Conditions: Subjects With Hyperlipidemia, Dyslipidemia
Keywords: Hyperlipidemia Dyslipidemia Proprotein convertase subtilisin/kexin type 9 (PCSK9) Inhibition Arterial Wall Inflamation Elevated lipoprotein a
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 129
Healthy volunteers: no

Brief summary:
A study to assess the effects of proprotein convertase subtilisin/ kexin type 9 (PCSK9) inhibition on the arterial wall inflammation in patients with elevated lipoprotein(a).

Detailed description:

Arms:
arm 1: Participants received placebo to evolocumab by subcutaneous injection once a month (QM) for 12 weeks. arm 2: Participants received 420 mg evolocumab by subcutaneous injection once a month (QM) for 12 weeks.

Interventions: intervention 1: Evolocumab intervention 2: Placebo
Intervention descriptions: intervention 1: Administered subcutaneously once a month using an autoinjector/pen. intervention 2: Administered subcutaneously once a month using an autoinjector/pen.

Protocol document:
Prot_000.pdf: 
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Product:  Evolocumab 
Protocol Number:  20130293 
Date:  08 February 2017 
Page 2 of 63 
CONFIDENTIAL 
Investigator’s Agreement 
I have read the attached protocol entitled “A RaNdomized Double-blInd Placebo 
ConTrolled Study Characterizing THe Effects of PCSK9 Inhibition On Arterial Wall 
inflammation in Patients with Elevated Lp(a) (ANITSCHKOW)”, dated 
08 February 2017, 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) 


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Product:  Evolocumab 
Protocol Number:  20130293 
Date:  08 February 2017 
Page 5 of 63 
FDG-PET/CT and laboratory tests (fasting lipids, Lp(a), OxPL/ApoB, IL-6, hsCRP1, biomarkers 
[serum, plasma and cell], and Lp(a) isoform number) will be conducted and adverse events, 
serious adverse events, ADEs, disease-related events, and changes in concomitant medications 
will be recorded. 
The overall study design is described by a study schema at the end of this synopsis section.  For 
a full list of study procedures, including the timing of each procedure, please refer to Section 7 
and the Schedule of Assessments (Table 1). 
Statistical Considerations:  The superiority of evolocumab to placebo will be assessed for all 
efficacy endpoints on the full analysis set (FAS), which includes all randomized subjects who 
receive at least one dose of IP.  The primary endpoint is the percentage change from baseline in 
MDS TBR at week 16.  Percentage change for MDS TBR will be modeled as an analysis of 
covariance (ANCOVA) model with the treatment group and the stratification factor in the model.  
FDG-PET/CT observations made after an on-study cardiovascular event will be included in the 
primary analysis, and a sensitivity analysis excluding these observations will be conducted.  To 
handle missing data, the correlations between the model errors as well as baseline values of 
MDS TBR and Lp(a) (and on-study percent change from baseline in Lp(a)) will be modeled.  
Analysis of the secondary endpoints Lp(a), ApoB and LDL-C will use a repeated measures model 
on the FAS including terms for treatment group, stratification factors, scheduled visit, and the 
interaction of treatment with scheduled visit.  Safety endpoints will be summarized descriptively 
by treatment group.  For a full description of statistical analysis methods, please refer to 
Section 10. 
Sponsor:  Amgen Inc. 
Data Element Standards 
Version(s)/Date(s):   
5:  20 March 2015  
 
CONFIDENTIAL 
 
 


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Product:  Evolocumab 
Protocol Number:  20130293 
Date:  08 February 2017 
Page 7 of 63 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term Definition/Explanation 
ADE 
adverse device effect 
AE 
adverse event 
AI 
autoinjector  
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
Apo(a) 
apolipoprotein(a) 
Apo(B) 
apolipoprotein(B) 
AST 
aspartate aminotransferase 
CHD 
coronary heart disease 
CI 
confidence interval 
CRF 
case report form 
CT 
computed tomography 
CTCAE 
common terminology criteria for adverse events 
DILI 
drug induced liver injury  
DRE 
disease-related event 
EDC 
electronic data capture 
eGRF 
estimated glomerular filtration rate  
End of Study (end of 
trial) 
defined as the date when the last subject has completed all planned 
study procedures up to and including the End of Study visit as outlined in 
the Schedule of Assessments 
End of Study (primary 
completion) 
defined as when the last subject is assessed or receives an intervention 
for the purposes of final collection of data for the primary endpoint(s) 
End of Study for 
Individual Subject 
defined as the last day that protocol-specified procedures are conducted 
for an individual subject 
End of Treatment 
defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject 
EOS 
end of study 
FAS 
full analysis set 
FDG 
fluorodeoxyglucose 
FDG-PET/CT 
fluorodeoxyglucose-positron emission tomography/computed 
tomography 
FSH 
follicle-stimulating hormone  
GCP 
Good Clinical Practice 
HDL-C 
high-density lipoprotein cholesterol 
hsCRP 
high sensitivity C-reactive protein 


Product:  Evolocumab 
Protocol Number:  20130293 
Date:  08 February 2017 
Page 8 of 63 
CONFIDENTIAL 
 
 
Abbreviation or Term Definition/Explanation 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IL-6 
Interleukin-6 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IP 
investigational product 
IPIM 
Investigational Product Instruction Manual 
IRB/IEC 
institutional review board/independent ethics committee 
IVRS 
interactive voice response system, telecommunication technology that is 
linked to a central computer in real time as an interface to collect and 
process information. 
IWRS 
interactive web response system 
LDL-C 
Low-density lipoprotein-cholesterol 
LDLR 
low-density lipoprotein receptor 
Lp(a) 
lipoprotein(a) 
MDS 
most diseased segment 
NSAID 
nonsteroidal anti-inflammatory drug 
OxPL 
oxidized phospholipids 
PCI 
percutaneous coronary intervention 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
QM 
once monthly 
SAE 
serious adverse event 
SC 
subcutaneous 
Source Data 
information from an original record or certified copy of the original record 
containing patient 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 protocol-specified investigational 
product(s)/protocol-required therapies is/are administered to the subject 
SUV 
standardized uptake value 
TBL 
total bilirubin 
TBR 
target-to-background ratio 
ULN 
upper limit of normal 


Product:  Evolocumab 
Protocol Number:  20130293 
Date:  08 February 2017 
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 ......................................................................................................... 13 
1.4 
Exploratory ................................................................................................. 13 
2. 
BACKGROUND AND RATIONALE ........................................................................ 13 
2.1 
Disease ....................................................................................................... 13 
2.2 
Amgen Investigational Product Background ............................................... 15 
2.3 
Rationale .................................................................................................... 15 
2.4 
Clinical Hypotheses .................................................................................... 16 
3. 
EXPERIMENTAL PLAN ......................................................................................... 16 
3.1 
Study Design .............................................................................................. 16 
3.2 
Number of Sites .......................................................................................... 17 
3.3 
Number of Subjects .................................................................................... 17 
3.4 
Replacement of Subjects ............................................................................ 17 
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 ................................................................. 18 
4.1.1 
Inclusion Criteria – Assessed at Screening 1 ............................. 18 
4.1.2 
Inclusion Criteria – Assessed at Screening 2 ............................. 18 
4.1.3 
Exclusion Criteria ........................................................................ 18 
5. 
SUBJECT ENROLLMENT ..................................................................................... 20 
5.1 
Randomization/Treatment Assignment ...................................................... 21 
5.2 
Site Personnel Access to Individual Treatment Assignments .................... 21 
6. 
TREATMENT PROCEDURES ............................................................................... 21 
6.1 
Classification of Product and Medical Device ............................................. 21 
6.2 
Investigational Product ............................................................................... 22 
6.2.1 
Amgen Investigational Product ................................................... 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 


Product:  Evolocumab 
Protocol Number:  20130293 
Date:  08 February 2017 
Page 10 of 63 
CONFIDENTIAL 
 
 
6.3 
Hepatotoxicity Stopping and Rechallenge Rules ........................................ 23 
6.3.1 
Criteria for Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required 
Therapies due to Potential Hepatotoxicity .................................. 23 
6.3.2 
Criteria for Conditional Withholding of Amgen 
Investigational Product and Other Protocol-required 
Therapies due to Potential Hepatotoxicity .................................. 24 
6.3.3 
Criteria for Rechallenge of Amgen Investigational 
Product and Other Protocol-required Therapies After 
Potential Hepatotoxicity .............................................................. 25 
6.4 
Concomitant Therapy ................................................................................. 25 
6.5 
Medical Devices ......................................................................................... 25 
6.6 
Product Complaints .................................................................................... 26 
6.7 
Excluded Treatments, Medical Devices, and/or Procedures 
During Study Period ................................................................................... 26 
7. 
STUDY PROCEDURES ......................................................................................... 27 
7.1 
Schedule of Assessments .......................................................................... 27 
7.2 
General Study Procedures ......................................................................... 29 
7.2.1 
Screening Enrollment and/or Randomization ............................. 29 
7.2.2 
Rescreening ............................................................................... 29 
7.2.3 
Treatment ................................................................................... 29 
7.2.4 
End of Study Visit ....................................................................... 30 
7.3 
Description of Study Procedures ................................................................ 30 
7.3.1 
Informed Consent ....................................................................... 30 
7.3.2 
Demographics ............................................................................ 30 
7.3.3 
Medical History ........................................................................... 30 
7.3.4 
Physical Examination ................................................................. 30 
7.3.5 
Vital Signs ................................................................................... 31 
7.3.6 
Height, Weight, and Waist Circumference .................................. 31 
7.3.7 
Adverse Events, Serious Adverse Events, Adverse 
Device Effects, and Disease-related Events .............................. 31 
7.3.8 
Prior and Concomitant Medications ............................................ 32 
7.4 
FDG-PET/CT .............................................................................................. 32 
7.5 
Laboratory Assessments ............................................................................ 33 
7.5.1 
Blinding of Laboratory Test Results ............................................ 34 
7.5.2 
Serum Pregnancy Test ............................................................... 35 
7.6 
Biomarker Development ............................................................................. 35 
7.7 
Pharmacogenetic Studies ........................................................................... 35 
7.8 
Sample Storage and Destruction ................................................................ 36 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 37 
8.1 
Subjects’ Decision to Withdraw .................................................................. 37 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 37 


