection of Events for Adjudication 
X 
Record Continuously 
X 
Angina diarye 
Record Continuously 
Laboratory Assessments 
Hematology, Chemistry  
(central laboratory) 
X 
X 
X 
Hepatitis Sample Collection 
X 
Section:  
Section 7.1, Table 1 Schedule of Assessments, Footnotes 
Replace: 
c  During the screening period, two consecutive ETTs are required > 48 hours and ≤ 14 days apart that meet inclusion criteria and were 
reviewed by a core ECG laboratory to confirm eligibility. 
e   Angina diary will be completed by subjects beginning on the day of Visit 1 and through the EOS/ET visit to record angina episodes not 
occurring during ETTs through EOS. 
With: 
c During the screening period, two ETTs are required > 48 hours and ≤ 14 days apart that meet inclusion criteria, and they will be 
reviewed by a core ECG laboratory to confirm eligibility.  No more than 3 ETTs can be performed during the screening period. 
Each ETT should occur within 14 days of each other and the total screening period for ETTs should not exceed 28 days. 
e   Angina diary will be completed by subjects beginning on the day of Visit 1 and through the EOS/ET visit to record angina episodes not 
occurring during ETTs. 
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CONFIDENTIAL 
 
 
Section:   
7.2.1 Screening 
Delete:  
Informed consent must be obtained before completing any other screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  After signing the written 
informed consent, the site will register the subject in IVRS/IWRS and screen the subject 
in order to assess eligibility for participation.  The screening window is up to 6 weeks.  If 
a subject has not met all eligibility criteria at the end of the 6-week window, the subject 
will be registered as a screen fail.  Screen fail subjects may be eligible for re-screening 
once as described in Section 5. 
Section: 
7.3.4 Columbia-Suicide Severity Rating Scale (C-SSRS) 
Add: 
The C-SSRS is a clinician rating of suicidal behavior and ideation.  The C-SSRS 
consists of a maximum of 20 items which define 5 subtypes of suicidal ideation and 
behavior in addition to self-injurious behavior with no suicidal intent.  The C-SSRS 
will be administered to assess possible suicide ideation and behavior.  Reports of 
suicidal ideation with intent to act (severity of 4 or 5) and reports of actual, 
aborted, or interrupted suicide attempts or behavior preparatory for making an 
attempt indicate subjects at high risk for suicide.  If such reports are identified, 
the investigator is to appropriately manage the subject in accordance with 
standard of care.   
Section: 
7.3.7 Exercise Treadmill Test 
Delete: 
The ETT will be conducted using the standard Bruce protocol.  A motor-driven treadmill 
should be utilized under uniform conditions, optimally by the same technician and 
supervising physician for each ETT.  The subject should wear comfortable clothing and 
shoes suitable for exercise (eg, no boots or flip flops) for all ETTs.  On the day of the 
treadmill test subjects may consume a light breakfast > 2 hours prior to the ETT.  
Subjects should not use sublingual nitroglycerin ≤ 4 hours prior to the test and should 
not take their antianginal medications on the morning of the scheduled ETT (within 
4 hours of ETT).  All ETTs for a given subject should be performed in approximately the 
same conditions (time, temperature, food intake and caffeine and nicotine consumption 
before the exercise test) with the same investigator who should supervise the ETT 
performance in the same way throughout the study. 
Section: 
7.3.8 Exercise Treadmill Test Scheduling, 2nd and 3rd paragraph 
Replace: 
If the total exercise time (TET) in ETT 1 and ETT 2 differs by > 1 and ≤ 2 minutes, an 
additional screening ETT (ETT 3) may be conducted; ETT 3 should occur within 
> 48 hours and ≤ 14 days after ETT 2 and begin within ± 2 hours of the recorded time at 
which the ETT 2 began.  Subjects may enroll in the trial if there is ≤ 1 minute difference 
in the TET between ETT 2 and ETT 3.  The qualifying ETTs should have associated 
ECGs that have been deemed acceptable by the core ECG laboratory before a subject 
can be randomized. 
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CONFIDENTIAL 
 
 
With: 
If the TET in ETT 1 and ETT 2 differs by > 1 minute or > 20% duration, using the 
longest duration qualifying ETT, an additional screening ETT (ETT 3) must be 
conducted; ETT 3 should occur within > 48 hours and ≤ 14 days after ETT 2 and begin 
within ± 2 hours of the recorded time at which the ETT 2 began.  No more than 
3 screening ETTs can be conducted.  Each ETT should occur within 14 days of 
each other and the total screening period for ETTs should not exceed 28 days. 
Subjects may enroll in the trial if there is ≤ 1 minute difference and ≤ 20% duration 
difference in the TET between the 2 qualifying ETTs performed during screening.  
The qualifying ETTs should have associated ECGs that have been deemed acceptable 
by the core ECG laboratory before a subject can be randomized. 
Section: 
7.3.9.2 Electrocardiograph, 3rd paragraph 
Replace: 
If ST-segment changes occur, run a printout every 30 seconds until resolution.  
Additional exercise ECGs will be obtained per the recovery period schedule as 
appropriate. 
With: 
If ST-segment changes occur, a printout will be run every 30 seconds until resolution.  
Additional exercise ECGs will be obtained per the recovery period schedule as 
appropriate. 
Section: 
7.3.9.3 ST-Segment Depression, Definition 
Replace: 
During exercise, the depth of the ST-segment depression is measured at 60 msec after 
the J-point.   
1 mm ST-segment depression is defined as: 
• 
Horizontal or down-sloping ST depression  
o If the ST level at baseline is above the isoelectric line, the 
isoelectric line is the reference point for measurements 
o If the ST level at baseline is below the isoelectric line, the baseline 
ST level is the reference point for measurements 
o Examples: 
 
If the standing at-rest value is +0.2, then a 1 mm 
ST-segment depression would be reached when the 
subject’s ST value is -1.0 mm 
 
If the standing at-rest value is -0.2, then a 1 mm segment 
depression would be reached when the subject’s ST value 
equals -1.2 mm 
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CONFIDENTIAL 
 
 
With: 
ST-segment depression must occur during exercise performance.  The depth of the 
ST-segment depression is measured at 60 msec after the J-point.   
A ≥ 1 mm ST-segment depression is defined as: 
• 
Horizontal or down-sloping ST depression  
o If the ST level at baseline is above the isoelectric line, the 
isoelectric line is the reference point for measurements 
o If the ST level at baseline is below the isoelectric line, the baseline 
ST level is the reference point for measurements 
o Examples: 
 
If the standing at-rest value is +0.2, then a 1 mm 
ST-segment depression would be reached when the 
subject’s ST value is -1.0 mm 
 
If the standing at-rest value is -0.2, then a 1 mm segment 
depression would be reached when the subject’s ST value 
equals -1.2 mm 
Section: 
7.3.9.3 ST-Segment Depression, Criteria for Stopping 
Replace: 
The following symptoms are reasons for stopping the ETT: 
• 
Unacceptable angina, shortness of breath, or fatigue  
• 
Arrhythmia (eg, sustained ventricular tachycardia, ventricular triplets, high degree 
of ventricular ectopy, heart block, bradyarrythmia) 
With: 
The following symptoms are reasons for stopping the ETT: 
• 
Unacceptable angina (a condition for which the ETT must be interrupted 
because of excessive chest pain, rather than because of exercise 
limitation) 
• 
Shortness of breath or fatigue  
• 
Arrhythmia (eg, sustained ventricular tachycardia, ventricular triplets, high degree 
of ventricular ectopy, heart block, bradyarrythmia) 
Section:   
7.3.11 Collection of Events for Adjudication 
Add: 
Cardiovascular and cerebrovascular events will be collected from the date of 
randomization through the end of the study (12 weeks after last dose of IP) and 
adjudicated in a blinded fashion by an independent clinical events committee (CEC).   
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CONFIDENTIAL 
 
 
Section: 
7.3.12 Laboratory Assessments 
Add: 
All screening and on-study laboratory samples will be processed and sent to the central 
laboratory, unless otherwise noted.  The results of this testing will be maintained in the 
source documents at the site.   
Section: 
7.3.12, Table 3 Analyte Listing, footnotes 
Add: 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood 
urea nitrogen; CK = creatine kinase; CK-MB = creatine kinase MB isoenzyme; 
RBC = red blood cell; SGOT = serum glutamic-oxaloacetic transaminase; 
SGPT = serum glutamic pyruvic transaminase; WBC = white blood cell 
Section: 
7.3.14 Angina Diary 
Replace: 
7.3.13.1 
Angina Diary 
Angina diary will be completed by subjects beginning on the day of Visit 1 and through 
the EOS/ET visit to record angina episodes not occurring during ETTs through EOS 
(refer to Table 1). 
With: 
7.3.14  
Angina Diary 
Angina diary will be completed by subjects beginning on the day of Visit 1 and through 
the EOS/ET visit to record angina episodes not occurring during ETTs (refer to Table 1). 
Section: 
8.3.1   Reasons for Removal From Treatment 
Add: 
Reasons for removal from protocol-required investigational products or procedural 
assessments include any of the following: 
• 
subject request   
• 
safety concern (eg, due to an adverse event, ineligibility determined, protocol 
deviation, non-compliance, pregnancy) 
• 
death 
• 
lost to follow-up 
• 
decision by Sponsor (other than subject request, safety concern, lost to follow-up) 
Section: 
9.1.1 Disease Related Events, 1st paragraph 
Add: 
Disease Related Events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease.  Such events do not meet the 
definition of an adverse event unless assessed to be more severe than expected 
for the subject’s baseline condition.  Disease-related events for the purposes of 
this study include angina pectoris and related symptoms such as chest pain and 
shortness of breath (refer to Section 7.3.10).  Angina pectoris and related 
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CONFIDENTIAL 
 
 
symptoms do not meet the definition of an adverse event unless assessed to be 
more severe than expected relative to the subject’s baseline condition (refer to 
Section 9.1.3). 
Section: 
9.1.1 Disease Related Events, 2nd paragraph 
Delete: 
• 
Death due to the disease under study is to be recorded on the Event CRF 
Angina pectoris does not meet the definition of an adverse event unless assessed to be 
more severe than expected relative to the subject’s baseline condition. 
Section: 
9.1.3 Serious Adverse Events  
Add: 
A disease related event is to be reported as a serious adverse event if: 
• 
the subject’s pre-existing condition becomes worse than what the 
investigator would consider typical for a patient with the same underlying 
condition, or 
• 
if the investigator believes a causal relationship exists between the 
investigational medicinal product(s)/protocol-required therapies and the 
event, 
• 
and the event meets at least 1 of the serious criteria above 
Section: 
9.2.1 Reporting Procedures for Disease Related Events 
Add: 
The investigator is responsible for ensuring that all Disease Related Events observed by 
the investigator are reported by the subject that occur after the first dose of 
investigational medicinal products/study treatment/protocol-required therapies through 
the end of study period (12 weeks after the last dose of IP), are reported using the 
Event CRF.  Additionally, the investigator is required to report a fatal Disease Related 
Event on the Event CRF.   
Section: 
9.2.2.1 Reporting Procedures for Adverse Events That Do Not Meet 
Serious Criteria, 1st and 2nd paragraph 
Add: 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of investigational 
products through the end of study period (12 weeks after the last dose of IP) are 
reported using the Event CRF. 
The investigator must assign the following adverse event attributes: 
• 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
• 
Dates of onset and resolution (if resolved), 
• 
Severity  
• 
Assessment of relatedness to investigational product(s) and/or any study-
mandated activity or procedure, and 
• 
Action taken. 
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CONFIDENTIAL 
 
