Conditions: Coronary Artery Disease (CAD)
Keywords: Optical coherence tomography (OCT) Intravascular ultrasound (IVUS) Coronary angiography Coronary artery disease Cardiovascular events Coronary atherosclerotic plaques Lipid-lowering therapy Statin Maximally tolerated statin therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 164
Healthy volunteers: no

Brief summary:
To evaluate the effect of evolocumab on fibrous cap thickness (FCT) in participants with non-ST-elevation acute coronary syndrome (NSTE-ACS) who are taking maximally tolerated statin therapy.

Detailed description:
This study seeks to identify morphologic changes, such as increase in FCT in atherosclerotic plaques associated with treatment with evolocumab and maximally tolerated statin therapy with or without additional lipid-modifying medication in patients presenting with NSTE-ACS using optical coherence tomography (OCT; primary, secondary, and exploratory endpoints).

Arms:
arm 1: Participants receive evolocumab subcutaneous injection once every month (QM) for 48 weeks. As prescribed and provided by the investigator, participants will be treated with maximally tolerated statin therapy, not expected to change for the duration of the study participation. arm 2: Participants receive placebo subcutaneous injection QM for 48 weeks. As prescribed and provided by the Investigator, participants will be treated with maximally tolerated statin therapy, not expected to change for the duration of the study participation.

Interventions: intervention 1: Evolocumab intervention 2: Placebo intervention 3: Statin therapy
Intervention descriptions: intervention 1: Participants will receive evolocumab (AMG 145) subcutaneous monthly. intervention 2: Participants will receive matching placebo subcutaneous monthly. intervention 3: high-intensity statin treatment with atorvastatin ≥ 40 mg daily or equivalent as background therapy

Investigators will up-titrate statin therapy to the maximally tolerated dose, in accordance with local guidelines, prior to randomization.

Protocol document:
Prot_002.pdf: 
Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 1 of 94 
CONFIDENTIAL 
 
 
Title Page 
Protocol Title: 
High-Resolution Assessment of 
Coronary Plaques in a Global Evolocumab 
Randomized Study (HUYGENS) 
Short Protocol Title: 
Imaging of Coronary Plaques in Subjects 
Treated With Evolocumab 
Protocol Number: 
20160184 
Investigational Product: 
Evolocumab 
Trade Name: 
Repatha® 
Sponsor 
Name of Sponsor: 
Amgen Inc. 
Address: 
One Amgen Center Drive, Thousand Oaks, CA, 
91320, USA 
Telephone Number: 
+1 (805) 447-1000 
Key 
Sponsor 
Contact 
Name: 
 MD 
Address: 
One Amgen Center Drive, Thousand Oaks, CA, 
91320, USA 
Telephone Number: 
 
Email Address: 
 
EudraCT Number: 
2017-003236-37 
NCT Number: 
Unavailable for first version  
Protocol Date: 
Document Version 
Date 
Original 
19 April 2018 
Version/Date: 
Data Element 
Standards Version 
Date 
5.0 
20 March 2015 
 
 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN; Canadian sites, 
1-866-50-AMGEN; for all other countries, 1-805-447-1000; Amgen’s general number 
in the US, 1-805-447-1000. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 2 of 94 
CONFIDENTIAL 
 
 
Investigator's Agreement: 
I have read the attached protocol entitled High-Resolution Assessment of 
Coronary Plaques in a Global Evolocumab Randomized Study (HUYGENS), dated 
19 April 2018, and agree to abide by all provisions set forth therein.   
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP), Declaration of Helsinki, and applicable 
national or local regulations/guidelines.   
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) 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 3 of 94 
CONFIDENTIAL 
 