Product:  Evolocumab 
Protocol Number:  20130293 
Date:  08 February 2017 
Page 11 of 63 
CONFIDENTIAL 
 
 
8.3 
Reasons for Removal From Run-in, Treatment, or Study .......................... 38 
8.3.1 
Reasons for Removal From Treatment ...................................... 38 
8.3.2 
Reasons for Removal From Study ............................................. 38 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 38 
9.1 
Definition of Safety Events ......................................................................... 38 
9.1.1 
Disease-related Events .............................................................. 38 
9.1.2 
Adverse Events .......................................................................... 39 
9.1.3 
Serious Adverse Events ............................................................. 40 
9.2 
Safety Event Reporting Procedures ........................................................... 40 
9.2.1 
Reporting Procedures for Disease-related Events ..................... 40 
9.2.2 
Adverse Events .......................................................................... 41 
9.2.2.1 
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria ............................ 41 
9.2.2.2 
Reporting Procedures for Serious Adverse 
Events ...................................................................... 42 
9.2.2.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 43 
9.3 
Pregnancy and Lactation Reporting ........................................................... 44 
10. 
STATISTICAL CONSIDERATIONS ....................................................................... 44 
10.1 
Study Endpoints, Analysis Sets, and Covariates ........................................ 44 
10.1.1 
Study Endpoints ......................................................................... 44 
10.1.1.1 
Primary Endpoint ..................................................... 44 
10.1.1.2 
Secondary Endpoints ............................................... 44 
10.1.1.3 
Safety Endpoints ...................................................... 44 
10.1.1.4 
Exploratory Endpoints .............................................. 45 
10.1.2 
Analysis Sets .............................................................................. 45 
10.1.3 
Covariates and Subgroups ......................................................... 45 
10.2 
Sample Size Considerations ...................................................................... 45 
10.3 
Access to Individual Subject Treatment Assignments by Amgen 
or Designees .............................................................................................. 46 
10.4 
Planned Analyses ....................................................................................... 46 
10.4.1 
Primary Analysis ......................................................................... 46 
10.5 
Planned Methods of Analysis ..................................................................... 46 
10.5.1 
General Considerations .............................................................. 46 
10.5.2 
Primary Efficacy Endpoint .......................................................... 46 
10.5.3 
Secondary Efficacy Endpoint(s) ................................................. 47 
10.5.4 
Safety Endpoints ........................................................................ 47 
11. 
REGULATORY OBLIGATIONS ............................................................................. 47 
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 


Product:  Evolocumab 
Protocol Number:  20130293 
Date:  08 February 2017 
Page 12 of 63 
CONFIDENTIAL 
 
 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................... 50 
12.1 
Protocol Amendments and Study Termination ........................................... 50 
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 ....................................................................................... 53 
12.7 
Compensation ............................................................................................ 53 
13. 
REFERENCES ....................................................................................................... 54 
14. 
APPENDICES ........................................................................................................ 56 
List of Tables 
Table 1.  Schedule of Assessments
 
 ................................................................................ 28
Table 2.  Analyte Listing
 
 .................................................................................................. 34
List of Appendices 
Appendix A.  Additional Safety Assessment Information
 
 ................................................ 57
Appendix B.  Sample Serious Adverse Event Report Form (Sample eSerious 
Adverse Event Contingency Report Form – paper-based 
Form)
 
 ....................................................................................................... 59
Appendix C.  Pregnancy and Lactation Notification Worksheets
 
 .................................... 62


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CCI


Product:  Evolocumab 
Protocol Number:  20130293 
Date:  08 February 2017 
Page 14 of 63 
CONFIDENTIAL 
 
 
hyperlipidemia that is not due to a specific genetic disorder, although there are 
polygenetic influences.  Mixed dyslipidemia is generally defined as elevated LDL-C and 
high triglycerides and/or low high-density lipoprotein cholesterol (HDL-C).  Data from 
epidemiologic studies show that LDL-C is a strong independent predictor of coronary 
heart disease (CHD) risk across diverse patient populations (The Emerging Risk Factors 
Collaboration, 2009). 
Lipoprotein(a) [Lp(a)] is a modified form of LDL.  It is composed of an LDL particle 
covalently bound to apolipoprotein(a) [apo(a)].  Lipoprotein (a) is distinctly different from 
other plasma lipoproteins given that it is an assembly of two critical elements; a central 
core linked by a disulfide bridge to a signature protein, apo(a).  The first element shares 
similarities with LDL, is rich in cholesterol and contains ApoB.  The other element, 
apo(a), consists of a number of pleated structures, kringles IV and V, of which kringle IV 
type 2 is repeated in a variable number, from 2 to more than 40 times.  The variation in 
kringle IV type 2 repeats gives rise to considerable differences in the size and molecular 
weight of apo(a) and is the major determinant of Lp(a) plasma level (up to 90%) 
(Dube et al, 2012). 
Serum levels of Lp(a) are primarily dependent on the production of apo(a), which is 
mainly regulated genetically.  Lipoprotein (a) collects in the arterial wall and is 
subsequently scavenged by macrophages (Koschinsky and Marcovina, 2004).  
Additionally, Lp(a) is homologous to plasminogen and competitively inhibits binding of 
fibrin to plasminogen.  Lipoprotein (a) may therefore enhance thrombosis due to 
endothelial damage by interfering with the conversion of plasminogen to plasmin 
(Rouy et al, 1991). 
Serum levels of Lp(a) have a positive, continuous association with CHD risk, which is 
independent of LDL-C, non-HDL-C, and other cardiovascular risk factors 
(Nordestgaard et al, 2010, and Kamstrup et al, 2009).  For instance, in a meta-analysis 
of 24 cohort studies, Erqou et al (2009) identified a 13% increase in CHD risk 
(95% confidence interval [CI] 9–18) per 3.5-fold elevation in Lp(a) concentrations.  
However, the beneficial effects of pharmacological intervention to reduce Lp(a) on 
cardiovascular risk remain to be determined.  Despite a strong pathophysiologic 
rationale supporting reduction of Lp(a) as a therapeutic target, reliable pharmacologic 
means of reducing Lp(a) are still needed (Tziomalos et al, 2009).  When low-density 
lipoprotein receptor (LDLR) is highly expressed and ApoB is low, the LDLR appears to 
play a key role in hepatic catabolism of Lp(a); proprotein convertase subtilisin/kexin type 


Product:  Evolocumab 
Protocol Number:  20130293 
Date:  08 February 2017 
Page 15 of 63 
CONFIDENTIAL 
 
 
9 (PCSK9) inhibits these processes, which provides a mechanism for direct reduction of 
Lp(a) with PCSK9 inhibition (Romagnuolo et al, 2015). 
2.2 
Amgen Investigational Product Background 
Recycling of the hepatic cell surface LDLR plays a critical role in regulating serum LDL-C 
levels.  Proprotein convertase subtilisin/kexin type 9 binds to the LDLR and 
downregulates hepatic cell surface LDLR, which, in turn, leads to increased levels of 
circulating LDL- C.  Humans with PCSK9 loss-of-function mutations have cholesterol 
levels lower than normal and reduced incidence of CHD (Abifadel et al, 2009).  
Evolocumab (formerly referred to as AMG 145) is a fully human monoclonal 
immunoglobulin G2, developed at Amgen Inc., that specifically binds to PCSK9 
preventing its interaction with the LDLR.  The inhibition of PCSK9 by evolocumab leads 
to increased LDLR expression and subsequent decreased circulating concentrations of 
LDL-C. 
Refer to the Evolocumab Investigator’s Brochure for more information on evolocumab. 
2.3 
Rationale 
Beyond the atherogenic potential of the Lp(a) LDL-like core, Lp(a) appears to be the 
preferential carrier of OxPL in the plasma and thus closely involved in atherosclerotic 
inflammation (Leibundgut et al, 2013).  The inflammatory response to the accumulation 
of oxidized lipids in the artery wall plays a pivotal role in the atherosclerotic disease 
process, and plaque inflammation is associated with plaque rupture and 
atherothrombotic events (Tsimikas and Hall, 2012).  It remains to be shown whether 
lowering Lp(a) can reverse these changes, providing a crucial link between lipid lowering 
and decreased inflammatory activity.  Whereas, Lp(a) is relatively refractory to both 
lifestyle and drug intervention, evolocumab 420 mg once monthly (QM) reduced Lp(a) by 
approximately 28% compared to placebo measured using the mean of weeks 10 and 12, 
in phase 3 evolocumab studies (20110114, 20110115, and 20110117).  The safety and 
efficacy of evolocumab 420 mg subcutaneous (SC) QM in adults has been extensively 
studied in phase 2 and phase 3 clinical trials. 
Over the last decade FDG-PET/CT has shown great potential in visualizing, quantifying, 
and characterizing atherosclerotic inflammation non-invasively (Rosenbaum et al, 2012) 
and is a highly sensitive modality that can be utilized as a surrogate imaging marker for 
vessel wall inflammation (Joshi et al, 2011).  FDG-PET/CT imaging has been shown to 
be reproducible for imaging of atherosclerotic plaque inflammation (Rudd et al 2007) and 
the FDG uptake signal correlates with macrophage content (Tawakol et al, 2006).  In 