 
Section: 
9.2.2.1 Reporting Procedures for Adverse Events That Do Not Meet 
Serious Criteria, 4th paragraph 
Add: 
This relationship is indicated by a “yes” or “no” response to the question:  Is there a 
reasonable possibility that the event may have been caused by the investigational 
medicinal products?   
Section: 
9.2.2.2 Reporting Procedures for Serious Adverse Events 
Add: 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through the end of the study period (12 weeks after the last dose of 
investigational product) are recorded in the subject’s medical record and are submitted 
to Amgen, including serious adverse events that are reported to the Event Adjudication 
Committee for adjudication.   
Section: 
9.2.2.4 Serious Adverse Events That Are Not To Be Reported In An 
Expedited Manner  
Add: 
A serious adverse event of stable angina will not be reported in an expedited manner as 
this is anticipated to occur in the study population at some frequency independent of the 
protocol-required therapies.  The Data Monitoring Committee (DMC) will monitor these 
events on an ongoing basis.  As there are no identified risks for AMG 334, all 
adverse events are considered ‘unexpected’ for regulatory reporting purposes. 
Section: 
9.3 
Pregnancy and Lactation Reporting 
Add: 
The pregnancy should be reported to Amgen’s Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C).  Amgen Global Patient Safety will 
follow-up with the investigator regarding additional information that may be 
requested. 
If a lactation case occurs following a female subject’s exposure to protocol-required 
therapies, report the lactation case to Amgen as specified below.  
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur through 12 weeks after a single dose of investigational 
product.   
Any lactation case should be reported to Amgen’s Global Patient Safety within 24 hours 
of the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up 
with the investigator regarding additional information that may be requested.  
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CONFIDENTIAL 
 
 
Section: 
10.5.2 Data Monitoring Committee (DMC) 
Replace: 
10.5.2 Data Monitoring Committee 
A DMC will review and make recommendations regarding the safety of the study 
participants throughout the study.  The DMC will be composed of members with relevant 
expertise.  Safety data will be reviewed and the DMC will advise the study sponsor on 
findings that may impact the conduct of the study. 
With: 
10.5.2 Data Monitoring Committee (DMC) 
An independent DMC has been established to oversee the safety of study 
participants for several AMG 334 Migraine programs, including this study.  The 
DMC will be composed of members with relevant expertise (cardiology, neurology, 
and statistics).  DMC meetings are held approximately every 3 months and ad hoc 
meetings may be requested at any time by either the DMC or the sponsor.  Safety 
data, including adverse events and laboratory data, will be reviewed frequently 
throughout the study, and the DMC will advise the study sponsor on findings that 
may impact the conduct of the study, including a recommendation to terminate 
the study.  All serious unexpected serious adverse reactions will be promptly 
shared with the DMC. 
Section: 
10.5.5 Safety Endpoints, 3rd paragraph  
Delete: 
Subject incidence of all treatment-emergent adverse events will be tabulated by 
treatment groups.  Tables of fatal adverse events, serious adverse events, leading to 
withdrawal from investigational product, treatment-related adverse events, serious 
treatment-related adverse events, adverse events of special interest if any, and Disease 
Related Events also will be provided. 
Section: 
10.5.5 Safety Endpoints, 5th paragraph  
Delete: 
The analyses of selected safety laboratory endpoints will include summary statistics over 
time by treatment group.  Shift tables of the worst on-study safety laboratory toxicity 
based on grade relative to baseline will be tabulated by treatment group.  Tabulations of 
grades ≥ 3 laboratory toxicities will be provided. 
Section: 
12.6 
Publication Policy, 2nd paragraph 
Replace: 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors), which states: 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published.  Authors should meet conditions 1, 2, and 3. 
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CONFIDENTIAL 
 
 
With: 
Authorship of any publications resulting from this study will be determined on the basis 
of the Recommendations for the Conduct, Reporting, Editing, and Publication 
of Scholarly Work in Medical Journals (International Committee of Medical Journal 
Editors, 2013, updated 2014), which states: 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published; (4) agreement to be accountable for all aspects of the 
work in ensuring that questions related to the accuracy or integrity of any part 
of the work are appropriately investigated and resolved.  Authors should meet 
conditions 1, 2, 3, and 4. 
Section: 
13 
References 
Add: 
Amgen. AMG 334 Investigator Brochure, version 5.0. 
Section: 
Appendix A, Additional Safety Assessment Information 
Replace: 
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.2.2.2. 
With: 
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.1.3. 
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CONFIDENTIAL 
 
 
Section: 
Appendix B. Sample Serious Adverse Event Report Form 
Delete:   
 
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CONFIDENTIAL 
 
 
 
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Date:  28 January 2016 
Page 1 of 13 
CONFIDENTIAL 
 
 
Country-specific protocol supplement for the European Union, Voluntary 
Harmonization Procedure Countries 
 
Title:  A Randomized, Double-blind, Placebo-controlled Study to Evaluate the 
Effect of AMG 334 on Exercise Time During a Treadmill Test in Subjects With 
Stable Angina 
Amgen Protocol Number (AMG 334) 20140254 
 
Supplement version # 1: 
28 January 2016 
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CONFIDENTIAL 
 
 
1. 
Explanation of Country-specific Changes to the Protocol 
This supplement to the protocol, dated 28 January 2016, provides language for the 
European Union (EU) Voluntary Harmonization Procedure (VHP) country-specific 
regulatory requirements and other procedures to follow in the execution of the global 
study in the EU VHP countries.  These changes are being made in response to specific 
requests from the VHP coordinator. 
The requests and changes made are as follows: 
• 
Include a summary of clinical safety data (added to Section 2, Background and 
Rationale) 
• 
Require highly effective methods of contraception (updated 
Exclusion Criteria 206) 
• 
Add exclusionary criterion regarding hepatic function (added 
Exclusion Criteria 219) 
• 
Add additional safety assessments and measures (added to Section 7, Study 
Procedures): 
o A 12-lead electrocardiogram conducted and blood pressure measurement 
collected 4 hours after the completion of the Exercise Treadmill Test 
(ETT) on day 1 
o During the ETT, record:  (1) maximum systolic blood pressure, 
(2) maximum heart rate, and (3) maximum ST-segment depression 
o Biomarker sampling for troponin I measurement performed 4 hours after 
the end of the ETT 
o An assessment of anti-AMG 334 antibodies at day 1, week 4, and end of 
study 
o Appropriate measures of emergency assistance (including 
cardiopulmonary resuscitation, access to intensive care unit, and 
specialized interventions such as coronary catheterization) must be 
available 
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CONFIDENTIAL 
 
 
2. 
Summary of Text Changes to Protocol for EU VHP Countries 
The summary of changes outlined below is used to specify the differences from the 
global protocol amendment 3 (27 January 2016) for the EU VHP countries. 
Section: 
4.1.2.2  Reproductive (Exclusion Criteria) 
Text in global protocol: 
206 
Females of reproductive potential who are not willing to use acceptable 
method(s) of effective birth control during treatment with AMG 334 and for an 
additional 12 weeks after receiving a single dose of AMG 334 
• 
Acceptable methods of effective contraception  include: true sexual 
abstinence when this is in line with the preferred and usual lifestyle of the 
subject [periodic abstinence (eg, calendar, ovulation, symptothermal, 
post-ovulation methods), declaration of abstinence for the duration of the 
study, and withdrawal are not acceptable methods of contraception], or use of 
hormonal birth control methods (oral, implantable, injectable, transdermal, 
intravaginal), intrauterine devices (IUDs), intrauterine hormonal-releasing 
system (IUS), surgical contraceptive methods (vasectomy with medical 
assessment of the surgical success of this procedure or bilateral tubal 
ligation), or two (2) barrier methods (one by each partner and at least one of 
the barrier methods must include spermicide (unless spermicide is not 
approved in the country or region) - the male must use a condom and the 
female must choose either a diaphragm OR cervical cap, OR contraceptive 
sponge  (a male and female condom cannot be used together due to the risk 
of tearing). 
New text for EU VHP Countries: 
206 
Females of reproductive potential who are not willing to use highly effective 
methods of birth control during treatment with AMG 334 and for an additional 
12 weeks after receiving a single dose of AMG 334 
• 
Highly effective methods of contraception as per Clinical Trial Facilitation 
Group recommendations include:  
• 
Combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation: 
o oral 
o intravaginal 
o transdermal 
• 
Progestogen-only hormonal contraception associated with 
inhibition of ovulation: 
o oral 
o injectable 
o implantable 
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CONFIDENTIAL 
 
 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner (with medical assessment of the surgical 
success of this procedure) 
• 
Sexual abstinence 
Section: 
4.1.2.6  Hepatic (Exclusion Criteria, new section) 
Add text for VHP countries: 
4.1.2.6  
Hepatic 
219 
Hepatic disease by history or total bilirubin ≥ 2.0 x upper limit of normal 
(ULN) or alanine transaminase (ALT) or aspartate aminotransferase (AST) 
≥ 3.0 x ULN, as assessed by the central laboratory at initial screening. 
 
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CONFIDENTIAL 
 
 
Section: 
7.1  Schedule of Assessments, Table 1 
Text in global protocol: 
Procedure 
Screening Period (up to 6 weeks) 
On-Study Period (12 weeks) 
EOS/ET 
Screening Visitsi 
On-Study Visitsi 
Visit 1 
Visit 2 
Visit 3 
Visit 4k 
Day 1 
Pre-dosea 
Day 1 Post-
dose 
Week 2h 
Week 4 
Week 8 
Week 12 
General and Safety Assessments 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Physical Examination, including weight 
X 
 
 
 
 
 
 
 
 
X 
Targeted Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Randomizationb 
 
 
 
 
X 
 
 
 
 
 
Columbia-Suicide Severity Rating Scale 
X 
 
 
 
X 
 
 
X 
X 
X 
ETTc 
 
Xc 
Xc 
Xc 
 
X 
 
 
 
 
Blood Pressure, Heart Rated 
X 
 
 
 
X 
X 
 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
Record Continuously 
X 
Serious Adverse Events 
X 
Record Continuously 
X 
Adverse Events and Disease Related Events 
 
 
 
 
 
X 
Record Continuously 
X 
Collection of Events for Adjudication 
 
 
 
 
 
X 
Record Continuously 
X 
Angina diarye 
 
Record Continuously 
 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
Hematology, Chemistry  
(central laboratory) 
X 
 
 
 
X 
 
 
 
 
X 
Hepatitis Sample Collection 
X 
 
 
 
 
 
 
 
 
 
Urine pregnancy testf  
(females of reproductive potential) 
X 
 
 
 
X 
 
 
 
 
X 
Pharmacokinetic Sampling 
 
 
 
 
 
Xg 
 
 
 
 
Biomarker Sampling 
 
 
 
 
X 
 
 
 
 
 
Urine drug screenj 
X 
 
 
 
 
 
 
 
 
 
Dosing 
 
 
 
 
 
 
 
 
 
 
AMG 334 or Placebo 
 
 
 
 
 
X 
 
 
 
 
Footnotes defined on next page. 
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CONFIDENTIAL 
 
 
ECG = electrocardiogram; EOS = end of study; ET = early termination; ETT = Exercise Treadmill Test; PK = pharmacokinetic.  
a Pre-dose assessments should be conducted on day 1 prior to randomization. 
b Week 1 begins on the date of randomization.  Study day 1 is defined as the date investigational product is received.  
c During the screening period, two ETTs are required > 48 hours and ≤ 14 days apart that meet inclusion criteria, and they will be reviewed by a core ECG laboratory to 
confirm eligibility.  No more than 3 ETTs can be performed during the screening period.  Each ETT should occur within 14 days of each other and the total screening 
period for ETTs should not exceed 28 days. 
d Blood pressure and heart rate should be assessed at all visits following the standard procedure.  During ETT visits, the standard procedure will be conducted prior to 
the ETT; blood pressure assessments will also be conducted following the monitoring procedure described for the ETT. 
e Angina diary will be completed by subjects beginning on the day of Visit 1 and through the EOS/ET visit to  record angina episodes not occurring during ETTs. 
f Results of pre-dose pregnancy test must be reviewed prior to administration of investigational product on day 1.  
g PK sample to be drawn on day 1 after completion of exercise treadmill test post-randomization (ETTr). 
h Visit at week 2 can be done via telephone contact. 
i Study visit windows are ± 1 week.  
j Urine drug screen may also be performed as needed throughout the study per investigator judgment. 
k Optional Visit 4 to be performed if ETT3 is required for eligibility determination. 
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CONFIDENTIAL 
 