 
Table of Contents 
Table of Contents .............................................................................................................. 3 
1. 
Protocol Synopsis..................................................................................................... 7 
2. 
Study Schema and Schedule of Activities .............................................................. 13 
2.1 
Study Schema ............................................................................................ 13 
2.2 
Schedule of Activities ................................................................................. 14 
3. 
Introduction ............................................................................................................ 17 
3.1 
Study Rationale .......................................................................................... 17 
3.2 
Background ................................................................................................ 17 
3.2.1 
Cardiovascular Disease .............................................................. 17 
3.2.2 
Intracoronary Imaging ................................................................. 18 
3.2.3 
Amgen Investigational Product Background:  
Evolocumab ............................................................................... 20 
3.3 
Benefit/Risk Assessment ............................................................................ 20 
3.3.1 
Benefits of Evolocumab .............................................................. 20 
3.3.1.1 
Reduction in Low-density Lipoprotein 
Cholesterol (LDL-C) ................................................. 20 
3.3.1.2 
Regression of Coronary Atherosclerosis ................. 21 
3.3.1.3 
Reduction in the Risk of Cardiovascular 
Events ...................................................................... 22 
3.3.2 
Risks of Evolocumab .................................................................. 22 
3.3.3 
Conclusion .................................................................................. 24 
4. 
Objectives, Endpoints, and Hypotheses ................................................................. 25 
4.1 
Objectives and Endpoints ........................................................................... 25 
4.2 
Hypothesis .................................................................................................. 26 
5. 
Study Design .......................................................................................................... 26 
5.1 
Overall Design ............................................................................................ 26 
5.2 
Number of Subjects .................................................................................... 27 
5.2.1 
Replacement of Subjects ............................................................ 27 
5.2.2 
Number of Sites .......................................................................... 27 
5.3 
End of Study ............................................................................................... 27 
5.3.1 
End of Study Definition ............................................................... 27 
5.3.2 
Study Duration for Subjects ........................................................ 28 
5.4 
Justification for Investigational Product Dose ............................................. 28 
5.5 
Patient Input on Study Design .................................................................... 28 
6. 
Study Population .................................................................................................... 28 
6.1 
Inclusion Criteria ......................................................................................... 29 
6.2 
Exclusion Criteria ........................................................................................ 30 
6.3 
Lifestyle Restrictions ................................................................................... 31 
6.3.1 
Meals and Dietary Restrictions ................................................... 31 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 4 of 94 
CONFIDENTIAL 
 
 
6.4 
Subject Enrollment ..................................................................................... 31 
6.5 
Screen Failures .......................................................................................... 32 
7. 
Treatments ............................................................................................................. 32 
7.1 
Treatment Procedures ................................................................................ 32 
7.1.1 
Investigational Products ............................................................. 32 
7.1.1.1 
Dosage Formulation:  Evolocumab .......................... 32 
7.1.1.2 
Evolocumab:  Dosage, Administration, and 
Schedule .................................................................. 33 
7.1.2 
Non-investigational Products ...................................................... 34 
7.1.3 
Medical Devices ......................................................................... 34 
7.1.4 
Other Protocol-required Therapies ............................................. 34 
7.1.5 
Other Treatment Procedures ...................................................... 36 
7.1.6 
Product Complaints .................................................................... 36 
7.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ................................................ 36 
7.2 
Method of Treatment Assignment .............................................................. 37 
7.3 
Blinding ....................................................................................................... 37 
7.3.1 
Site Personnel Access to Individual Treatment 
Assignments ............................................................................... 37 
7.3.2 
Access to Individual Subject Treatment Assignments 
by Amgen or Designees ............................................................. 38 
7.4 
Dose Modification ....................................................................................... 38 
7.4.1 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ...................................... 38 
7.4.1.1 
Amgen Investigational Product:  
Evolocumab ............................................................. 38 
7.4.1.2 
Non-Amgen Non-Investigational Product:  
Background Lipid-lowering Therapy ........................ 38 
7.4.2 
Hepatotoxicity Stopping and Rechallenge Rules ........................ 39 
7.5 
Preparation/Handling/Storage/Accountability ............................................. 39 
7.6 
Treatment Compliance ............................................................................... 39 
7.7 
Treatment of Overdose ............................................................................... 39 
7.8 
Prior and Concomitant Treatment .............................................................. 40 
7.8.1 
Prior Treatment ........................................................................... 40 
7.8.2 
Concomitant Treatment .............................................................. 40 
8. 
Discontinuation Criteria .......................................................................................... 40 
8.1 
Discontinuation of Study Treatment ........................................................... 40 
8.2 
Discontinuation From the Study ................................................................. 41 
8.2.1 
Reasons for Removal From Invasive Procedures ...................... 42 
8.2.2 
Reasons for Removal From Study ............................................. 42 
8.3 
Lost to Follow-up ........................................................................................ 42 
9. 
Study Assessments and Procedures ..................................................................... 43 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 5 of 94 
CONFIDENTIAL 
 