Product:  Evolocumab 
Protocol Number:  20130293 
Date:  08 February 2017 
Page 16 of 63 
CONFIDENTIAL 
 
 
quantitative PET/CT image analysis, the artery (right carotid, left carotid, or thoracic 
aorta) with the highest FDG uptake (highest mean of the maximum TBR at baseline) is 
identified as the index vessel.  The maximum standardized uptake value (SUV) is 
calculated as a time- and dose- corrected tissue radioactivity divided by body weight for 
each region of interest and the TBR is calculated from the ratio of the SUV of the artery 
compared to mean background venous activity.  FDG uptake signal is expressed as 
TBR of the whole index vessel or the MDS of the index vessel.  The MDS is defined as 
the 1.5-cm arterial segment, centered on the slice of artery demonstrating the highest 
FDG uptake at baseline, and calculated as a mean of maximum TBR values derived 
from 3 contiguous axial segments (Fayad et al, 2011).  These assessments have been 
used as standard endpoints in the most recent trials for the evaluation of arterial wall 
inflammation with various lipid-lowering treatments (van Wijk et al, 2014; 
Tawakol et al, 2013; Fayad et al, 2011). 
The primary endpoints of this study are the percentage change from baseline in the 
arterial wall inflammation by FDG-PET/CT assessed as a TBR within the MDS of the 
index vessel (carotid arteries or aorta) at week 16. 
2.4 
Clinical Hypotheses 
The primary clinical hypothesis is that administration of evolocumab 420 mg SC QM will 
result in greater change from baseline TBR at week 16 than placebo in subjects with 
elevated baseline Lp(a). 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a phase 3b, multi-center, double-blind, randomized, placebo-controlled study 
evaluating the effect of evolocumab on arterial wall inflammation as measured by 
FDG-PET/CT following 16 weeks of treatment in subjects with elevated levels of Lp(a).  
Eligible subjects will have hyperlipidemia with Lp(a) ≥ 50 mg/dL and LDL-C ≥ 100 mg/dL.  
In addition, the subjects must have TBR max > 1.6 on FDG PET/CT in order to qualify 
for enrollment.  If subjects are on statin or other lipid-lowering therapy (not required to 
participate in this study), they must be on a stable dose for at least 8 weeks prior to 
screening and during the entire time of screening and throughout the study. 
The study will include 2 screening visits (screen 1 and screen 2) during the screening 
period, which will be a maximum total of 56 days.  Subjects will be randomized 1:1 into 
2 treatment groups:  evolocumab 420 mg QM SC or placebo QM SC.  Randomization 
will be stratified for balance by baseline background statin therapy (on statin vs not on 


Product:  Evolocumab 
Protocol Number:  20130293 
Date:  08 February 2017 
Page 17 of 63 
CONFIDENTIAL 
 
 
statin) and by screening Lp(a) (< 175 mg/dL or ≥ 175 mg/dL).  The treatment period will 
be 12 weeks in duration with study visits every 4 weeks.  At the end of study (EOS) visit 
at week 16, FDG PET/CT will be conducted.   
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 
Approximately 9 sites in the Netherlands will participate in this study.  Other sites and 
countries may be added if required to meet recruitment goals. 
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”.  Approximately 
120 subjects will be enrolled. 
3.4 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
Including the screening and study treatment, the maximum duration of study 
participation for a subject will be 24 weeks.  After signing the informed consent 
form (ICF), subjects should be randomized within 56 days.   
3.5.2 
End of Study 
The EOS and the primary completion date are defined as the date on which the last 
subject completes the week 16 EOS visit procedures or ends the study early.   
4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).  This log may be completed and updated via an interactive voice response 
(IVRS) system/interactive web response system (IWRS).   
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1).   


Product:  Evolocumab 
Protocol Number:  20130293 
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CONFIDENTIAL 
 
 
4.1 
Inclusion and Exclusion Criteria 
4.1.1 
Inclusion Criteria – Assessed at Screening 1 
101 
Subject has provided written informed consent prior to initiation of any study 
specific activities/procedures 
102 
Male or female, ≥ 50 years of age at the time of informed consent 
103 
Subject with fasting Lp(a) ≥ 50 mg/dL at screening 1 
104 
Subject with fasting LDL-C ≥ 100 mg/dL at screening 1 
105 
For those subjects receiving lipid lowering therapy (not required to participate in 
this study), lipid-lowering therapy, including statin dose, must be unchanged for 
≥ 8 weeks prior to screening 
4.1.2 
Inclusion Criteria – Assessed at Screening 2 
106 
Subjects with TBRmax > 1.6 (either right carotid, left carotid or thoracic aorta) on 
FDG-PET/CT 
4.1.3 
Exclusion Criteria 
201 
Currently receiving, or less than 4 weeks since receiving, treatment in another 
investigational device or drug study(ies), or participating in other investigational 
procedures 
202 
Known diagnosis of diabetes mellitus or screening fasting serum glucose 
≥ 126 mg/dL or HbA1C ≥ 6.5% 
203 
Subject with a history of homozygous familial hypercholesterolemia 
204 
Recent cardiovascular event (myocardial infarction, unstable angina, 
percutaneous coronary intervention (PCI), coronary artery bypass graft, or 
stroke) within 3 months prior to randomization, or planned cardiac surgery, PCI 
or carotid stenting, or planned major non-cardiac surgery during the course of the 
study period 
205 
Subject currently undergoing lipid apheresis 
206 
Known contraindications or limitations to FDG-PET/ CT (eg, scanner weight limit, 
devices that can cause image artifacts, or carotid/aortic stents/grafts) 
207 
Auto-immune disease/vasculitis, active inflammatory diseases, proven or 
suspected bacterial infections.  Recent (< 1 month prior to screening) or ongoing 
serious infection requiring intravenous antibiotic therapy 
208 
Recent (< 6 weeks prior to screening) or current treatment with medications that 
may have a significant effect on plaque inflammation as measured by plaque 
TBR, including:  oral, rectal, or injectable corticosteroids or immunosuppressive 
medications (eg, cyclosporine, methotrexate, tacrolimus, azathioprine, 
anti-thymocyte globulin, sirolimus, anti-TNF agents such as infliximab, anti-IL6 
therapy such as tocilizumab, or anti-IL1 therapy) 


Product:  Evolocumab 
Protocol Number:  20130293 
Date:  08 February 2017 
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CONFIDENTIAL 
 
 
209 
Recent (< 6 weeks prior to screening) or current treatment with aspirin 
(> 325 mg/day) or nonsteroidal anti-inflammatory drugs (NSAIDs) 
(> 1000 mg/day) 
210 
Known sensitivity to any of the active substances or excipients 
(eg, carboxymethylcellulose) to be administered during dosing 
211 
Subject has taken a cholesterol ester transfer protein inhibitor (eg, anacetrapbib, 
dalcetrapib, evacetrapib) or mipomersen or lomitapide in the last 12 months prior 
to screening 
212 
Known systemic disorders such as hepatic, renal, hematologic, and malignant 
diseases or any clinically significant medical condition that could interfere with 
the conduct of the study 
213 
History of malignancy (except non-melanoma skin cancers, cervical in-situ 
carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within 
the last 5 years 
214 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, or unreliability as a study participant (eg, alcohol or other drug abuse 
in the past year or psychosis), to the best of the subject’s and investigator’s 
knowledge 
215 
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 
216 
Subject has previously received evolocumab or any other therapy to inhibit 
PCSK9 
217 
Female subject who is pregnant or breastfeeding or planning to become 
pregnant or breastfeed during treatment with investigational medicinal 
product (IMP) (evolocumab or placebo) and for an additional 15 weeks after the 
last dose of IMP (evolocumab or placebo) 
218 
Female subject is not willing to use an acceptable method(s) of effective birth 
control during treatment with IMP (evolocumab or placebo) and for an additional 
15 weeks after the end of treatment with IMP (evolocumab or placebo).  Female 
subjects, who have had a hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy, or who are postmenopausal, are not required to use 
contraception 
− 
Menopause is defined as 12 months of spontaneous and continuous 
amenorrhea in a female ≥ 55 years old; or age < 55 years but no 
spontaneous menses for at least 2 years; or 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. 