 
Section: 
7.1  Schedule of Assessments, Table 1 
New text for EU VHP Countries: 
Procedure 
Screening Period (up to 6 weeks) 
On-Study Period (12 weeks) 
EOS/ET 
Screening Visitsk 
On-Study Visitsk 
Visit 1 
Visit 2 
Visit 3 
Visit 4m 
Day 1 
Pre-dosea 
Day 1 Post-
dose 
Week 2j 
Week 4 
Week 8 
Week 12 
General and Safety Assessments 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Physical Examination, including weight 
X 
 
 
 
 
 
 
 
 
X 
Targeted Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Randomizationb 
 
 
 
 
X 
 
 
 
 
 
Columbia-Suicide Severity Rating Scale 
X 
 
 
 
X 
 
 
X 
X 
X 
ETTc 
 
Xc 
Xc 
Xc 
 
X 
 
 
 
 
Blood Pressure, Heart Rated 
X 
 
 
 
X 
X 
 
X 
X 
X 
ECG 
X 
 
 
 
 
Xe 
 
 
 
 
Concomitant Medications 
X 
Record Continuously 
X 
Serious Adverse Events 
X 
Record Continuously 
X 
Adverse Events and Disease Related Events 
 
 
 
 
 
X 
Record Continuously 
X 
Collection of Events for Adjudication 
 
 
 
 
 
X 
Record Continuously 
X 
Angina diaryf 
 
Record Continuously 
 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
Hematology, Chemistry  
(central laboratory) 
X 
 
 
 
X 
 
 
 
 
X 
Hepatitis Sample Collection 
X 
 
 
 
 
 
 
 
 
 
Urine pregnancy testg  
(females of reproductive potential) 
X 
 
 
 
X 
 
 
 
 
X 
Pharmacokinetic Sampling 
 
 
 
 
 
Xh 
 
 
 
 
Biomarker Sampling 
 
 
 
 
 
Xi 
 
 
 
 
Anti-AMG 334 antibodies 
 
 
 
 
X 
 
 
X 
 
X 
Urine drug screenl 
X 
 
 
 
 
 
 
 
 
 
Dosing 
 
 
 
 
 
 
 
 
 
 
AMG 334 or Placebo 
 
 
 
 
 
X 
 
 
 
 
Footnotes defined on next page. 
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Page 8 of 13 
CONFIDENTIAL 
 
 
ECG = electrocardiogram; EOS = end of study; ET = early termination; ETT = Exercise Treadmill Test; PK = pharmacokinetic.  
a Pre-dose assessments should be conducted on day 1 prior to randomization. 
b Week 1 begins on the date of randomization.  Study day 1 is defined as the date investigational product is received. 
c During the screening period, 2 ETTs are required > 48 hours and ≤ 14 days apart that meet inclusion criteria, and they will be reviewed by a core ECG laboratory to 
confirm eligibility.  No more than 3 ETTs can be performed during the screening period.  Each ETT should occur within 14 days of each other and the total screening 
period for ETTs should not exceed 28 days. 
d Blood pressure and heart rate should be assessed at all visits following the standard procedure.  During ETT visits, the standard procedure will be conducted prior to 
the ETT; blood pressure assessments will also be conducted following the monitoring procedure described for the ETT. 
e ECG will be performed 4 hours after the end of the ETT. 
f Angina diary will be completed by subjects beginning on the day of Visit 1 and through the EOS/ET visit to record angina episodes not occurring during ETTs. 
g Results of pre-dose pregnancy test must be reviewed prior to administration of investigational product on day 1. 
h PK sample to be drawn on day 1 after completion of exercise treadmill test post-randomization (ETTr). 
i Biomarker sampling for troponin I measurement will be performed 4 hours after the end of the ETT. 
j Visit at week 2 can be done via telephone contact. 
k Study visit windows are ± 1 week. 
l Urine drug screen may also be performed as needed throughout the study per investigator judgment. 
m Optional Visit 4 to be performed if ETT 3 is required for eligibility determination. 
 
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CONFIDENTIAL 
 
 
Section: 
7.3.7  Exercise Treadmill Test 
Text in global protocol: 
The ETT will be conducted using the standard Bruce protocol.  A motor-driven treadmill 
should be utilized under uniform conditions, optimally by the same technician and 
supervising physician for each ETT.  The subject should wear comfortable clothing and 
shoes suitable for exercise (eg, no boots or flip flops) for all ETTs.  On the day of the 
treadmill test subjects may consume a light breakfast > 2 hours prior to the ETT.  
Subjects should not use sublingual nitroglycerin ≤ 4 hours prior to the test.  All ETTs for 
a given subject should be performed in approximately the same conditions (time, 
temperature, food intake and caffeine and nicotine consumption before the exercise test) 
with the same investigator who should supervise the ETT performance in the same way 
throughout the study.  Subjects may touch the treadmill bars or handles lightly to assist 
with balance, however they must not be allowed to hold onto or lean on the treadmill 
bars or handles during the ETT.  The appropriate site staff should examine all ECG 
tracings and ETT records to ensure subject safety. 
Add text for EU VHP countries: 
The ETT will be conducted using the standard Bruce protocol.  A motor-driven treadmill 
should be utilized under uniform conditions, optimally by the same technician and 
supervising physician for each ETT.  The subject should wear comfortable clothing and 
shoes suitable for exercise (eg, no boots or flip flops) for all ETTs.  On the day of the 
treadmill test subjects may consume a light breakfast > 2 hours prior to the ETT.  
Subjects should not use sublingual nitroglycerin ≤ 4 hours prior to the test.  All ETTs for 
a given subject should be performed in approximately the same conditions (time, 
temperature, food intake and caffeine and nicotine consumption before the exercise test) 
with the same investigator who should supervise the ETT performance in the same way 
throughout the study.  Subjects may touch the treadmill bars or handles lightly to assist 
with balance, however they must not be allowed to hold onto or lean on the treadmill 
bars or handles during the ETT.  The appropriate site staff should examine all ECG 
tracings and ETT records to ensure subject safety.  Appropriate measures of 
emergency assistance (including cardiopulmonary resuscitation, access to 
intensive care unit, and specialized interventions such as coronary 
catheterization) must be available. 
 
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CONFIDENTIAL 
 
 
Section: 
7.3.9.1  Blood Pressure 
Text in global protocol: 
In addition to the standard blood pressure assessments conducted at each visit, during 
all ETTs blood pressure should be recorded as follows: 
• 
Prior to the ETT 
• 
In a standing position after 2 minutes of standing 
• 
Within 30 seconds prior to each change in stage and at peak exercise during the 
ETT, in a standing position 
• 
At the end of the ETT in a sitting position 
• 
During recovery in a sitting position, every minute for 5 minutes after the end of 
the ETT, then every 5 minutes, as needed, until values return to near baseline 
values, per the judgment of the investigator. 
Add text for EU VHP countries: 
In addition to the standard blood pressure assessments conducted at each visit, during 
all ETTs blood pressure should be recorded as follows: 
• 
Prior to the ETT 
• 
In a standing position after 2 minutes of standing 
• 
Within 30 seconds prior to each change in stage and at peak exercise during the 
ETT, in a standing position 
• 
At the end of the ETT in a sitting position 
• 
During recovery in a sitting position, every minute for 5 minutes after the end of 
the ETT, then every 5 minutes, as needed, until values return to near baseline 
values, per the judgment of the investigator 
• 
Maximum SBP during the ETT will be recorded 
Section: 
7.3.9.2  Electrocardiograph, 3rd paragraph 
Text in global protocol: 
If ST-segment changes occur, a printout will be run every 30 seconds until resolution.  
Additional exercise ECGs will be obtained per the recovery period schedule as 
appropriate. 
Add text for EU VHP countries: 
If ST-segment changes occur, a printout will be run every 30 seconds until resolution.  
Additional exercise ECGs will be obtained per the recovery period schedule as 
appropriate.  Maximum heart rate and maximum ST-segment depression during 
ETT will be recorded. 
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Page 11 of 13 
CONFIDENTIAL 
 
 
After the ETTr, all subjects will be followed up at the site for at least 4 hours.  At 
the end of the 4-hour follow-up period, the following procedures will be 
performed: 
• 
12-lead rest ECG in a sitting position 
• 
Blood pressure measurement in a sitting position 
• 
Blood sampling for measurement of troponin I 
Subjects can be kept at the site for longer than 4 hours at the discretion of the 
investigator. 
Section: 
7.3.12  Laboratory Assessments, Table 3 
Text in global protocol: 
Chemistry 
Sodium 
Potassium 
Chloride  
Bicarbonate 
Total protein 
Albumin 
Calcium 
Adjusted calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
AST (SGOT) 
ALT (SGPT) 
Hematology 
WBC 
RBC 
Hemoglobin 
Hematocrit 
Platelets 
WBC Differential 
• 
Bands/stabs 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Neutrophils 
 
Other Labs 
Hepatitis B surface antigen  
Hepatitis B core antibody 
Hepatitis C virus antibody 
 
PK 
Cardiac biomarkers 
• 
Troponin-I 
• 
CK 
• 
CK-MB 
Urine drug screen 
Urine pregnancy test (local) 
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Date:  28 January 2016 
Page 12 of 13 
CONFIDENTIAL 
 
 
New text for EU VHP countries: 
Chemistry 
Sodium 
Potassium 
Chloride  
Bicarbonate 
Total protein 
Albumin 
Calcium 
Adjusted calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
AST (SGOT) 
ALT (SGPT) 
Hematology 
WBC 
RBC 
Hemoglobin 
Hematocrit 
Platelets 
WBC Differential 
• 
Bands/stabs 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Neutrophils 
 
Other Labs 
Hepatitis B surface antigen  
Hepatitis B core antibody 
Hepatitis C virus antibody 
 
PK 
Cardiac biomarkers 
• 
Troponin-I 
Urine drug screen 
Urine pregnancy test (local) 
Anti-AMG 334 antibodies 
(Amgen/designee) 
Section: 
7.3.15  Anti-AMG 334 Antibody Analysis 
Text in global protocol: 
Not applicable. 
Text for EU VHP countries: 
7.3.15  
Anti-AMG 334 Antibody Analysis 
Blood samples will be collected for the measurement of anti-AMG 334 binding 
antibodies at the following time points:  before dose on day 1, week 4, EOS, and at 
additional time points as needed (see Table 1).  Samples testing positive for 
binding antibodies will also be tested for neutralizing antibodies and may be 
further characterized for quantity/titer, isotype, affinity, and/or presence of 
immune complexes.  Additional blood samples may be obtained to rule out 
anti-AMG 334 antibodies during the study.  Subjects who test positive for 
neutralizing antibodies to AMG 334 at the final scheduled study visit will be asked 
to return for additional follow-up testing.  This testing should occur approximately 
every 3 months starting from when the site has been notified of the positive result, 
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Date:  28 January 2016 
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CONFIDENTIAL 
 
 
until:  (1) neutralizing antibodies are no longer detectable or (2) the subject has 
been followed for a period of at least 1 year (± 4 weeks).  More frequent testing 
(eg, every month), or testing for a longer period of time may be requested in the 
event of safety-related concerns.  Follow-up testing will not be required where it is 
established that the subject did not receive AMG 334.  Subjects who test positive 
for binding, non-neutralizing antibodies and have clinical sequelae that are 
considered potentially related to an anti-AMG 334 antibody response may also be 
asked to return for additional follow-up testing. 
Section: 
7.4  Biomarkers, 3rd paragraph 
Text in global protocol: 
Blood samples are to be collected at the following time points: day 1 pre-dose for all 
subjects to enable testing of baseline cardiac markers (eg, troponin) or other safety 
measures, if needed. 
New text for EU VHP countries: 
Blood samples are to be collected at day 1 post-ETT (4 hours) for all subjects to enable 
testing of troponin I or other safety measures, if needed. 
Section: 
10.5.5  Safety Endpoints, 6th paragraph 
Text in global protocol: 
The analyses of vital signs will include summary statistics over time by treatment group. 
Add text for EU VHP countries: 
The analyses of vital signs will include summary statistics over time by treatment group.  
Specifically, change from baseline in maximum SBP, maximum heart rate, and 
maximum ST-segment depression (mm) on day 1 post dose will be summarized by 
treatment group. 
The incidence and percentage of subjects who develop anti-AMG 334 antibodies 
(binding and if positive, neutralizing) at any time will be tabulated by treatment 
group. 
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Protocol Number:  20140254 (Supplement version 3) 
Date:  14 November 2016 
Page 1 of 19 
CONFIDENTIAL 
 
 
Country-specific Protocol Supplement for Specific European Union Countries 
Title:  A Randomized, Double-blind, Placebo-controlled Study to Evaluate the 
Effect of AMG 334 on Exercise Time During a Treadmill Test in Subjects With 
Stable Angina 
Amgen Protocol Number (AMG 334) 20140254 
 
Supplement version # 1: 
28 January 2016 
Supplement version # 2: 
28 October 2016 
Supplement version # 3: 
14 November 2016 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN, Canadian sites, 
1-866-50-AMGEN; <<for all other countries, insert the local toll-free Medical Information 
number>> Amgen’s general number in the US (1-805-447-1000).  
 
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CONFIDENTIAL 
 
 
1. 
Overview of Country-specific Changes to the Protocol 
This supplement (dated 14 November 2016) to the protocol amendment 4, dated 
28 October 2016, provides language for European Union (EU) country-specific 
procedures to follow in the execution of the global study in the specified EU countries.   
Three supplements have been prepared: 
Supplement version # 1, protocol amendment 3: 28 January 2016 
Supplement version # 2, protocol amendment 4: 28 October 2016 
Supplement version # 3, protocol amendment 4: 14 November 2016 
1.1 
Supplement #1 
1.1.1 
Explanation of Country-specific Changes to the Protocol 
(Supplement #1) 
Protocol amendment 3 was amended primarily to include the requested Voluntary 
Harmonization Procedure (VHP) changes as a supplement to the study protocol, 
ensuring the core body of the protocol remains the same for all participating countries 
including those outside of the VHP. Supplement version number 1 incorporated those 
changes which were made in response to specific requests during the VHP procedure. 
The requests and changes made are as follows for supplement version # 1 dated 
28 January 2016 as previously provided with protocol amendment 3: 
• 
Include a summary of clinical safety data (added to Section 2, Background and 
Rationale) 
• 
Require highly effective methods of contraception (updated 
Exclusion Criteria 206) 
• 
Add exclusionary criterion regarding hepatic function (added 
Exclusion Criteria 219) 
• 
Add additional safety assessments and measures (added to Section 7, Study 
Procedures): 
o A 12-lead electrocardiogram conducted and blood pressure measurement 
collected 4 hours after the completion of the Exercise Treadmill Test 
(ETT) on day 1 
o During the ETT, record:  (1) maximum systolic blood pressure, 
(2) maximum heart rate, and (3) maximum ST-segment depression 
o Biomarker sampling for troponin I measurement performed 4 hours after 
the end of the ETT 
o An assessment of anti-AMG 334 antibodies at day 1, week 4, and end of 
study 
o Appropriate measures of emergency assistance (including 
cardiopulmonary resuscitation, access to intensive care unit, and 
specialized interventions such as coronary catheterization) must be 
available 
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CONFIDENTIAL 
 
 
1.1.2 
Summary of Text Changes to Protocol for EU VHP Countries for 
Supplement #1 
The summary of changes outlined below is used to specify the differences from the 
global protocol amendment 3 (27 January 2016) for the EU VHP countries. 
Section:  4.1.2.2  Reproductive (Exclusion Criteria) 
Text in global protocol: 
206 
Females of reproductive potential who are not willing to use acceptable 
method(s) of effective birth control during treatment with AMG 334 and for an 
additional 12 weeks after receiving a single dose of AMG 334 
• 
Acceptable methods of effective contraception  include: true sexual 
abstinence when this is in line with the preferred and usual lifestyle of the 
subject [periodic abstinence (eg, calendar, ovulation, symptothermal, 
post-ovulation methods), declaration of abstinence for the duration of the 
study, and withdrawal are not acceptable methods of contraception], or use of 
hormonal birth control methods (oral, implantable, injectable, transdermal, 
intravaginal), intrauterine devices (IUDs), intrauterine hormonal-releasing 
system (IUS), surgical contraceptive methods (vasectomy with medical 
assessment of the surgical success of this procedure or bilateral tubal 
ligation), or two (2) barrier methods (one by each partner and at least one of 
the barrier methods must include spermicide (unless spermicide is not 
approved in the country or region) - the male must use a condom and the 
female must choose either a diaphragm OR cervical cap, OR contraceptive 
sponge  (a male and female condom cannot be used together due to the risk 
of tearing). 
New text for EU VHP Countries: 
206 
Females of reproductive potential who are not willing to use highly effective 
methods of birth control during treatment with AMG 334 and for an additional 
12 weeks after receiving a single dose of AMG 334 
• 
Highly effective methods of contraception as per Clinical Trial Facilitation 
Group recommendations include:  
• 
Combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation: 
o oral 
o intravaginal 
o transdermal 
• 
Progestogen-only hormonal contraception associated with 
inhibition of ovulation: 
o oral 
o injectable 
o implantable 
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CONFIDENTIAL 
 
 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner (with medical assessment of the surgical 
success of this procedure) 
• 
Sexual abstinence 
Section:  4.1.2.6  Hepatic (Exclusion Criteria, new section) 
Add text for VHP countries: 
4.1.2.6  
Hepatic 
219 
Hepatic disease by history or total bilirubin ≥ 2.0 x upper limit of normal 
(ULN) or alanine transaminase (ALT) or aspartate aminotransferase (AST) 
≥ 3.0 x ULN, as assessed by the central laboratory at initial screening. 
 
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CONFIDENTIAL 
 
 
Section:  7.1  Schedule of Assessments, Table 1 
Text in global protocol: 
Procedure 
Screening Period (up to 6 weeks) 
On-Study Period (12 weeks) 
EOS/ET 
Screening Visitsi 
On-Study Visitsi 
Visit 1 
Visit 2 
Visit 3 
Visit 4k 
Day 1 
Pre-dosea 
Day 1 Post-
dose 
Week 2h 
Week 4 
Week 8 
Week 12 
General and Safety Assessments 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Physical Examination, including weight 
X 
 
 
 
 
 
 
 
 
X 
Targeted Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Randomizationb 
 
 
 
 
X 
 
 
 
 
 
Columbia-Suicide Severity Rating Scale 
X 
 
 
 
X 
 
 
X 
X 
X 
ETTc 
 
Xc 
Xc 
Xc 
 
X 
 
 
 
 
Blood Pressure, Heart Rated 
X 
 
 
 
X 
X 
 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
Record Continuously 
X 
Serious Adverse Events 
X 
Record Continuously 
X 
Adverse Events and Disease Related Events 
 
 
 
 
 
X 
Record Continuously 
X 
Collection of Events for Adjudication 
 
 
 
 
 
X 
Record Continuously 
X 
Angina diarye 
 
Record Continuously 
 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
Hematology, Chemistry  
(central laboratory) 
X 
 
 
 
X 
 
 
 
 
X 
Hepatitis Sample Collection 
X 
 
 
 
 
 
 
 
 
 
Urine pregnancy testf  
(females of reproductive potential) 
X 
 
 
 
X 
 
 
 
 
X 
Pharmacokinetic Sampling 
 
 
 
 
 
Xg 
 
 
 
 
Biomarker Sampling 
 
 
 
 
X 
 
 
 
 
 
Urine drug screenj 
X 
 
 
 
 
 
 
 
 
 
Dosing 
 
 
 
 
 
 
 
 
 
 
AMG 334 or Placebo 
 
 
 
 
 
X 
 
 
 
 
Footnotes defined on next page. 
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CONFIDENTIAL 
 
 
ECG = electrocardiogram; EOS = end of study; ET = early termination; ETT = Exercise Treadmill Test; PK = pharmacokinetic.  
a Pre-dose assessments should be conducted on day 1 prior to randomization. 
b Week 1 begins on the date of randomization.  Study day 1 is defined as the date investigational product is received.  
c During the screening period, two ETTs are required > 48 hours and ≤ 14 days apart that meet inclusion criteria, and they will be reviewed by a core ECG laboratory to 
confirm eligibility.  No more than 3 ETTs can be performed during the screening period.  Each ETT should occur within 14 days of each other and the total screening 
period for ETTs should not exceed 28 days. 
d Blood pressure and heart rate should be assessed at all visits following the standard procedure.  During ETT visits, the standard procedure will be conducted prior to 
the ETT; blood pressure assessments will also be conducted following the monitoring procedure described for the ETT. 
e Angina diary will be completed by subjects beginning on the day of Visit 1 and through the EOS/ET visit to  record angina episodes not occurring during ETTs. 
f Results of pre-dose pregnancy test must be reviewed prior to administration of investigational product on day 1.  
g PK sample to be drawn on day 1 after completion of exercise treadmill test post-randomization (ETTr). 
h Visit at week 2 can be done via telephone contact. 
i Study visit windows are ± 1 week.  
j Urine drug screen may also be performed as needed throughout the study per investigator judgment. 
k Optional Visit 4 to be performed if ETT3 is required for eligibility determination. 
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Date:  14 November 2016 
Page 7 of 19 
CONFIDENTIAL 
 
 
Section:  7.1  Schedule of Assessments, Table 1 
New text for EU VHP Countries: 
Procedure 
Screening Period (up to 6 weeks) 
On-Study Period (12 weeks) 
EOS/ET 
Screening Visitsk 
On-Study Visitsk 
Visit 1 
Visit 2 
Visit 3 
Visit 4m 
Day 1 
Pre-dosea 
Day 1 Post-
dose 
Week 2j 
Week 4 
Week 8 
Week 12 
General and Safety Assessments 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Physical Examination, including weight 
X 
 
 
 
 
 
 
 
 
X 
Targeted Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Randomizationb 
 
 
 
 
X 
 
 
 
 
 
Columbia-Suicide Severity Rating Scale 
X 
 
 
 
X 
 
 
X 
X 
X 
ETTc 
 
Xc 
Xc 
Xc 
 
X 
 
 
 
 
Blood Pressure, Heart Rated 
X 
 
 
 
X 
X 
 
X 
X 
X 
ECG 
X 
 
 
 
 
Xe 
 
 
 
 
Concomitant Medications 
X 
Record Continuously 
X 
Serious Adverse Events 
X 
Record Continuously 
X 
Adverse Events and Disease Related Events 
 
 
 
 
 
X 
Record Continuously 
X 
Collection of Events for Adjudication 
 
 
 
 
 
X 
Record Continuously 
X 
Angina diaryf 
 
Record Continuously 
 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
Hematology, Chemistry  
(central laboratory) 
X 
 
 
 
X 
 
 
 
 
X 
Hepatitis Sample Collection 
X 
 
 
 
 
 
 
 
 
 
Urine pregnancy testg  
(females of reproductive potential) 
X 
 
 
 
X 
 
 
 
 
X 
Pharmacokinetic Sampling 
 
 
 
 
 
Xh 
 
 
 
 
Biomarker Sampling 
 
 
 
 
 
Xi 
 
 
 
 
Anti-AMG 334 antibodies 
 
 
 
 
X 
 
 
X 
 
X 
Urine drug screenl 
X 
 
 
 
 
 
 
 
 
 
Dosing 
 
 
 
 
 
 
 
 
 
 
AMG 334 or Placebo 
 
 
 
 
 
X 
 
 
 
 
Footnotes defined on next page. 
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Date:  14 November 2016 
Page 8 of 19 
CONFIDENTIAL 
 
 
ECG = electrocardiogram; EOS = end of study; ET = early termination; ETT = Exercise Treadmill Test; PK = pharmacokinetic.  
a Pre-dose assessments should be conducted on day 1 prior to randomization. 
b Week 1 begins on the date of randomization.  Study day 1 is defined as the date investigational product is received. 
c During the screening period, 2 ETTs are required > 48 hours and ≤ 14 days apart that meet inclusion criteria, and they will be reviewed by a core ECG laboratory to 
confirm eligibility.  No more than 3 ETTs can be performed during the screening period.  Each ETT should occur within 14 days of each other and the total screening 
period for ETTs should not exceed 28 days. 
d Blood pressure and heart rate should be assessed at all visits following the standard procedure.  During ETT visits, the standard procedure will be conducted prior to 
the ETT; blood pressure assessments will also be conducted following the monitoring procedure described for the ETT. 
e ECG will be performed 4 hours after the end of the ETT. 
f Angina diary will be completed by subjects beginning on the day of Visit 1 and through the EOS/ET visit to record angina episodes not occurring during ETTs. 
g Results of pre-dose pregnancy test must be reviewed prior to administration of investigational product on day 1. 
h PK sample to be drawn on day 1 after completion of exercise treadmill test post-randomization (ETTr). 
i Biomarker sampling for troponin I measurement will be performed 4 hours after the end of the ETT. 
j Visit at week 2 can be done via telephone contact. 
k Study visit windows are ± 1 week. 
l Urine drug screen may also be performed as needed throughout the study per investigator judgment. 
m Optional Visit 4 to be performed if ETT 3 is required for eligibility determination. 
 