Product:  Evolocumab 
Protocol Number:  20130293 
Date:  08 February 2017 
Page 20 of 63 
CONFIDENTIAL 
 
 
− 
Acceptable methods of effective birth control include:  true sexual abstinence 
if 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 a trial, and withdrawal are not 
acceptable methods of contraception); surgical contraceptive methods (male 
partner who has had vasectomy with medical confirmation of surgical 
success or bilateral tubal ligation), use of hormonal birth control methods 
(oral, injectable, implantable transdermal, or intravaginal), intrauterine device, 
intrauterine hormone-releasing system, or 2 barrier methods (each partner 
must use 1 barrier method– males must use a condom with spermicide and 
females must choose either a diaphragm with spermicide, OR cervical cap 
with spermicide, OR contraceptive sponge with spermicide). 
Note:  Additional medications given during treatment with evolocumab may alter 
the contraceptive requirements.  These additional medications may require an 
increase in the number of contraceptive methods and/or length of time that 
contraception is to be utilized or length of time breastfeeding is to be avoided 
after the last dose of protocol-required therapies.  The investigator is to discuss 
these contraceptive changes with the study subject. 
219 
Subject has had exposure to investigational drugs targeting Lp(a) within the last 
12 months, prior to Screening. 
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, ICF, and all other subject information 
and/or recruitment material, if applicable (see Section 11.2).  All subjects must 
personally sign and date the ICF before commencement of study specific 
activities/procedures. 
Upon completion of the screening period the subject is evaluated by the investigator and 
providing the subject continues to meet the inclusion/exclusion criteria, the subject is 
subsequently eligible to be enrolled in the study and randomized.  Subjects will be 
enrolled on the day they are randomized.  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 (defined as the point at 
which the subject signs the ICF) receives a unique subject identification number before 
any study-related activities/procedures are performed.  The subject identification number 
will be assigned by the IVRS/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.  Subjects who are unable to complete or meet the initial Part 1 eligibility criteria 


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(see Section 4.1.1) will be permitted to rescreen but any subject who does not meet the 
Part 2 criteria eligibility (Section 4.1.2) will not be allowed to rescreen. 
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.  This number will not necessarily be the same as the randomization number 
assigned for the study. 
5.1 
Randomization/Treatment Assignment 
Subjects who meet the eligibility requirements (Section 4.1) will be randomly assigned in 
a 1:1 allocation ratio to 2 treatment groups (evolocumab and placebo) in a double-blind 
manner.  Randomization will be stratified by baseline background statin therapy (on 
statin vs not on statin) and by screening Lp(a) (< 175 mg/dL or ≥ 175 mg/dL). 
The randomization date is to be documented in the subject’s medical record and on the 
enrollment CRF.  Randomization numbers will be provided to the site through an 
IVRS/IWRS. 
5.2 
Site Personnel Access to Individual Treatment Assignments 
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.   
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Product and Medical Device 
The Amgen investigational product (IP) used in this study includes:  evolocumab and 
matching placebo (IMP) in a prefilled autoinjector (AI)/Pen (investigational medical 
device). 
Note:  Ancillary device(s) (ie, medical device(s) not under study) are described in 
Section 6.5. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of evolocumab and placebo. 


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6.2 
Investigational Product 
6.2.1 
Amgen Investigational Product 
Evolocumab and matching placebo will be manufactured and packaged by Amgen Inc. 
and distributed using Amgen clinical study drug distribution procedures.  
Evolocumab will be supplied in a prefilled AI/Pen with a volume of 1.0 mL. 
Placebo will be presented in identical containers and stored/packaged the same as 
evolocumab. 
6.2.1.1 
Dosage, Administration, and Schedule 
6.2.1.1.1 
Placebo Run-in 
Subjects will receive a placebo administration with three 1.0 mL SC injections with the 
prefilled AI/Pen to confirm tolerance of SC administration at screening visit 2.  The SC 
injections with the AI/Pen should be administered in a consecutive fashion with all 
injections completed within 30 minutes.   
6.2.1.1.2 
Randomized Treatment Period 
The IP (420 mg evolocumab or matching placebo via AI/Pen) will be administered QM 
for 12 weeks on day 1, week 4 (± 7 days); week 8 (± 7 days); and week 12 (± 7 days).   
The IP will be administered as an SC injection with a total volume of 3.0 mL QM, via 
3 separate autoinjections of 1.0 mL administered consecutively with all injections 
completed within 30 minutes.   
The IP will be administered in accordance with instructions in the IPIM and the 
Instructions for Use.  All doses of evolocumab and placebo are mandated to be 
administered at the study site.  Investigational product administration by SC injection 
must occur after after all other visit assessments are completed.  After IP administration 
at the first dosing visit, subjects will be held for observation for at least 30 minutes before 
being discharged.   
The date and completion time of administration, the body location of the injection, and 
whether the injection was fully or partially administered are to be recorded on each 
subject’s CRF. 
Overdose with this product has not been reported.   


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6.2.1.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
No dose adjustments are allowed in this study.  If, in the opinion of the investigator, a 
subject is unable to tolerate a specific dose of IP, that subject will discontinue IP but will 
continue to return for all other study procedures and measurements until the EOS.   
If a subject is late for administration of IP, administration should occur as soon as 
possible.  A dose of IP should not be administered within less than 7 days of a previous 
dose.  If a subject arrives for a visit with IP administration and IP was administered within 
the prior 7 days, the dose should not be administered but all other study procedures 
should be conducted.  Administration of IP should occur as soon as possible but at least 
7 days after the previous administration.  Subjects who completely miss a dose of IP will 
continue in the study and receive the next dose of IP per their schedule of 
administration. 
6.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis (as 
described below) may meet the criteria for withholding or permanent discontinuation of 
Amgen IP or other protocol-required therapies as specified in the Guidance for Industry 
Drug-Induced Liver Injury:  Premarketing Clinical Evaluation (July 2009).   
6.3.1 
Criteria for Permanent Discontinuation of Amgen Investigational 
Product and Other Protocol-required Therapies due to Potential 
Hepatotoxicity 
Evolocumab should be discontinued permanently and the subject should be followed 
according to the recommendations in Appendix A (Additional Safety Assessment 
Information) for possible drug-induced liver injury (DILI), if ALL of the criteria below are 
met:   
• 
TBL > 2x upper limit of normal (ULN) or INR > 1.5 
• 
AND increased AST or ALT from the relevant baseline value as specified below:   
Baseline AST or ALT value 
AST or ALT elevation 
< ULN 
> 3x ULN 
CONFIDENTIAL 
 
 


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• 
AND no other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT and/or 
TBL values include, but are not limited to: 
− 
Hepatobiliary tract disease 
− 
Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus, cytomegalovirus, 
herpes simplex virus, varicella, toxoplasmosis, and parvovirus) 
− 
Right sided heart failure, hypotension, or any cause of hypoxia to the liver 
causing ischemia 
− 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants, and mushrooms  
− 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation 
(eg, indinavir, atazanavir) 
− 
Alpha-one antitrypsin deficiency 
− 
Alcoholic hepatitis 
− 
Autoimmune hepatitis  
− 
Wilson’s disease and hemochromatosis 
− 
Nonalcoholic fatty liver disease including steatohepatitis 
− 
Non-hepatic causes (eg, rhabdomylosis, hemolysis) 
6.3.2 
Criteria for Conditional Withholding of Amgen Investigational 
Product and Other Protocol-required Therapies due to Potential 
Hepatotoxicity 
For subjects who do not meet the criteria for permanent discontinuation of evolocumab 
outlined above and have no underlying liver disease, and eligibility criteria requiring 
transaminases and TBL < 1.5x ULN at baseline or subjects with underlying liver disease 
and baseline abnormal transaminases, the following rules are recommended for 
withholding of Amgen IP and other protocol-required therapies: 
• 
Elevation of either AST or ALT according to the following schedule: 
Baseline AST or ALT value 
AST or ALT elevation 
Any 
> 8x ULN at any time 
Any 
> 5x ULN but < 8x ULN for ≥ 2 weeks 
Any 
> 5x ULN but < 8x ULN and unable to adhere to enhanced 
monitoring schedule 
Any 
> 3x ULN with clinical signs or symptoms that are 
consistent with hepatitis (such as right upper quadrant 
pain/tenderness, fever, nausea, vomiting, jaundice). 
• 
OR:  TBL > 3x ULN at any time 
• 
OR:  ALP > 8x ULN at any time 


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Evolocumab should be withheld pending investigation into alternative causes of DILI.  If 
IP is withheld, the subject is to be followed according to recommendations in Appendix A 
for possible DILI.  Rechallenge may be considered if an alternative cause for impaired 
liver tests (ALT, AST, ALP) and/or elevated TBL, is discovered and the laboratory 
abnormalities resolve to normal or baseline (Section 6.3.3).   
6.3.3 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then evolocumab should be permanently 
discontinued.  Subjects who clearly meet the criteria for permanent discontinuation (as 
described in Section 6.3.1) should never be rechallenged. 
6.4 
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 6.7.  If subjects are on statin or other lipid lowering therapy (not required 
to participate in this study), they must be on a stable dose for at least 8 weeks prior to 
screening and during the entire time of screening and throughout the study. 
Concomitant therapies are to be collected in the CRF from the signing of the ICF through 
the EOS visit. 
For concomitant therapies being taken for hyperlipidemia, collect therapy name, 
indication, dose, unit, frequency, route, start date, and stop date.  For other medications 
being taken, collect therapy name, indication, unit, frequency, route, start date and stop 
date. 
6.5 
Medical Devices 
The prefilled AI/Pen used in this study will be provided by Amgen.  Additional details for 
the AI/Pen is to be provided in the IPIM. 
Other medical devices, which are not considered test articles, may be used in the 
conduct of this study as part of standard care.  These devices that are commercially 
available are not usually provided or reimbursed by Amgen (except, for example, if 
required by local regulation).  The investigator will be responsible for obtaining supplies 
of these devices.   