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CONFIDENTIAL 
 
 
Section:  7.3.7  Exercise Treadmill Test 
Text in global protocol: 
The ETT will be conducted using the standard Bruce protocol.  A motor-driven treadmill 
should be utilized under uniform conditions, optimally by the same technician and 
supervising physician for each ETT.  The subject should wear comfortable clothing and 
shoes suitable for exercise (eg, no boots or flip flops) for all ETTs.  On the day of the 
treadmill test subjects may consume a light breakfast > 2 hours prior to the ETT.  
Subjects should not use sublingual nitroglycerin ≤ 4 hours prior to the test.  All ETTs for 
a given subject should be performed in approximately the same conditions (time, 
temperature, food intake and caffeine and nicotine consumption before the exercise test) 
with the same investigator who should supervise the ETT performance in the same way 
throughout the study.  Subjects may touch the treadmill bars or handles lightly to assist 
with balance, however they must not be allowed to hold onto or lean on the treadmill 
bars or handles during the ETT.  The appropriate site staff should examine all ECG 
tracings and ETT records to ensure subject safety. 
Add text for EU VHP countries: 
The ETT will be conducted using the standard Bruce protocol.  A motor-driven treadmill 
should be utilized under uniform conditions, optimally by the same technician and 
supervising physician for each ETT.  The subject should wear comfortable clothing and 
shoes suitable for exercise (eg, no boots or flip flops) for all ETTs.  On the day of the 
treadmill test subjects may consume a light breakfast > 2 hours prior to the ETT.  
Subjects should not use sublingual nitroglycerin ≤ 4 hours prior to the test.  All ETTs for 
a given subject should be performed in approximately the same conditions (time, 
temperature, food intake and caffeine and nicotine consumption before the exercise test) 
with the same investigator who should supervise the ETT performance in the same way 
throughout the study.  Subjects may touch the treadmill bars or handles lightly to assist 
with balance, however they must not be allowed to hold onto or lean on the treadmill 
bars or handles during the ETT.  The appropriate site staff should examine all ECG 
tracings and ETT records to ensure subject safety.  Appropriate measures of 
emergency assistance (including cardiopulmonary resuscitation, access to 
intensive care unit, and specialized interventions such as coronary 
catheterization) must be available. 
Product: 
Date: 
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CONFIDENTIAL 
 
 
Section:  7.3.9.1  Blood Pressure 
Text in global protocol: 
In addition to the standard blood pressure assessments conducted at each visit, during 
all ETTs blood pressure should be recorded as follows: 
• 
Prior to the ETT 
• 
In a standing position after 2 minutes of standing 
• 
Within 30 seconds prior to each change in stage and at peak exercise during the 
ETT, in a standing position 
• 
At the end of the ETT in a sitting position 
• 
During recovery in a sitting position, every minute for 5 minutes after the end of 
the ETT, then every 5 minutes, as needed, until values return to near baseline 
values, per the judgment of the investigator. 
Add text for EU VHP countries: 
In addition to the standard blood pressure assessments conducted at each visit, during 
all ETTs blood pressure should be recorded as follows: 
• 
Prior to the ETT 
• 
In a standing position after 2 minutes of standing 
• 
Within 30 seconds prior to each change in stage and at peak exercise during the 
ETT, in a standing position 
• 
At the end of the ETT in a sitting position 
• 
During recovery in a sitting position, every minute for 5 minutes after the end of 
the ETT, then every 5 minutes, as needed, until values return to near baseline 
values, per the judgment of the investigator 
• 
Maximum SBP during the ETT will be recorded 
Section:  7.3.9.2  Electrocardiograph, 3rd paragraph 
Text in global protocol: 
If ST-segment changes occur, a printout will be run every 30 seconds until resolution.  
Additional exercise ECGs will be obtained per the recovery period schedule as 
appropriate. 
Add text for EU VHP countries: 
If ST-segment changes occur, a printout will be run every 30 seconds until resolution.  
Additional exercise ECGs will be obtained per the recovery period schedule as 
appropriate.  Maximum heart rate and maximum ST-segment depression during 
ETT will be recorded. 
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Page 11 of 19 
CONFIDENTIAL 
 
 
After the ETTr, all subjects will be followed up at the site for at least 4 hours.  At 
the end of the 4-hour follow-up period, the following procedures will be 
performed: 
• 
12-lead rest ECG in a sitting position 
• 
Blood pressure measurement in a sitting position 
• 
Blood sampling for measurement of troponin I 
Subjects can be kept at the site for longer than 4 hours at the discretion of the 
investigator. 
Section:  7.3.12  Laboratory Assessments, Table 3 
Text in global protocol: 
Sodium 
Chemistry 
Potassium 
Chloride  
Bicarbonate 
Total protein 
Albumin 
Calcium 
Adjusted calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
AST (SGOT) 
ALT (SGPT) 
WBC 
Hematology 
RBC 
Hemoglobin 
Hematocrit 
Platelets 
WBC Differential 
• 
Bands/stabs 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Neutrophils 
 
Hepatitis B surface antigen  
Other Labs 
Hepatitis B core antibody 
Hepatitis C virus antibody 
 
PK 
Cardiac biomarkers 
• 
Troponin-I 
• 
CK 
• 
CK-MB 
Urine drug screen 
Urine pregnancy test (local) 
Product: 
Date: 
AMG 334
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Protocol Number:  20140254 (Supplement version 3) 
Date:  14 November 2016 
Page 12 of 19 
CONFIDENTIAL 
 
 
New text for EU VHP countries: 
Sodium 
Chemistry 
Potassium 
Chloride  
Bicarbonate 
Total protein 
Albumin 
Calcium 
Adjusted calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin 
Alkaline phosphatase 
AST (SGOT) 
ALT (SGPT) 
WBC 
Hematology 
RBC 
Hemoglobin 
Hematocrit 
Platelets 
WBC Differential 
• 
Bands/stabs 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Neutrophils 
 
Hepatitis B surface antigen  
Other Labs 
Hepatitis B core antibody 
Hepatitis C virus antibody 
 
PK 
Cardiac biomarkers 
• 
Troponin-I 
Urine drug screen 
Urine pregnancy test (local) 
Anti-AMG 334 antibodies 
(Amgen/designee) 
Section:  7.3.15  Anti-AMG 334 Antibody Analysis 
Text in global protocol: 
Not applicable. 
Text for EU VHP countries: 
7.3.15  
Anti-AMG 334 Antibody Analysis 
Blood samples will be collected for the measurement of anti-AMG 334 binding 
antibodies at the following time points:  before dose on day 1, week 4, EOS, and at 
additional time points as needed (see Table 1).  Samples testing positive for 
binding antibodies will also be tested for neutralizing antibodies and may be 
further characterized for quantity/titer, isotype, affinity, and/or presence of 
immune complexes.  Additional blood samples may be obtained to rule out 
anti-AMG 334 antibodies during the study.  Subjects who test positive for 
neutralizing antibodies to AMG 334 at the final scheduled study visit will be asked 
to return for additional follow-up testing.  This testing should occur approximately 
every 3 months starting from when the site has been notified of the positive result, 
Product: 
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AMG 334
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Date:  14 November 2016 
Page 13 of 19 
CONFIDENTIAL 
 
 
until:  (1) neutralizing antibodies are no longer detectable or (2) the subject has 
been followed for a period of at least 1 year (± 4 weeks).  More frequent testing 
(eg, every month), or testing for a longer period of time may be requested in the 
event of safety-related concerns.  Follow-up testing will not be required where it is 
established that the subject did not receive AMG 334.  Subjects who test positive 
for binding, non-neutralizing antibodies and have clinical sequelae that are 
considered potentially related to an anti-AMG 334 antibody response may also be 
asked to return for additional follow-up testing. 
Section:  7.4  Biomarkers, 3rd paragraph 
Text in global protocol: 
Blood samples are to be collected at the following time points: day 1 pre-dose for all 
subjects to enable testing of baseline cardiac markers (eg, troponin) or other safety 
measures, if needed. 
New text for EU VHP countries: 
Blood samples are to be collected at day 1 post-ETT (4 hours) for all subjects to enable 
testing of troponin I or other safety measures, if needed. 
Section:  10.5.5  Safety Endpoints, 6th paragraph 
Text in global protocol: 
The analyses of vital signs will include summary statistics over time by treatment group. 
Add text for EU VHP countries: 
The analyses of vital signs will include summary statistics over time by treatment group.  
Specifically, change from baseline in maximum SBP, maximum heart rate, and 
maximum ST-segment depression (mm) on day 1 post dose will be summarized by 
treatment group. 
The incidence and percentage of subjects who develop anti-AMG 334 antibodies 
(binding and if positive, neutralizing) at any time will be tabulated by treatment 
group. 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 144

Product:  AMG 334 
Protocol Number:  20140254 (Supplement version 3) 
Date:  14 November 2016 
Page 14 of 19 
CONFIDENTIAL 
 
 
1.2 
Supplement #2 
1.2.1 
Explanation of Country-specific Changes to the Protocol for 
Supplement #2 
The changes made are as follows for supplement version # 2 dated 28 October 2016 
provided with global protocol amendment 4 (dated 28 October 2016): 
• 
Day 1 visits moved to occur within “On-study visits” as predose was incorrectly 
placed within the screening period.  
1.2.2 
Summary of Text Changes to Protocol for Specific EU Countries for 
Supplement #2 
The summary of changes outlined below is used to specify the differences from the 
global protocol amendment 4 (28 October 2016) for the following EU countries: Bulgaria, 
Czech Republic, Latvia, Poland, and Romania. 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 145

Product:  AMG 334 
Protocol Number:  20140254 (Supplement version 3) 
Date:  14 November 2016 
Page 15 of 19 
CONFIDENTIAL 
 
 
Section 7.1, Schedule of Assessments, Table 1 
Text in global protocol: 
Procedure 
Screening Period (up to 6 weeks) 
On-Study Period (12 weeks) 
EOS/ET 
Screening Visits 
On-Study Visitsj 
Visit 
1a 
Visit 
2a 
Visit 3 
Visit 4l 
Day 1 
Week 2i 
Week 4 
Week 8 
Week 12 
Predoseb 
Post-dose 
General and Safety Assessments 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Physical Examination, including weight 
X 
 
 
 
 
 
 
 
 
X 
Targeted Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Randomizationc 
 
 
 
 
X 
 
 
 
 
 
Columbia-Suicide Severity Rating Scale 
X 
 
 
 
X 
 
 
X 
X 
X 
ETTc 
 
Xd 
Xd 
Xd 
 
X 
 
 
 
 
Blood Pressure, Heart Ratee 
X 
 
 
 
X 
X 
 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
Record Continuously 
X 
Serious Adverse Events 
X 
Record Continuously 
X 
Adverse Events and Disease Related Events 
 
 
 
 
 
X 
Record Continuously 
X 
Collection of Events for Adjudication 
 
 
 
 
 
X 
Record Continuously 
X 
Angina diaryf 
 
Record Continuously 
 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
Hematology, Chemistry  
(central laboratory) 
X 
 
 
 
X 
 
 
 
 
X 
Hepatitis Sample Collection 
X 
 
 
 
 
 
 
 
 
 
Urine pregnancy testg 
(females of reproductive potential) 
X 
 
 
 
X 
 
 
 
 
X 
Pharmacokinetic Sampling 
 
 
 
 
 
Xh 
 
 
 
 
Biomarker Sampling 
 
 
 
 
X 
 
 
 
 
 
Urine drug screenk 
X 
 
 
 
 
 
 
 
 
 
Dosing 
 
 
 
 
 
 
 
 
 
 
AMG 334 or Placebo 
 
 
 
 
 
X 
 
 
 
 
Footnotes defined on next page 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 146

Product:  AMG 334 
Protocol Number:  20140254 (Supplement version 3) 
Date:  14 November 2016 
Page 16 of 19 
CONFIDENTIAL 
 
 
ECG = electrocardiogram; EOS = end of study; ET = early termination; ETT = Exercise Treadmill Test; PK = pharmacokinetic.  
a Visits 1 and 2 in the screening period may be combined.  In the case where visits 1 and 2 are combined, all visit 1 assessments must be completed prior to the ETT 
for visit 2.  The laboratory assessment results do not need to be reviewed prior to the ETT for visit 2, but must be reviewed prior to subsequent ETT (or before 
randomization). 
b Predose assessments should be conducted on day 1 prior to randomization. 
c Week 1 begins on the date of randomization.  Study day 1 is defined as the date investigational product is received.  
d During the screening period, 2 ETTs are required > 48 hours and ≤ 14 days apart that meet inclusion criteria, and they will be reviewed by a core ECG laboratory to 
confirm eligibility.  No more than 3 ETTs can be performed during the screening period.  Each ETT should occur within 14 days of each other and the total screening 
period for ETTs should not exceed 28 days. 
e Blood pressure and heart rate should be assessed at all visits following the standard procedure.  During ETT visits, the standard procedure will be conducted prior to 
the ETT; blood pressure assessments will also be conducted following the monitoring procedure described for the ETT. 
f Angina diary will be completed by subjects beginning on the day of Visit 1 and through the EOS/ET visit to  record angina episodes not occurring during ETTs.  
g Results of predose pregnancy test must be reviewed prior to administration of investigational product on day 1.  
h PK sample to be drawn on day 1 after completion of exercise treadmill test post-randomization (ETTr). 
i Visit at week 2 can be done via telephone contact. 
j Study visit windows are ± 1 week.  
k Urine drug screen may also be performed as needed throughout the study per investigator judgment. 
l Optional Visit 4 to be performed if ETT3 is required for eligibility determination. 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 147

Product:  AMG 334 
Protocol Number:  20140254 (Supplement version 3) 
Date:  14 November 2016 
Page 17 of 19 
CONFIDENTIAL 
 
 
Section:7.1, Schedule of Assessments, Table 1 
Added text for Specific EU countries: 
Procedure 
Screening Period (up to 6 weeks) 
On-Study Period (12 weeks) 
EOS/ET 
Screening Visits 
On-Study Visitsl 
Visit 
1a 
Visit 
2a 
Visit 3 
Visit 4n 
Day 1  
Week 2k 
Week 4 
Week 8 
Week 12 
Predoseb 
Post-dose 
General and Safety Assessments 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Physical Examination, including weight 
X 
 
 
 
 
 
 
 
 
X 
Targeted Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Randomizationc 
 
 
 
 
X 
 
 
 
 
 
Columbia-Suicide Severity Rating Scale 
X 
 
 
 
X 
 
 
X 
X 
X 
ETTd 
 
Xd 
Xd 
Xd 
 
Xd 
 
 
 
 
Blood Pressure, Heart Ratee 
X 
 
 
 
X 
X 
 
X 
X 
X 
ECG 
X 
 
 
 
 
Xf 
 
 
 
 
Concomitant Medications 
X 
Record Continuously 
X 
Serious Adverse Events 
X 
Record Continuously 
X 
Adverse Events and Disease Related Events 
 
 
 
 
 
X 
Record Continuously 
X 
Collection of Events for Adjudication 
 
 
 
 
 
X 
Record Continuously 
X 
Angina diaryg 
X 
Record Continuously 
X 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
Hematology, Chemistry  
(central laboratory) 
X 
 
 
 
X 
 
 
 
 
X 
Hepatitis Sample Collection 
X 
 
 
 
 
 
 
 
 
 
Urine pregnancy testh 
(females of reproductive potential) 
X 
 
 
 
X 
 
 
 
 
X 
Pharmacokinetic Sampling 
 
 
 
 
 
Xi 
 
 
 
 
Biomarker Sampling 
 
 
 
 
 
Xj 
 
 
 
 
Anti-AMG 334 Antibodies 
 
 
 
 
X 
 
 
X 
 
X 
Urine drug screenm 
X 
 
 
 
 
 
 
 
 
 
Dosing 
 
 
 
 
 
 
 
 
 
 
AMG 334 or Placebo 
 
 
 
 
 
X 
 
 
 
 
Footnotes defined on next page 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 148

Product:  AMG 334 
Protocol Number:  20140254 (Supplement version 3) 
Date:  14 November 2016 
Page 18 of 19 
CONFIDENTIAL 
 
 
ECG = electrocardiogram; EOS = end of study; ET = early termination; ETT = Exercise Treadmill Test; PK = pharmacokinetic.  
a Visits 1 and 2 in the screening period may be combined.  In the case where visits 1 and 2 are combined, all visit 1 assessments must be completed prior to the ETT 
for visit 2.  The laboratory assessment results do not need to be reviewed prior to the ETT for visit 2, but must be reviewed prior to subsequent ETT (or before 
randomization). 
b Predose assessments should be conducted on day 1 prior to randomization. 
c Week 1 begins on the date of randomization.  Study day 1 is defined as the date investigational product is received.  
d During the screening period, 2 ETTs are required > 48 hours and ≤ 14 days apart that meet inclusion criteria, and they will be reviewed by a core ECG laboratory to 
confirm eligibility.  No more than 3 ETTs can be performed during the screening period.  Each ETT should occur within 14 days of each other and the total screening 
period for ETTs should not exceed 28 days. 
e Blood pressure and heart rate should be assessed at all visits following the standard procedure.  During ETT visits, the standard procedure will be conducted prior to 
the ETT; blood pressure assessments will also be conducted following the monitoring procedure described for the ETT. 
f ECG will be performed 4 hours after the end of ETT. 
g Angina diary will be completed by subjects beginning on the day of Visit 1 and through the EOS/ET visit to  record angina episodes not occurring during ETTs.  
h Results of predose pregnancy test must be reviewed prior to administration of investigational product on day 1.  
i PK sample to be drawn on day 1 after completion of exercise treadmill test post-randomization (ETTr). 
j Biomarker sampling for troponin I measurement will be performed 4 hours after the end of the ETT. 
k Visit at week 2 can be done via telephone contact. 
l Study visit windows are ± 1 week.  
m Urine drug screen may also be performed as needed throughout the study per investigator judgment. 
n Optional Visit 4 to be performed if ETT3 is required for eligibility determination. 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 149

Product:  AMG 334 
Protocol Number:  20140254 (Supplement version 3) 
Date:  14 November 2016 
Page 19 of 19 
CONFIDENTIAL 
 
 
1.3 
Explanation of Country-specific Changes to the Protocol for 
Supplement #3 
This supplement is only being submitted to the EU specific countries referenced in this 
combined supplement. 
The changes made are as follows for supplement version # 3 dated 14 November 2016 
provided with global protocol amendment 4 (dated 28 October 2016): 
• 
Supplement 1 and 2 are combined in one document and named supplement 
version #3.  This was done to clarify that the previous supplement was not 
superseded and that both supplements are to be used in the conduct of the study 
per the latest amendment. 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 150

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 1 of 19 
CONFIDENTIAL 
 
 
Amendment 4 
Protocol Title:  A Randomized, Double-blind, Placebo-controlled Study to Evaluate 
the Effect of AMG 334 on Exercise Time During a Treadmill Test in Subjects With 
Stable Angina 
 
Amgen Protocol Number 20140254 
Version 1.0 Date: 
12 June 2015 
Amendment 1 Date: 
06 August 2015 
Amendment 2 Date: 
17 November 2015 (European Union, Voluntary 
Harmonization Procedure countries only) 
Amendment 3 Date: 
27 January 2016 
Amendment 4 Date: 
28 October 2016 
 
Rationale: 
The following changes are being made to the study for the reasons indicated: 
• 
Change in primary hypotheses, specifically that the true difference in change 
from baseline in exercise duration, if any, is not as much as a 90 second 
decrease, not 60 seconds.  There is no established non-inferiority margin for 
TET.  Two previous studies testing a comparable hypothesis used margins of 
60 seconds and 90 seconds, respectively (Chaitman et al, 2012; Patterson et al, 
2005).  Per protocol, a qualifying TET must be ≥ 3 to ≤ 12 minutes, and the 
difference between 2 qualifying ETTs must be ≤ 1 minute different or within 
20% duration (using the longest duration qualifying ETT).  In some cases (when 
the TET is >5 minutes), a 20% difference in TET will exceed 60 seconds.  As 
such, 60 seconds is not considered to be a clinically meaningful difference, and 
therefore a non-inferiority margin of -90 sec was selected (Patterson, et. al, 
2005). 
• 
Sample size was changed from 120 subjects to at least 54 based on the revised 
margin of 90 seconds while maintaining 80% power.   
• 
Clarification of rescreening of screen failures due to technical difficulties will be 
reviewed by Amgen to determine if rescreening is permitted. 
• 
Clarification of text regarding dosage adjustments, delays, rules for withholding 
or restarting, or permanent discontinuation 
• 
Clarification of timing use of antianginals post ETT 
• 
Clarification of who will be blinded and timing of unblinding 
• 
Clarification of primary analysis 
• 
Clarification of primary efficacy endpoint 
• 
Schedule of Assessments:  Day 1 visits moved to occur within on study visits, as 
these were previously shown incorrectly within the screening period.  An 
instructional footnote was also added for screening visits. 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 151

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Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 3 of 19 
CONFIDENTIAL 
 
 
Add: 
Amendment 4 Date: 28 October 2016 
Section:  Investigator’s Agreement 
Replace:   
I have read the attached protocol entitled A Randomized, Double-blind, 
Placebo-controlled Study to Evaluate the Effect of AMG 334 on Exercise Time During a 
Treadmill Test in Subjects With Stable Angina, dated 27 January 2016 and agree to 
abide by all provisions set forth therein.   
With: 
I have read the attached protocol entitled A Randomized, Double-blind, 
Placebo-controlled Study to Evaluate the Effect of AMG 334 on Exercise Time During a 
Treadmill Test in Subjects With Stable Angina, dated 28 October 2016 and agree to 
abide by all provisions set forth therein.   
Section:  Protocol Synopsis, Hypothesis 
Replace: 
Hypotheses:  The primary hypothesis is that AMG 334 does not significantly decrease 
exercise capacity, as measured by change from baseline in exercise duration, compared 
to placebo, and that the true treatment difference in change from baseline in exercise 
duration is -60 seconds or more.   
With: 
Hypothesis:  The primary hypothesis is that AMG 334 does not significantly decrease 
exercise capacity, as measured by change from baseline in exercise duration, compared 
to placebo, and that the true treatment difference in change from baseline in exercise 
duration is less than a 90 second decrease.   
Section:  Protocol Synopsis, Sample Size 
Replace: 
Approximately 120 subjects will be randomized 
With: 
At least 54 subjects will be randomized 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 153