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6.6 
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 drugs or devices provisioned and/or repackaged /modified by Amgen. 
Drugs or devices includes evolocumab/placebo and prefilled AI/Pen.  
Any product complaint(s) associated with an IP or device supplied by Amgen is to be 
reported according to the instructions provided in the IPIM. 
6.7 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
The following treatments are not permitted during the study: 
• 
Treatments for inhibition of PCSK9 or any investigational therapies other than 
study provided IP 
• 
Any lipid therapies not taken at the time of screening and enrollment 
• 
Treatment with medications that may have a significant effect on plaque 
inflammation as measured by plaque TBR, including:  oral, rectal, or injectable 
corticosteroids or immunosuppressive medications (eg, cyclosporine, 
methotrexate, tacrolimus, azathioprine, anti-thymocyte globulin, sirolimus, 
anti-TNF agents such as infliximab, anti- IL6 therapy such as tocilizumab, or 
anti-IL1 therapy). 
• 
Treatment with aspirin (> 325 mg/day) or NSAIDs (> 1000 mg/day) 
Please contact the Amgen medical monitor or designee if any of these therapies should 
be initiated during the study.  Note that a change in lipid-lowering therapy does not 
necessarily require ending IP (except in case of non-study provided PCSK9 inhibition 
therapy). 
The following treatments are not recommended because of their potential impact on 
metabolism of certain statins: 
• 
Medications or foods that are known potent inhibitors of CYP3A (eg, 
itraconazole, ketoconazole, and other antifungal azoles, macrolide antibiotics 
erythromycin, clarithromycin, and the ketolide antibiotic telithromycin, human 
immunodeficiency virus or hepatitis C virus protease inhibitors, antidepressant 
nefazodone and grapefruit juice in large quantities [> 1 quart daily, ie, 
approximately 1 L]) should not be used during the study. 


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7. 
STUDY PROCEDURES 
Screening assessments and study procedures outlined in this section and in Table 1 can 
only be performed after obtaining informed consent. 
All on-study visits should be scheduled from day 1 (date of the first dose of 
evolocumab/placebo) on the 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 time point, 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 rescreen 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 
Screening assessments and study procedures are outlined in this section and in Table 1 
(Schedule of Assessments). 


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Table 1.  Schedule of Assessments 
Screen 1 
Screen 2 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
EOS 
Study Day / Week / Other time point 
-56 days from Day 1 
Day 1 
Week 4  
(± 7d) 
Week 8  
(± 7d) 
Week 12 
(± 7d) 
Week16 
(-7d) 
General Procedures 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Vital signs  
X 
 
 
 
 
 
 
Review for AEs/SAEs/ADEs/DREs 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
 
 
 
 
 
 
Body weight, waist circumference, and height 
X 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
Laboratory 
 
 
 
 
 
 
 
 
Central Laboratory 
 
 
 
 
 
 
 
 
Fasting lipids 
X 
 
X 
 
X 
 
X 
 
Lp(a) 
X 
 
X 
 
X 
 
X 
 
OxPL/ApoB, IL-6, hsCRP
a
 
 
 
X 
 
 
 
X 
 
Biomarkers (serum, plasma and cell pellet
b
) 
 
 
X 
 
 
 
X 
 
Lp(a) Isoform number 
 
 
X 
 
 
 
X 
 
Chemistry 
X 
 
 
 
 
 
 
 
Hematology 
 
 
X 
 
 
 
 
 
Urinalysis 
 
 
X 
 
 
 
 
 
eGFR 
X 
 
 
 
 
 
 
 
Hemoglobin A1C 
X 
 
 
 
 
 
 
Serum pregnancy and FSH
c
 
X 
 
 
 
 
 
 
 
Local Laboratory 
 
 
 
 
 
 
 
 
Serum pregnancy and FSH
c
 
 
 
 
 
 
X 
 
Investigational Product 
 
 
 
 
 
 
 
Placebo run-in 
 
X 
 
 
 
 
 
Investigational Product (office) administration 
 
 
X 
X 
X 
X 
 
FDG-PET/CT 
 
X
d,e
 
 
 
 
 
X
d 
ADE=adverse device effect; AE=adverse event; DRE=disease-related event; eGFR=estimated glomerular filtration rate; hsCRP=high sensitivity C-reactive protein; 
Lp(a)=lipoprotein(a); OxPL/ApoB=oxidized phospholipids/apolipoprotein(B); SAE=serious adverse event. 
a.UCSD (OxPL/apoB) and Amgen (IL-6). 
b.Cell pellet is collected only at day 1 (residual cell pellet from the plasma biomarker sample). 
c.FSH will be performed if needed per Exclusion 218 (see Section 4.1.3). 
d.Pregnancy testing (either serum or urine) will be performed locally prior to the FDG-PET/CT scan. 
e.FDG-PET CT images need to be approved by the Core lab before the subject can be randomized. 


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7.2 
General Study Procedures 
The procedures performed at each study visit are outlined Table 1.  Details regarding 
each type of procedure are provided in subsequent sub-sections.   
Refer to the applicable supplemental central laboratory, IVRS/IWRS, IPIM, and study 
manuals for detailed collection and handling procedures.   
7.2.1 
Screening Enrollment and/or Randomization 
Informed consent must be obtained before completing any other screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  After signing the written 
ICF, site will register the subject in the IVRS/IWRS and screen the subject in order to 
assess eligibility for participation.  The screening window is 56 days.  If a subject has not 
met all eligibility criteria at the end of the 56-day window, the subject will be registered as 
a screen fail.  Screen fail subjects may be eligible for rescreening once as described in 
Section 7.2.2. 
7.2.2 
Rescreening 
Subjects who are unable to complete or meet eligibility on initial screening will be 
permitted to rescreen once.  Rescreen subjects must first be registered as screen failed 
in IVRS/IWRS and subsequently registered as rescreened.  Subjects will retain the same 
subject identification number assigned at the original screening.  Subjects who are to be 
rescreened must be re-consented and repeat all screening 1 procedures.  Subjects can 
only undergo 1 initial FDG-PET/CT during screen 2; therefore subjects who screen fail 
on the basis of the TBR criteria may not be rescreened.   
7.2.3 
Treatment 
Visits will occur per the Schedule of Assessments (Table 1) during the treatment period 
from day 1 (week 1, baseline) through week 12.  Visits during the treatment period must 
be completed within ± 7 days of the target visit date. 
Evolocumab/placebo is to be administered at the site after blood draw procedures.  IP 
administration should be the last procedure to be performed during each visit. 
If a subject withdraws from the study early, all efforts should be made to complete and 
report the observations as thoroughly as possible up to the date of withdrawal.  The 
procedures for the EOS visit should be completed at the time of withdrawal 
(Section 7.2.4). 


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7.2.4 
End of Study Visit 
At week 16, subjects will return to the site for the EOS visit for the procedures specified 
in the Schedule of Assessments (Table 1). 
End of Study is defined as the date when the last subject has completed all planned 
study procedures up to and including the EOS visit as outlined in the Schedule of 
Assessments (Table 1).   
Subjects who do not complete their EOS visit and assessments are considered early 
termination.  Subjects who terminate the study early prior to week 12 will not be eligible 
to perform the final FDG-PET/CT imaging. 
7.3 
Description of Study Procedures 
The sections below provide a description of the individual study procedures for required 
timepoints. 
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 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness.  
Additionally demographic data will be used to study the impact on biomarkers variability 
and pharmacokinetics of the protocol-required therapies. 
7.3.3 
Medical History 
The investigator or designee will collect a complete medical and surgical history that 
started within 120 days prior to enrollment through the signing of the ICF.  Medical 
history will include information on the subject’s concurrent medical conditions.  Record 
all findings on the medical history CRF. 
In addition to the medical history above, cardiovascular history and history of cancer 
and/or malignancy must date back to the original diagnosis.  Record all findings on the 
medical history CRF. 
7.3.4 
Physical Examination 
A physical examination will be conducted as per standard of care.  Physical examination 
findings should be recorded on the appropriate CRF (eg, medical history, event). 


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7.3.5 
Vital Signs 
The following measurements must be performed:  systolic/diastolic blood pressure, heart 
rate, respiratory rate, and temperature.  Subject must be in a supine position in a rested 
and calm state for at least 5 minutes before blood pressure assessments are conducted.  
If the subject is unable to be in the supine position, the subject should be in most 
recumbent position possible.  The position selected for a subject should be the same 
throughout the study and documented on the vital signs CRF.  The arm with the highest 
systolic reading at screening will then be used for further BP readings throughout study.  
The appropriate sized cuff should be used. 
The temperature location selected for a subject should be the same that is used 
throughout the study and documented on the vital signs CRF. 
If abnormalities are found and they are considered an adverse event, record on the 
Event CRF. 
7.3.6 
Height, Weight, and Waist Circumference 
Height in inches and weight in pounds should be measured without shoes. 
For measurement of waist circumference, subjects should wear minimal clothing to 
ensure that the measuring tape is correctly positioned.  Subjects should stand erect with 
the abdomen relaxed, arms at the sides, feet together and with their weight equally 
divided over both legs.  To perform the waist measurement, the lowest rib margin is first 
located and marked with a pen.  The iliac crest is then palpated in the midaxillary line, 
and also marked.  It is recommended to apply an elastic tape horizontally midway 
between the lowest rib margin and the iliac crest, and tie firmly so that it stays in position 
around the abdomen about the level of the umbilicus.  The elastic tape thus defines the 
level of the waist circumference, which can then be measured by positioning the 
measuring tape over the elastic tape.  Subjects are asked to breathe normally, and to 
breathe out gently at the time of the measurement to prevent them from contracting their 
muscles or from holding their breath.  Measurements should be performed using the 
same procedure throughout the study.  The reading is taken to the nearest centimeter or 
½ inch and entered in the source document. 
7.3.7 
Adverse Events, Serious Adverse Events, Adverse Device Effects, 
and Disease-related Events 
Adverse events, serious adverse events, adverse device effects (ADE)s, and 
disease-related events observed by the investigator or reported by the subject will be 
collected at all study visits from the signing of the ICF through the EOS visit. 


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7.3.8 
Prior and Concomitant Medications 
Prior therapies, which include general and targeted therapies (eg, statins and lipid 
lowering), taken 6 months prior to enrollment should be collected with the following 
information:  therapy name, indication, dose, unit, frequency, route, start date, and stop 
date. 
Concomitant therapies are to be collected from the signing of the ICF through the EOS 
visit, and should include the therapy name, indication, dose, unit, frequency, route, start 
date, and stop date.  Concomitant medications include over-the-counter products and 
vitamins administered while the subject is on study.   
7.4 
FDG-PET/CT 
Subjects must be fasting prior to the FDG-PET/CT.  FDG-PET/CT images of the carotid 
arteries and ascending thoracic aorta will be obtained using the standard methods 
(Fayad et al, 2011) as outlined in the study 20130293 imaging training.  The blinded 
images will be analyzed by a central core lab.  The initial step of image analysis entails 
delineating the pre-defined sections of the target vessels (either right carotid, left carotid, 
or thoracic aorta). 
Arterial FDG uptake is measured within pre-defined sections of the target vessels and 
measurements in the aorta, right and left carotids are made.  The maximum SUV will be 
calculated as a time- and dose-corrected tissue radioactivity divided by body weight for 
each region of interest.  The TBR is calculated from the ratio of the SUV of the artery 
compared to background venous activity.  The superior vena cava will be used for 
correction of aortic values and the internal jugular veins will be used for correction of 
carotid values.  Arterial FDG uptake (TBR) is evaluated in the 3 target arterial locations 
(right carotid, left carotid, or thoracic aorta).  The artery with the highest FDG uptake 
(highest mean of the maximum TBR) at baseline will be identified as the index vessel.  
The average of the maximum TBR activity within the MDS of the index vessel (MDS 
TBR) will be defined as the 1.5-cm arterial segment, centered on the slice of artery 
demonstrating the highest FDG uptake at baseline, and calculated as a mean of 
maximum TBR values derived from 3 contiguous axial segments.  The primary objective 
of the study is to determine the change in TBR of the MDS at 16 weeks compared to 
baseline in subjects taking evolocumab compared to placebo segments. 


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7.5 
Laboratory Assessments 
All screening and on-study laboratory samples will be processed and sent to the central 
laboratory with the exception of serum pregnancy after screen 1 visit (Section 7.5.2).   
The central laboratory will provide a study manual that outlines handling, labeling, and 
shipping procedures for all samples.   
Subjects must be fasting for ≥ 9 hours before each study visit where fasting lipid 
samples are obtained. 
All blood samples will be obtained by venipuncture before IP administration.  The date 
and time of sample collection will be recorded in the source documents at the site.  
Specific analytes for serum chemistry, hematology, urinalysis, and other testing to be 
conducted on blood and urine samples are shown in Table 2.  Although not specifically 
listed, additional components, abnormal, and/or atypical cells will also be reported if 
present. 
As the laboratory testing requirement at each visit is different, total volumes ranging from 
approximately 5 to 70 mL of blood may be collected per visit, depending on the visit 
requirements.  If a subject completes the entire study, the total amount of blood collected 
per protocol is estimated to be approximately 210 mL.  However, additional blood draws 
and testing may be required for the care of the subject at the discretion of the 
investigator. 


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Table 2.  Analyte Listing 
Chemistry 
Hematology 
Urinalysis 
Other Labs 
Sodium 
Potassium  
Chloride 
Bicarbonate 
Total protein  
Albumin  
Calcium 
Magnesium 
Phosphorus 
Glucose (Fasting) 
BUN or Urea  
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin  
CK 
ALP  
LDH 
AST (SGOT)  
ALT (SGPT) 
Hemoglobin 
Hematocrit  
MCV 
MCH  
MCHC 
RDW  
Platelets  
RBC  
WBC 
Differential 
• Neutrophil 
• Bands 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes 
Specific 
Gravity 
 pH  
Blood  
Protein  
Glucose 
Bilirubin 
WBC  
RBC Epithelial 
Cells Bacteria 
Casts Crystals 
Fasting Lipids 
• 
Total cholesterol 
• 
HDL-C 
• 
LDL-C 
• 
Triglycerides 
• 
VLDL-C 
• 
non-HDL-C 
• 
Total Cholesterol/ HDL-C ratio 
• 
ApoA1 
• 
ApoB/ApoA1 ratio 
• 
ApoB  
Lp(a)  
OxPL/ApoB 
IL-6 
hsCRP 
Lp(a) isoform distribution 
 
Anti-evolocumab antibodies (drawn 
per investigator’s discretion for 
safety assessments) 
HbA1c 
eGFR (calculated) 
Serum pregnancy test and FSH (if 
needed per Exclusion 218) 
Serum biomarkers for collection 
7.5.1 
Blinding of Laboratory Test Results 
In order to protect the blinding of the double-blind treatment period, the following 
labs will be blinded to the Amgen study team and site staff from post-day 1 until 
unblinding of the clinical database and not reported to sites: fasting lipid panel 
(see Table 2), Lp(a), OxPL/ApoB, IL-6, hsCRP, and Lp(a) isoform distribution. 
In addition, investigators and staff involved with this trial and all medical staff 
involved in the subject’s medical care should not perform non-protocol testing of 
these analytes during a subject’s study participation and until at least 12 weeks 
after the subject’s last administration of IP or the end of the study, whichever is 
later, to prevent unblinding the patient and site to the treatment assignment, 
except when it is medically necessary.  


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If a local lipid panel is drawn, all reasonable steps must be undertaken to avoid 
informing the subject and study personnel of the results. 
7.5.2 
Serum Pregnancy Test 
All females, except those who are confirmed surgically sterile or at least 2 years 
postmenopausal, must have a negative serum pregnancy test at baseline, prior to 
administering the first dose of evolocumab/placebo.  The central laboratory will provide 
the baseline pregnancy tests.  Pregnancy testing will be performed locally at each site 
prior to each FDG-PET/CT scan (serum or urine) and at visit 4 (week 12) (serum).  If a 
pregnancy test is positive prior to the FDG-PET/CT scan, the subject should not undergo 
the procedure and the pregnancy should be reported in accordance with Section 9.3.   
7.6 
Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biological 
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.  Amgen may attempt 
to develop test(s) designed to identify subjects most likely to respond positively or 
negatively to evolocumab. 
For all subjects in the study, 3 samples of EDTA-plasma and 3 serum of (3 vials of 
500 µL each) will be collected vials at each time point of collection (prior to dosing on 
day 1 and at the end of the study [week 16]) for biomarker development.  The samples 
must be kept at -70°C at all times and shipped in 1 batch on dry ice at the end of the 
study.   
7.7 
Pharmacogenetic Studies 
In the pharmacogenetic portion of this study, DNA analyses may be performed.  These 
pharmacogenetic analyses focus on inherited genetic variations to evaluate their 
possible correlation to the disease and/or responsiveness to the therapies used in this 
study.  The goals of the optional studies include the use of genetic markers to help in the 
investigation of elevated Lp(a) and/or to identify subjects who may have positive or 
negative response to the IP.   
For all subjects in the study who have consented to pharmacogenetic analyses, 1 cell 
pellet sample (ie, the residual pellet from the EDTA-plasma biomarker sample) of 500 µL 
will be collected at day 1.  The samples must be kept at -70°C at all times and shipped in 
1 batch on dry ice at the end of the study. 


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7.8 
Sample Storage and Destruction 
Any blood 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 
underlying inflammatory conditions, the dose response and/or prediction of response to 
evolocumab, and characterize aspects of the molecule (eg, mechanism of action/target, 
metabolites).  Results from this analysis 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 pharmacogenetic, 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 ICF. 
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 
blood 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 


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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.  See 
Section 11.3 for subject 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 continue receiving IP 
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 IP 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) and the level of follow-up that is agreed to by the subject (eg, in person, by 
telephone/mail, through family/friends, in correspondence/communication with other 
physicians, from review of the medical records).   
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 
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 IP 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 IP and/or other 
protocol-required therapies by a separate protocol or as provided for by the local 
country’s regulatory mechanism, based on parameters consistent with Section 12.1. 


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8.3 
Reasons for Removal From Run-in, Treatment, or Study 
8.3.1 
Reasons for Removal From Treatment 
A subject may be removed from study treatment or procedural assessments for any of 
the following reasons: 
• 
Subject request 
• 
Safety concern (eg, due to adverse event, ineligibility determined, protocol 
deviation, non-compliance, requirement for alternative therapy, or pregnancy) 
• 
Decision by sponsor (other than subject request, safety concern, lost to 
follow-up) 
• 
Death 
• 
Lost to follow-up 
8.3.2 
Reasons for Removal From Study 
A subject may be removed from the study for any of the following reasons: 
• 
Withdrawal of consent from study  
• 
Decision by sponsor 
• 
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. 
Disease-related events for the purposes of this study include manifestations and 
complications of atherosclerotic vascular disease such as coronary artery disease, 
angina, myocardial infarction, ischemic stroke, transient ischemic attack, carotid artery 
disease, peripheral vascular disease (including complications such as claudication or 
amputation), testing suggesting progression of atherosclerotic vascular disease, and 
treatment for atherosclerotic vascular disease and its complications such as 
revascularization procedures (coronary and non-coronary) and surgeries.  Such events 
do not meet the definition of an adverse event unless assessed to be more severe than 
expected for the subject’s condition. 
Disease-related events and/or disease-related outcomes that do not qualify as serious 
adverse events:   


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• 
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 IP /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.   
An ADE is any adverse event related to the use of a medical device.  Adverse device 
effects include adverse events resulting from insufficient or inadequate instructions for 
use, adverse events resulting from any malfunction of the device, or adverse events 
resulting from use error or from intentional misuse of the device. 
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 event 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 as described above 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 
IMP/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, DILI (see Appendix A for 
DILI reporting criteria), or events that necessitate an emergency room visit, outpatient 
surgery, or urgent intervention. 
The criteria for grade 4 in the Common Terminology Criteria for Adverse Events 
(CTCAE) grading scale differs from the regulatory criteria for serious adverse events.  It 
is left to the investigator’s judgment to report these grade 4 abnormalities as serious 
adverse events. 
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 or reported by the subject that occur after the signing of the ICF through 


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the EOS visit are reported using the Event CRF.  Additionally, the investigator is required 
to report a fatal disease-related Event on the Event CRF.   
Events assessed by the investigator to be related to the IMP/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 from the signing of the ICF through the 
EOS visit 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 (and/or toxicity per protocol), 
• 
Assessment of relatedness to IP (evolocumab/placebo and/or the AI/Pen), or 
other protocol-required therapies/protocol-required procedure or activity, and 
• 
Action taken. 
The adverse event grading scale used will be the 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 IMP 
(evolocumab or placebo) and/or the investigational device (AI/Pen).  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 IMP (evolocumab or placebo) and/or the 
investigational device (AI/Pen)?”  
The investigator must assess whether the adverse event is possibly related to use of the 
investigational device (AI/Pen) or any study-mandated activity (eg, administration of IP, 
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 IP, protocol-required therapies, device(s)), and/or 
procedure?”  