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 4 of 19 
CONFIDENTIAL 
 
 
Section:  Protocol Synopsis, Statistical Considerations 
Replace: 
The primary endpoint is the change from baseline in exercise duration. 
In the primary analysis, the primary endpoint will be analyzed using an analysis of 
variance model with terms for treatment group and randomization strata (< 7 or 
≥ 7 minutes).  A two-sided 90% confidence interval (CI) for the mean difference in 
change from baseline in exercise duration will be calculated.  If the lower bound of the CI 
of the difference is more than -60 seconds, then the hypothesis that AMG 334 does not 
decrease exercise duration will be supported.  The mean change from baseline in 
exercise duration for each treatment group and the 90% CIs will be reported. 
With: 
The primary endpoint is the change from baseline in exercise duration as measured by 
TET during the ETT. 
In the primary analysis, the primary endpoint will be analyzed using an analysis of 
variance model with terms for treatment group and randomization strata (< 7 or 
≥ 7 minutes).  A two-sided 90% confidence interval (CI) for the mean difference in 
change from baseline in exercise duration will be calculated.  If the lower bound of the CI 
of the difference is more than -90 seconds, then the hypothesis that AMG 334 does not 
decrease exercise duration will be supported.  The mean change from baseline in 
exercise duration for each treatment group and the 90% CIs will be reported. 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 154

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 5 of 19 
CONFIDENTIAL 
 
 
Section:  Study Design and Treatment Schema 
Replace: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Written Informed Consent 
Screening Period 
Eligible Subjects Randomized 1:1 
(N = 120)
Placebo Intravenous (IV) 
(N = 60) 
AMG 334 140 mg IV   
(N = 60) 
End of Study 
Week 12
Screening Period 
Up to 6 Weeks 
On-Study Period 
~12 Weeks 
• Single administration of investigational 
product on Day 1 
• Exercise Treadmill Test (ETTr) on Day 1 
• Follow-up visits at week 2, 4, 8  
 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 155

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 6 of 19 
CONFIDENTIAL 
 
 
With: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Written Informed Consent 
Screening Period 
Eligible Subjects Randomized 1:1 
(N = 54)
Placebo Intravenous (IV) 
(N = 27) 
AMG 334 140 mg IV   
(N = 27) 
End of Study 
Week 12
Screening Period 
Up to 6 Weeks 
On-Study Period 
~12 Weeks 
• Single administration of investigational 
product on Day 1 
• Exercise Treadmill Test (ETTr) on Day 1 
• Follow-up visits at week 2, 4, 8  
 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 156

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 7 of 19 
CONFIDENTIAL 
 
 
Section:  Study Glossary 
Delete: 
Abbreviation or Term 
Definition/Explanation 
AE 
Adverse Event 
SAE 
Serious Adverse Event 
Replace: 
Abbreviation or Term 
Definition/Explanation 
End of Study (end of trial) defined as when the last subject is assessed or receives an 
intervention for evaluation in the study (ie, study week 12) 
With: 
Abbreviation or Term 
Definition/Explanation 
End of Study (end of trial) defined as when the last subject is assessed or participates in 
study procedures for evaluation in the study (ie, study week 12) 
Section:  2.6 Clinical Hypothesis 
Replace:  
The primary hypothesis is that AMG 334 does not significantly decrease exercise 
capacity, as measured by change from baseline in exercise duration, compared to 
placebo and that the true treatment difference in change from baseline in exercise 
duration is -60 seconds or more.   
With:  
The primary hypothesis is that AMG 334 does not significantly decrease exercise 
capacity, as measured by change from baseline in TET, compared to placebo and that 
the true treatment difference in change from baseline in exercise duration is less than a 
90 second decrease. 
Section:  3.1 Study Design 
Replace: 
This is a phase 2a, multicenter, randomized, double-blind, placebo-controlled study in 
subjects with stable angina.  Approximately 120 subjects will be randomized in a 
1:1 ratio to receive either a single dose of AMG 334 or placebo prior to completing an 
ETT.  Randomization will be stratified by the TET average (< 7 minutes or ≥ 7 minutes) 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 157

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 8 of 19 
CONFIDENTIAL 
 
 
of the 2 qualifying ETTs performed during screening.  Treatment group will be blinded to 
the investigator, subjects, and the Amgen study team.   
With: 
This is a phase 2a, multicenter, randomized, double-blind, placebo-controlled study in 
subjects with stable angina.  At least 54 subjects will be randomized in a 1:1 ratio to 
receive either a single dose of AMG 334 or placebo prior to completing an ETT.  
Randomization will be stratified by the TET average (< 7 minutes or ≥ 7 minutes) of the 
2 qualifying ETTs performed during screening.  Treatment group will be blinded to the 
investigator, subjects, and the Amgen study team.   
Section:  3.3 Number of Subjects 
Replace: 
Approximately 120 subjects will be enrolled in this study (60 subjects in the placebo 
group and 60 in the AMG 334 group).  Refer to Section 10.2 for sample size 
considerations. 
With: 
At least 54 subjects will be enrolled in this study (27 subjects in the placebo group and 
27 in the AMG 334 group).  Refer to Section 10.2 for sample size considerations. 
Section:  3.5.2 End of Study 
Replace: 
Final completion:  The end of study ([EOS], end of trial) is defined as the time when the 
last subject is assessed or receives an intervention for evaluation in the study (ie, study 
week 12). 
With: 
Final completion:  The end of study ([EOS], end of trial) is defined as the time when the 
last subject is assessed or participates in study procedures for evaluation in the study 
(ie, study week 12). 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 158

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 9 of 19 
CONFIDENTIAL 
 
 
Section:  4.1.1 Inclusion Criteria 
Replace: 
106 
Completes 2 qualifying ETTs during screening period (as described for 
Screening in Section 7.3.8).  The following ETT qualifications are required: 
a. Limitation of exercise due to symptoms related to myocardial ischemia 
(such as angina pectoris, chest pain/discomfort, dyspnea, shortness 
of breath), or ≥ 3 mm ST segment depression   
b. ≥ 1.0 mm ischemic ST-segment depression during exercise 
performance   
c. Exercise duration of ≥ 3 to ≤ 12 minutes, and  
d. ≤ 1 minute difference or within 20% duration (using the longest 
duration qualifying ETT) in TET between the 2 qualifying ETTs 
e. ECG tracings from screening ETTs are acceptable to the core ECG 
laboratory 
With: 
106 
Completes 2 qualifying ETTs during screening period (as described for 
Screening in Section 7.3.7 and Section 7.3.8).  The following ETT qualifications 
are required: 
a. Limitation of exercise due to symptoms related to myocardial ischemia 
(such as angina pectoris, chest pain/discomfort, dyspnea, shortness 
of breath), or ≥ 3 mm ST segment depression   
b. ≥ 1.0 mm ischemic ST-segment depression during exercise 
performance   
c. Exercise duration of ≥ 3 to ≤ 12 minutes, and  
d. ≤ 1 minute difference or within 20% duration (using the longest 
duration qualifying ETT) in TET between the 2 qualifying ETTs 
e. ECG tracings from screening ETTs are acceptable to the core ECG 
laboratory 
Section:  5 Subject Enrollment, Paragraph 4 
Add: 
If for any other reason a subject should fail screening as a result of technical 
difficulties while conducting the ETTs during screening these cases should be 
reviewed, and it will be at Amgen discretion whether re-screening will be 
permitted. 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 159

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 10 of 19 
CONFIDENTIAL 
 
 
Section:  5.1 Randomization/Treatment Assignment 
Replace: 
Randomization must occur on day 1 pre-dose and after the completion of procedures 
associated with the end of the screening phase. 
Subjects will be randomized in a 1:1 allocation ratio to a single dose of AMG 334 or 
placebo prior to completing an ETT with approximately 60 subjects assigned to each 
treatment group.  Randomization will be stratified by the TET average (< 7 minutes or 
≥ 7 minutes) of the 2 qualifying ETTs performed during screening.  The randomization 
will be performed by IVRS/IWRS.  Treatment groups will be blinded to the investigator, 
subjects, and the Amgen study team. 
The randomization date is to be documented in the subject’s medical record and on the 
enrollment CRF.   
With: 
Randomization must occur on day 1 pre-dose and after the completion of procedures 
associated with the end of the screening phase. 
Subjects will be randomized in a 1:1 allocation ratio to a single dose of AMG 334 or 
placebo prior to completing an ETT with approximately 27 subjects assigned to each 
treatment group.  Randomization will be stratified by the TET average (< 7 minutes or 
≥ 7 minutes) of the 2 qualifying ETTs performed during screening.  The randomization 
will be performed by IVRS/IWRS.  Treatment groups will be blinded to the investigator, 
subjects, and the Amgen study team. 
The randomization date is to be documented in the subject’s medical record and on the 
enrollment CRF.   
Section:  6.2.1.2 Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
Replace: 
The dosage of investigational product is fixed for all subjects and cannot be adjusted. 
The investigator may discontinue investigational product administration for any subject 
who experiences a severe or life-threatening adverse event reported by the investigator 
to be related to investigational product.  Refer to Section 9 for details regarding adverse 
event reporting. 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 160

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 11 of 19 
CONFIDENTIAL 
 
 
Subjects who permanently discontinue investigational product during the double-blind 
on-study period are to return for all other study procedures until the end of the 
double-blind on-study period and study procedures for early termination (ET) visit, 
12 weeks after the last dose of investigational product.  If subjects refuse to complete all 
remaining study visits, then they should complete the ET visit.  
End of investigational product and early discontinuation from investigational product are 
to be registered in the IVRS/IWRS. 
With: 
The dosage of investigational product is fixed for all subjects and cannot be adjusted. 
The investigator may discontinue investigational product administration for any subject 
who experiences a severe or life-threatening adverse event reported by the investigator 
to be related to investigational product.  Refer to Section 9 for details regarding adverse 
event reporting. 
Subjects who are randomized but do not receive investigational product or receive 
partial dose are to remain on study and follow all other study procedures until the end 
of the study.  If subjects refuse to complete all remaining study visits, they should 
complete the early termination (ET) visit.  
End of investigational product and early discontinuation from investigational product are 
to be registered in the IVRS/IWRS. 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 161

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 12 of 19 
CONFIDENTIAL 
 
 
Section:  7.1 Schedule of Assessments 
Replace: 
Table 1.  Schedule of Assessments 
Procedure 
Screening Period (up to 6 weeks) 
On-Study Period (12 weeks) 
EOS/ET 
Screening Visitsi 
On-Study Visitsi 
Visit 1 
Visit 2 
Visit 3 
Visit 4k 
Day 1 
Pre-dosea 
Day 1 
Post-dose 
Week 2h 
Week 4 
Week 8 
Week 12 
General and Safety Assessments 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Physical Examination, including weight 
X 
 
 
 
 
 
 
 
 
X 
Targeted Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Randomizationb 
 
 
 
 
X 
 
 
 
 
 
Columbia-Suicide Severity Rating Scale 
X 
 
 
 
X 
 
 
X 
X 
X 
ETTc 
 
Xc 
Xc 
Xc 
 
X 
 
 
 
 
Blood Pressure, Heart Rated 
X 
 
 
 
X 
X 
 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
Record Continuously 
X 
Serious Adverse Events 
X 
Record Continuously 
X 
Adverse Events and Disease Related Events 
 
 
 
 
 
X 
Record Continuously 
X 
Collection of Events for Adjudication 
 
 
 
 
 
X 
Record Continuously 
X 
Angina diarye 
 
Record Continuously 
 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
Hematology, Chemistry  
(central laboratory) 
X 
 
 
 
X 
 
 
 
 
X 
Hepatitis Sample Collection 
X 
 
 
 
 
 
 
 
 
 
Urine pregnancy testf  
(females of reproductive potential) 
X 
 
 
 
X 
 
 
 
 
X 
Pharmacokinetic Sampling 
 
 
 
 
 
Xg 
 
 
 
 
Biomarker Sampling 
 
 
 
 
X 
 
 
 
 
 
Urine drug screenj 
X 
 
 
 
 
 
 
 
 
 
Dosing 
 
 
 
 
 
 
 
 
 
 
AMG 334 or Placebo 
 
 
 
 
 
X 
 
 
 
 
Footnotes defined on next page 
 
 
 
 
Product: 
Date: 
AMG 334
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Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 13 of 19 
CONFIDENTIAL 
 
 
ECG = electrocardiogram; EOS = end of study; ET = early termination; ETT = Exercise Treadmill Test; PK = pharmacokinetic.  
a Pre-dose assessments should be conducted on day 1 prior to randomization. 
b Week 1 begins on the date of randomization.  Study day 1 is defined as the date investigational product is received.  
c During the screening period, two ETTs are required > 48 hours and ≤ 14 days apart that meet inclusion criteria, and they will be reviewed by a core ECG laboratory to 
confirm eligibility.  No more than 3 ETTs can be performed during the screening period.  Each ETT should occur within 14 days of each other and the total screening 
period for ETTs should not exceed 28 days. 
d Blood pressure and heart rate should be assessed at all visits following the standard procedure.  During ETT visits, the standard procedure will be conducted prior to 
the ETT; blood pressure assessments will also be conducted following the monitoring procedure described for the ETT. 
e Angina diary will be completed by subjects beginning on the day of Visit 1 and through the EOS/ET visit to  record angina episodes not occurring during ETTs.  
f Results of pre-dose pregnancy test must be reviewed prior to administration of investigational product on day 1.  
g PK sample to be drawn on day 1 after completion of exercise treadmill test post-randomization (ETTr). 
h Visit at week 2 can be done via telephone contact. 
i Study visit windows are ± 1 week.  
j Urine drug screen may also be performed as needed throughout the study per investigator judgment. 
k Optional Visit 4 to be performed if ETT3 is required for eligibility determination. 
 