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If the severity of an adverse event worsens from the date of onset to the date of 
resolution, record a single event for each increased level of severity on the Event CRF. 
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 ICF through 
30 days after the last dose of IP or the EOS visit, whichever is later, are recorded in the 
subject’s medical record and are submitted to Amgen.  All serious adverse events must 
be submitted to Amgen within 24 hours following the investigator’s knowledge of the 
event via the Event CRF.   
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. 


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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 (GCP).   
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. 
9.2.2.3 
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 the 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 the 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.   
See Appendix B for a sample of the Serious Adverse Event Worksheet/electronic 
Serious Adverse Event Contingency Report Form. 
In addition, 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 (eSAE) 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 
(a paper-based form).  The data must be entered into the EDC system when the system 
is again available. 


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In addition to the attributes listed in Section 9.2.2.1, the investigator must also complete 
the serious adverse event section of the Event CRF. 
9.3 
Pregnancy and Lactation Reporting 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking protocol-required therapies report the pregnancy to Amgen as specified 
below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
report pregnancies that occur after the last dose of protocol-required therapies through 
15 weeks after the end of treatment with evolocumab. 
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).   
If a lactation case occurs while the female subject is taking protocol-required therapies 
report the lactation case to Amgen as specified below.   
In addition to reporting a lactation case during the study, investigators should report 
lactation cases that occur after the last dose of protocol-required therapies through 
15 weeks after the end of treatment with evolocumab/placebo.   
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). 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoint 
• 
Percentage change from baseline in TBR within the MDS of the index vessel 
(right carotid, left carotid, or thoracic aorta) by FDG-PET/CT at week 16 
10.1.1.2 
Secondary Endpoints 
• 
Percentage change in Lp(a) from baseline at week 16 
• 
Percentage change in LDL-C from baseline at week 16 
• 
Percentage change in ApoB from baseline at week 16 
10.1.1.3 
Safety Endpoints 
• 
Subject incidence of treatment emergent adverse events compared to placebo for 
the duration of the study 


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group compared to the control group.  A combined standard deviation of 20.0% for the 
percentage change from baseline to week 16 is assumed for MDS TBR.  After 
accounting for a dropout rate of 25%, the power is greater than 90% for testing 
superiority of evolocumab over placebo on the percentage change in MDS TBR at 
week 16.   
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 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 9.2.2.2). 
10.4 
Planned Analyses 
10.4.1 
Primary Analysis 
The primary analysis will be conducted when all subjects have either completed all the 
scheduled study visits or have early terminated from the study. 
10.5 
Planned Methods of Analysis 
10.5.1 
General Considerations 
Subject disposition, demographics, baseline characteristics, and exposure to IP will be 
summarized by treatment group. 
Summary statistics for continuous variables will include the number of subjects, mean, 
median, standard deviation or standard error, minimum, and maximum.  For categorical 
variables, the frequency and percentage will be given.  No adjustments for multiplicity 
will be applied. 
Unless specified otherwise, the FAS will be the default analysis set in this study and data 
will be summarized by randomized treatment group. The superiority of evolocumab to 
placebo will be assessed for all efficacy endpoints. The primary analysis will include 
testing for the primary and secondary endpoints. 
10.5.2 
Primary Efficacy Endpoint 
The primary endpoint is the percentage change from baseline in MDS TBR at week 16. 
In order to estimate the difference in mean percentage change from baseline in MDS 
TBR and to handle missing data for the primary endpoint, a multivariate regression 
model will be used. The response variables are percent change from baseline in MDS 


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TBR at week 16, baseline MDS TBR, percent change from baseline in Lp(a) at weeks 8 
and 16, and baseline Lp(a). Each response follows its own regression model: 
• 
Percent change in MDS TBR will be regressed on treatment group and the 
stratification factor; 
• 
Baseline MDS TBR will be regressed on the stratification factor; 
• 
Percentage change in Lp(a) will be regressed on the treatment group, 
stratification variable, visit, and treatment group by visit 
• 
Baseline Lp(a) will be regressed on the stratification factor. 
The variance-covariance matrix of the error terms from the response variables in the 
multivariate regression will be estimated. This analysis will use the FAS. 
FDG-PET/CT observations made after an on-study cardiovascular event will be included 
in the primary analysis. A sensitivity analysis excluding these observations will be 
conducted. 
10.5.3 
Secondary Efficacy Endpoint(s) 
Analysis of the secondary endpoints Lp(a), ApoB, and LDL-C will use a repeated 
measures model on the FAS including terms for treatment group, stratification factors, 
scheduled visit, and the interaction of treatment with scheduled visit. 
10.5.4 
Safety Endpoints 
The current Medical Dictionary for Regulatory Activities version at the time of the data 
lock will be used to code all adverse events to a system organ class and a preferred 
term. 
Subject incidence of all treatment emergent adverse events will be tabulated by system 
organ class and preferred term.  Tables of fatal adverse events, serious adverse events, 
adverse events leading to withdrawal from IP, device-related adverse events, and 
significant treatment-emergent adverse events will also be provided.  Subject incidence 
of disease-related events and fatal disease-related events will be tabulated by system 
organ class and preferred term.  Subject-level data may be provided instead of tables if 
the subject incidence is low. 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample ICF 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 Clinical Study Manager to the investigator.  The written 


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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 IP (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 
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 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 ICF is to be signed and personally dated by the subject and by the 
person who conducted the informed consent discussion. The original signed ICF 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 
ICF to the subject and must allow for questions.  Thereafter, both the subject and the 
witness must sign the ICF to attest that informed consent was freely given and 
understood. 
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed ICF, 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 ICF must be received by Amgen before 
recruitment of subjects into the study and shipment of Amgen IP. 
The investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator is to notify the IRB/IEC of deviations from the protocol or 


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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 renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IRB/IEC continuance of approval must be sent to Amgen. 
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.  
• 
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 ICFs) are to be kept in 
confidence by the investigator, except as described below. 
In compliance with International Conference on Harmonisation (ICH) Tripartite Guideline 
on 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 


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12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
If Amgen amends the protocol, agreement from the investigator must be obtained.  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. 
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 early termination (ET) and send a copy of the notification to 
Amgen.   
Subjects may be eligible for continued treatment with Amgen IP 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 
IP 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. 
In this study, the IVRS/IWRS captures the following data points and these are 
considered source data:  subject ID, enrollment date, IP dispensation date and IP box 
number dispensed. 
Case report form 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).   
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.   


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Elements to include: 
• 
Subject files containing completed CRFs, ICFs, 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 
• 
IP-related correspondence including Proof of Receipts, IP Accountability 
Record(s), Return of IP for Destruction Form(s), Final IP Reconciliation 
Statement, as applicable. 
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. 


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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. 
• 
The investigator signs only the Investigator Verification Form for this electronic 
data capture 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 early termination) 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.   


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12.6 
Publication Policy 
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; and (3) final 
approval of the version to be published.  Authors should meet conditions 1, 2, 
and 3. 
• 
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. 
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 Compensation for Injury section of the ICF that is available as 
a separate document. 


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13. 
REFERENCES 
Abifadel M, Rabès JP, Devillers M, et al. Mutations and polymorphisms in the proprotein 
convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. Hum 
Mutat. 2009;30:520–529. 
Dubé JB, Boffa MB, Hegele RA, Koschinsky ML. Lipoprotein(a):  more interesting than 
ever after 50 years. Curr Opin Lipido. 2012;23,133–40. 
Erqou S, Kaptoge S, Perry PL, et al. Lipoprotein(a) concentration and the risk of 
coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302:412–423. 
Evolocumab (AMG 145) Investigator’s Brochure, Edition 9.0. Amgen, 
17 September 2015. 
Fayad ZA, Mani V, Woodward M, et al. Rationale and design of dal-PLAQUE:  a study 
assessing efficacy and safety of dalcetrapib on progression or regression of 
atherosclerosis using magnetic resonance imaging and 18F-fluorodeoxyglucose positron 
emission tomography/computed tomography. Am Heart J. 2011;162(2):214-221. 
Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, 
July 2009. http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf. 
Joshi F, Rosenbaum D, Bordes S, Rudd, JHF. Vascular imaging with positron emission 
tomography. J Intern Med. 2011;270:99–109. 
Kamstrup PR, Tybjærg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated 
lipoprotein(a) and increased risk of myocardial infarction. JAMA. 2009;301:2331–2339. 
Koschinsky ML, Marcovina SM. Structure-function relationships in apolipoprotein(a):  
insights into lipoprotein(a) assembly and pathogenicity. Curr Opin Lipidol. 
2004;15:167-174. 
Leibundgut G, et al. Determinants of binding of oxidized phospholipids on apolipoprotein 
(a) and lipoprotein(a). J Lipid Res. 2013;54,2815–30. 
Nordestgaard BG, Chapman MJ, Ray K, et al. European Atherosclerosis Society 
Consensus Panel. Lipoprotein (a) as a cardiovascular risk factor. Eur Heart J. 
2010;31:2844–2853. 
The Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of 
vascular disease. JAMA. 2009;302;1993–2000. 
Romagnuolo R, Scipione CA, Boffa MB, et al. Lipoprotein(a) catabolism is regulated by 
proprotein convertase subtilisin/kexin type 9 through the low density lipoprotein receptor. 
J Biol Chem. 2015;290(18):11649-62. 
Rouy D, Grailhe P, Nigon F, Chapman J, Angles-Cano E. Lipoprotein(a) impairs 
generation of plasmin by fibrin-bound tissue-type plasminogen activator. In vitro studies 
in a plasma milieu. Arterioscler Thromb. 1991;11:629–638. 
Rudd JHF, Myers KS, Bansilal S, et al. 18Fluorodeoxyglucose Positron Emission 
Tomography Imaging of AtheroscleroticPlaque Inflammation Is Highly Reproducible:  
Implications For Atheroscrolsis Therapy Trials. J Am Coll Cardiol. 2007;50:892-896. 
Rosenbaum D, Millon A, Fayad Z. Molecular Imaging in Atherosclerosis:  FDG PET. 
Curr Atheroscler Rep. 2012;14,429–37. 
Tawakol A, Fayad ZA, Mogg R, et al. Intensification of Statin Therapy Results in a Rapid 
Reduction in Atherosclerotic Inflammation:  Results of A Multi-Center FDG-PET/CT 
Feasibility Study. J Am Coll Cardiol. 2013; 62:909-917. 


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Tawakol A, Migrino RQ, Bashian GG, Bedri S, Vermylen D, Cury RC, Yates D, 
LaMuraglia GM, Furie K, Houser S, Gewirtz H, Muller JE, Brady TJ, Fischman AJ. In 
vivo 18F-fluorodeoxyglucose positron emission tomography imaging  provides  a  
noninvasive  measure  of  carotid  plaque  inflammation  in  patients.  J  Am  Coll  
Cardiol. 2006;48(9):1818-24.  
Tsimikas S, Hall J. Lipoprotein(a) as a Potential Causal Genetic Risk factor of 
Cardiovascular Disease:  A rationale for Increased Efforts to Understand its 
Pathophysiology and Develop Targeted Therapies. J Am Coll Cardiol. 2012;60:716-21.  
Tziomalos K1, Athyros VG, Wierzbicki AS, Mikhailidis DP. Lipoprotein a: where are we 
now? Curr Opin Cardiol. 2009;24(4):351-7. 
van Wijk DF, Sjouke B, Figueroa A, et al. Nonpharmacological Lipoprotein Apheresis 
Reduces Arterial Inflammation in Familial Hypercholesterolemia. J Am Coll Cardiol. 
2014;64(14):1418-26. 


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14. 
APPENDICES 


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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
Refer to the NCI CTCAE Version 4.0 for AE grading and information.  The CTCAE is 
available at the following 
link:http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Drug-induced Liver Injury Reporting & Additional Assessments  
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation according to the criteria specified in Section 
Reporting 
6.3 require 
the following: 
• 
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 9.2.2.2. 
Additional Clinical Assessments and Observation 
All subjects in whom IP or protocol-required therapies is/are withheld (either permanently 
or conditionally) due to potential DILI as specified in Sections 6.3.1 and 6.3.2 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:   
• 
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 IP 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 with differential to assess for eosinophilia 


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- 
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 
- 
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 creatine phosphokinsase, haptoglobin, lactate dehydrogenase, 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 IP 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 (Sample eSerious 
Adverse Event Contingency Report Form – paper-based Form) 
 


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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 


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Amendment 3 
Protocol Title: A RaNdomized Double-blInd Placebo ConTrolled Study 
Characterizing THe Effects of PCSK9 Inhibition On Arterial Wall Inflammation in 
Patients With Elevated Lp(a) (ANITSCHKOW) 
 
Amgen Protocol Number (AMG145/Evolocumab) 20130293 
EudraCT number 2015‐003731‐35 
 
Amendment 3 Date: 
08 February 2017 
 
Rationale: 
The intent of this amendment is to clarify the blinding of central laboratory test results 
during the double-blind treatment period and provide guidance in obtaining local lipid 
panels. 


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Table 1.  Summary of Amendment Changes 
Section   
Text in Protocol  Amended Text  
Rationale for 
Change  
Header 
Global 
Replace:   
25 August 2016 
With:   
08 February 2017 
Update to new 
date. 
Front page 
 
Add: 
Amendment 3 Date 
08 February 2017 
 
Update to new 
date. 
Investigator’s 
agreement 
Paragraph 1 
Replace: 
I have read the attached protocol entitled “A RaNdomized Double-blInd Placebo ConTrolled 
Study Characterizing THe Effects of PCSK9 Inhibition On Arterial Wall inflammation in 
Patients with Elevated Lp(a) (ANITSCHKOW)”, dated 25 August 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 Characterizing THe Effects of PCSK9 Inhibition On Arterial Wall inflammation in 
Patients with Elevated Lp(a) (ANITSCHKOW)”, dated 08 February 2017, and agree to abide 
by all provisions set forth therein. 
Update to new 
date 
Section 7.5 
Paragraph 1 
Replace: 
All screening and on-study laboratory samples will be processed and sent to the central 
laboratory with the exception of serum pregnancy after screen 1 visit (Section 7.5.1).   
With: 
All screening and on-study laboratory samples will be processed and sent to the central 
laboratory with the exception of serum pregnancy after screen 1 visit (Section 7.5.2).   
Update to new 
Section number. 
Page 1 of 2 


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Table 1.  Summary of Amendment Changes 
Section 7.5  
Page 34 - 35 
Add: 
7.5.1 
Blinding of Laboratory Test Results 
In order to protect the blinding of the double-blind treatment period, the following labs 
will be blinded to the Amgen study team and site staff from post-day 1 until unblinding 
of the clinical database and not reported to sites: fasting lipid panel (see Table 2), 
Lp(a), OxPL/ApoB, IL-6, hsCRP, and Lp(a) isoform distribution. 
In addition, investigators and staff involved with this trial and all medical staff involved 
in the subject’s medical care should not perform non-protocol testing of these analytes 
during a subject’s study participation and until at least 12 weeks after the subject’s last 
administration of IP or the end of the study, whichever is later, to prevent unblinding 
the patient and site to the treatment assignment, except when it is medically necessary.  
If a local lipid panel is drawn, all reasonable steps must be undertaken to avoid 
informing the subject and study personnel of the results. 
Provide guidance 
in obtaining local 
lipid panels and 
clarify the blinding 
of central 
laboratory test 
results during the 
double-blind 
treatment period. 
Section 7.5 
Page 35 
Replace: 
7.5.1   Serum Pregnancy Test 
With: 
7.5.2   Serum Pregnancy Test 
Update section 
numbering 
Page 2 of 2 


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Amendment 1 
Protocol Title:  A RaNdomized Double-blInd Placebo ConTrolled Study 
Characterizing THe Effects of PCSK9 Inhibition On Arterial Wall inflammation in 
Patients With Elevated Lp(a) (ANITSCHKOW) 
 
Amgen Protocol Number (AMG 145 / Evolocumab) 20130293 
 
Protocol Date 
18 September 2015 
Amendment 1 Date: 
02 January 2016 
 
Rationale: 
The protocol was amended to change the age of the patients included in the study from 
≥ 45 to ≥ 50 years to meet the radiation dose limit required by the Dutch ethics 
committee. In addition, the study schema was updated for clarity. The primary and 
exploratory endpoints were reworded for clarity and the methods of analysis for the 
primary endpoint further detailed. 


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Amendment 2 
Protocol Title:  A RaNdomized Double-blInd Placebo ConTrolled Study 
Characterizing THe Effects of PCSK9 Inhibition On Arterial Wall Inflammation in 
Patients With Elevated Lp(a) (ANITSCHKOW) 
 
Amgen Protocol Number (AMG 145 / Evolocumab) 20130293 
EudraCT number 2015-003731-35 
 
Amendment Date: 
25 August 2016 
Rationale: 
− 
The protocol has been amended to provide clarification to minimize the risk of 
confounding the primary endpoint with prior therapies targeting Lp(a), an exclusion 
criterion has been added to exclude subjects with exposure to therapies targeting 
Lp(a) within the 12 months prior to Screening.  
− 
The protocol was amended to clarify the timing and method of pregnancy testing.  
No additional testing or change in testing has been introduced.  The ICF reflects this 
clarification in pregnancy testing.  
− 
The protocol was amended to include additional detail regarding the volume of 
blood drawn to satisfy the existing protocol-specified laboratory testing.  No 
additional testing has been introduced.  The informed consent form (ICF) reflects 
this additional level of detail regarding blood volume. 

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NCT Number: 02729025
This NCT number has been applied to the document for purposes 
of posting on clinicaltrials.gov


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