 
 
 
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Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 14 of 19 
CONFIDENTIAL 
 
 
With: 
Table 1.  Schedule of Assessments 
Procedure 
Screening Period (up to 6 weeks) 
On-Study Period (12 weeks) 
EOS/ET 
Screening Visits 
On-Study Visitsj 
Visit 1a 
Visit 2 a 
Visit 3 
Visit 4l 
Day 1 
Week 2i 
Week 4 
Week 8 
Week 12 
Pre-doseb 
Post-dose 
General and Safety Assessments 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Physical Examination, including weight 
X 
 
 
 
 
 
 
 
 
X 
Targeted Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Randomizationc 
 
 
 
 
X 
 
 
 
 
 
Columbia-Suicide Severity Rating Scale 
X 
 
 
 
X 
 
 
X 
X 
X 
ETTd 
 
Xd 
Xd 
Xd 
 
X 
 
 
 
 
Blood Pressure, Heart Ratee 
X 
 
 
 
X 
X 
 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
Record Continuously 
X 
Serious Adverse Events 
X 
Record Continuously 
X 
Adverse Events and Disease Related Events 
 
 
 
 
 
X 
Record Continuously 
X 
Collection of Events for Adjudication 
 
 
 
 
 
X 
Record Continuously 
X 
Angina diaryf 
X 
Record Continuously 
X 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
Hematology, Chemistry  
(central laboratory) 
X 
 
 
 
X 
 
 
 
 
X 
Hepatitis Sample Collection 
X 
 
 
 
 
 
 
 
 
 
Urine pregnancy testg 
(females of reproductive potential) 
X 
 
 
 
X 
 
 
 
 
X 
Pharmacokinetic Sampling 
 
 
 
 
 
Xh 
 
 
 
 
Biomarker Sampling 
 
 
 
 
X 
 
 
 
 
 
Urine drug screenk 
X 
 
 
 
 
 
 
 
 
 
Dosing 
 
 
 
 
 
 
 
 
 
 
AMG 334 or Placebo 
 
 
 
 
 
X 
 
 
 
 
Footnotes defined on next page 
 
 
 
 
Product: 
Date: 
AMG 334
Clinical Study Report:  20140254 Primary Analysis
13 April 2017
Page 164

Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 15 of 19 
CONFIDENTIAL 
 
 
ECG = electrocardiogram; EOS = end of study; ET = early termination; ETT = Exercise Treadmill Test; PK = pharmacokinetic.  
a Visits 1 and 2 in the Screening period may be combined.  In the case where visits 1 and 2 are combined, all visit 1 assessments must be completed prior 
to the ETT for visit 2.  The laboratory assessment results do not need to be reviewed prior to the ETT for visit 2, but must be reviewed prior to subsequent 
ETT (or before randomization). 
b Pre-dose assessments should be conducted on day 1 prior to randomization. 
c Week 1 begins on the date of randomization.  Study day 1 is defined as the date investigational product is received.  
d During the screening period, two ETTs are required > 48 hours and ≤ 14 days apart that meet inclusion criteria, and they will be reviewed by a core ECG laboratory to 
confirm eligibility.  No more than 3 ETTs can be performed during the screening period.  Each ETT should occur within 14 days of each other and the total screening 
period for ETTs should not exceed 28 days. 
e Blood pressure and heart rate should be assessed at all visits following the standard procedure.  During ETT visits, the standard procedure will be conducted prior to 
the ETT; blood pressure assessments will also be conducted following the monitoring procedure described for the ETT. 
f Angina diary will be completed by subjects beginning on the day of Visit 1 and through the EOS/ET visit to  record angina episodes not occurring during ETTs.  
g Results of pre-dose pregnancy test must be reviewed prior to administration of investigational product on day 1.  
h PK sample to be drawn on day 1 after completion of exercise treadmill test post-randomization (ETTr). 
i Visit at week 2 can be done via telephone contact. 
j Study visit windows are ± 1 week.  
k Urine drug screen may also be performed as needed throughout the study per investigator judgment. 
l Optional Visit 4 to be performed if ETT3 is required for eligibility determination. 
 
 
 
 
Product: 
Date: 
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Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 16 of 19 
CONFIDENTIAL 
 
 
Section:  7.3.8.1 Screening 
Add: 
For further guidance please refer to the EET study manual that outlines site 
requirements for conduct, tracing requirements, scheduling, and shipping 
procedures for all ETTs to be performed by a subject. 
Section:  10.2 Sample Size Considerations 
Replace: 
The primary endpoint is the change from baseline in TET.  Assuming between-subject 
standard deviation for change from baseline in exercise duration of 130 seconds 
(Chaitman et al., 2004), with a planned study size of at least 59 subjects in each group 
and a difference in change from baseline in exercise duration of 0 seconds between 
AMG 334 group and placebo group, there is an 80% probability (power) that the lower 
bound of the 90% confidence interval (CI) will exceed -60 seconds (Chaitman et al., 
2012).  Sixty-two subjects are needed in each group if considering 5% dropout. 
When approximately 80 subjects have been enrolled, Amgen may choose to alter the 
sample size based on the blinded variance in the pooled treatment groups. 
With: 
The primary endpoint is the change from baseline in TET.  Assuming between-subject 
standard deviation for change from baseline in exercise duration of 130 seconds 
(Chaitman et al., 2004), with a planned study size of at least 27 subjects in each group 
and a difference in change from baseline in exercise duration of 0 seconds between 
AMG 334 group and placebo group, there is an 80% probability (power) that the lower 
bound of the 90% confidence interval (CI) will exceed -90 seconds.  A margin larger 
than - 60 seconds between groups was required to accommodate the 60 second 
or 20% difference allowed in qualifying TETs for each subject.  Because of this 
within-subject TET variation, a maximum TET difference of 90 seconds between 
the AMG 334 group and placebo group was considered reasonable in this study.  
As such, a margin of - 90 secs was selected, which corresponds to the margin 
used in a previous study testing a comparable hypothesis (Patterson, et. al 2005).  
Twenty-nine subjects are needed in each group if considering 5% dropout. 
 
 
 
Product: 
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Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 17 of 19 
CONFIDENTIAL 
 
 
When approximately 45 subjects have been enrolled, Amgen may conduct a blinded 
sample re-estimation and choose to alter the sample size based on the blinded 
variance in the pooled treatment groups. 
Section:  10.3 Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
Replace: 
Blinded individuals will not have access to unblinded information until the study is 
formally unblinded.  Unblinding and potentially unblinding information should not be 
distributed to the study team, investigators or subjects prior to the study being formally 
unblinded (eg, the formal unblinding may occur at the final analysis rather than during 
the primary analysis) except as specified (eg, Section 5.2 and Section 9.2.2.3).   
Staff from Clinical Supply Chain, Biological Sample Management, PK and Drug 
Metabolism, Clinical Immunology, Clinical Pharmacology, Department of Molecular 
Sciences & Computational Biology, and Global Biostatistics Sciences departments who 
are responsible for tracking, assaying, or analyzing biological samples or checking the 
accuracy of randomization during the conduct of this study are considered unblinded to 
the treatment assignments in this study.  These individuals will not have access to 
subject level clinical data apart from the samples they are assaying and analyzing during 
the course of the study. 
With: 
Blinded individuals will not have access to unblinded information until the study is 
formally unblinded.  Unblinding and potentially unblinding information should not be 
distributed to the study team, investigators or subjects prior to the study being unblinded 
except as specified (eg, Section 5.2 and Section 9.2.2.3).  With the exception of site 
staff and subjects, the study will be unblinded at the time of the primary analysis.  
Complete unblinding of the study will occur at the final analysis. 
Staff from Clinical Supply Chain, Biological Sample Management, PK and Drug 
Metabolism, Clinical Immunology, Clinical Pharmacology, Department of Molecular 
Sciences & Computational Biology, and Global Biostatistics Sciences departments who 
are responsible for tracking, assaying, or analyzing biological samples or checking the 
accuracy of randomization during the conduct of this study are considered unblinded to 
the treatment assignments in this study.  These individuals will not have access to 
 
 
 
Product: 
Date: 
AMG 334
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Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 18 of 19 
CONFIDENTIAL 
 
 
subject level clinical data apart from the samples they are assaying and analyzing during 
the course of the study. 
Section:  10.4.1 Primary Analysis 
Replace: 
The primary analysis for the study will be performed after all subjects have completed 
the ETTr. 
With: 
The primary analysis of the primary and secondary endpoints will be performed after 
all subjects have completed the ETTr. 
Section:  10.5.3 Primary Efficacy Endpoint 
Replace: 
The primary endpoint is the change from baseline in exercise duration.  The primary 
hypothesis is that AMG 334 does not significantly decrease exercise capacity, as 
measured by change from baseline in exercise duration, compared to placebo, and that 
the true treatment difference in change from baseline in exercise duration is -60 seconds 
or more.   
In the primary analysis, the primary endpoint will be analyzed using an analysis of 
variance model with terms for treatment group and randomization strata (< 7 or 
≥ 7 minutes).  A two sided 90% CI for the mean difference in change from baseline in 
exercise duration will be calculated.  If the lower bound of the CI of the difference is 
more than -60 seconds, then the hypothesis that AMG 334 does not decrease exercise 
duration will be supported.  The mean change from baseline in exercise duration for 
each treatment group and the 90% CIs will be reported. 
With: 
The primary endpoint is the change from baseline in exercise duration as measured by 
TET during the ETT.  The primary hypothesis is that AMG 334 does not significantly 
decrease exercise capacity, as measured by change in TET compared to placebo, and 
that the true treatment difference in change from baseline in exercise duration is less 
than a 90 second decrease.   
In the primary analysis, the primary endpoint will be analyzed using an analysis of 
variance model with terms for treatment group and randomization strata (< 7 or 
 
 
 
Product: 
Date: 
AMG 334
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Product:  Erenumab (AMG 334) 
Protocol Number:  20140254 
Date:  28 October 2016 
Page 19 of 19 
CONFIDENTIAL 
 
 
≥ 7 minutes).  A two sided 90% CI for the mean difference in change from baseline in 
exercise duration will be calculated.  If the lower bound of the CI of the difference is 
more than -90 seconds, then the hypothesis that AMG 334 does not decrease exercise 
duration will be supported.  The mean change from baseline in exercise duration for 
each treatment group and the 90% CIs will be reported. 
Section:  References 
Add: 
Patterson D, Kloner R, Effron M, et al.  The effect of tadalafil on the time to 
exercise-induced myocardial ischaemia in subjects with coronary artery disease. 
Br J Clin Pharmacol. 2005, 60:459-468. 
 
 
 
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Date: 
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