 
9.1 
General Study Periods ............................................................................... 43 
9.1.1 
Screening, Enrollment and/or Randomization ............................ 43 
9.1.2 
Treatment Period ........................................................................ 44 
9.1.2.1 
Clinically Indicated Catherization Prior to 
Week 40 ................................................................... 45 
9.1.2.2 
Clinically Indicated Catherization at 
Week 40 Prior to Week 50 ....................................... 45 
9.1.3 
End of Study ............................................................................... 45 
9.2 
Description of General Study Assessments and Procedures ..................... 46 
9.2.1 
General Assessments ................................................................ 46 
9.2.1.1 
Informed Consent .................................................... 46 
9.2.1.2 
Demographics .......................................................... 46 
9.2.1.3 
Medical History ........................................................ 46 
9.2.1.4 
Physical Examination ............................................... 46 
9.2.1.5 
Physical Measurements ........................................... 46 
9.2.2 
Efficacy Assessments ................................................................. 46 
9.2.2.1 
Intracoronary Imaging (OCT and IVUS) ................... 47 
9.2.2.2 
LDL-C ....................................................................... 47 
9.2.3 
Safety Assessments ................................................................... 47 
9.2.3.1 
Adverse Events ........................................................ 48 
9.2.3.2 
Vital Signs ................................................................ 51 
9.2.3.3 
Vital Status ............................................................... 51 
9.2.4 
Clinical Laboratory Assessments ............................................... 51 
9.2.4.1 
Pregnancy Testing ................................................... 52 
9.2.5 
Biomarker Development ............................................................. 52 
10. 
Statistical Considerations ....................................................................................... 52 
10.1 
Sample Size Determination ........................................................................ 52 
10.2 
Analysis Sets, Subgroups, and Covariates ................................................ 53 
10.2.1 
Analysis Sets .............................................................................. 53 
10.2.2 
Covariates .................................................................................. 53 
10.2.3 
Subgroups .................................................................................. 54 
10.2.4 
Handling of Missing and Incomplete Data .................................. 54 
10.3 
Statistical Analyses ..................................................................................... 54 
10.3.1 
Planned Analyses ....................................................................... 54 
10.3.1.1 
Final Analysis ........................................................... 54 
10.3.2 
Methods of Analyses .................................................................. 54 
10.3.2.1 
General Considerations ........................................... 54 
10.3.2.2 
Efficacy Analyses ..................................................... 55 
10.3.2.3 
Safety Analyses ....................................................... 55 
11. 
References ............................................................................................................. 57 
12. 
Appendices ............................................................................................................ 60 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 6 of 94 
CONFIDENTIAL 
 
 
12.1 
Appendix 1.  List of Abbreviations and Definitions of Terms ...................... 61 
12.2 
Appendix 2.  Clinical Laboratory Tests ....................................................... 65 
12.3 
Appendix 3.  Study Governance Considerations ........................................ 66 
12.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ....................................... 74 
Definition of Serious Adverse Event ........................................................... 75 
Recording Adverse Events and Serious Adverse Events ........................... 76 
Evaluating Adverse Events and Serious Adverse Events .......................... 77 
Adverse Device Effects:  Recording, Evaluating and Reporting ................. 79 
12.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ......................................................... 83 
12.6 
Appendix 6.  Sample Storage and Destruction ........................................... 89 
12.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions 
and Follow-up Assessments ....................................................................... 91 
Criteria for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-
required Therapies Due to Potential Hepatotoxicity ................... 91 
Drug-induced Liver Injury Reporting and Additional 
Assessments .............................................................................. 93 
 
List of Tables 
Table 2-1.  Schedule of Activities .................................................................................... 14 
Table 7-1.  Acceptable Background Statin Therapy ........................................................ 35 
Table 12-1.  Analyte Listing ............................................................................................. 65 
Table 12-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................... 92 
List of Figures 
Figure 2-1.  Study Schema ............................................................................................. 13 
Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Form .................. 80 
Figure 12-2.  Pregnancy and Lactation Notification Worksheet ...................................... 87 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 7 of 94 
CONFIDENTIAL 
 
 
1. 
Protocol Synopsis 
Protocol Title:  High-Resolution Assessment of Coronary Plaques in 
a Global Evolocumab Randomized Study (HUYGENS) 
Short Protocol Title:  Imaging of Coronary Plaques in Subjects Treated With 
Evolocumab 
Study Phase:  3 
Indication:  Coronary Artery Disease (CAD) 
Rationale 
Plaque morphology plays pivotal role for the development of acute coronary syndromes 
(ACS).  Lipid-lowering therapy with statins has proven to have beneficial effects on 
plaque morphology in patients suffering from coronary artery disease (CAD).  Treatment 
with evolocumab in addition to optimal statin therapy has been shown to result in a 
regression of atherosclerotic plaque burden.  While treatment with evolocumab is 
associated with a reduction in cardiovascular events, it is uncertain whether additional 
effects on plaque, beyond regression, may contribute to this benefit.  The development 
of advanced imaging techniques permits evaluation of the effect of treatment on plaque 
phenotype features consistent with plaque instability.  This study seeks to identify 
morphologic changes, such as increase in fibrous cap thickness (FCT), in atherosclerotic 
plaques associated with treatment with evolocumab and maximally tolerated statin 
therapy with or without additional lipid-modifying medication in patients presenting with 
non-ST-segment elevation (NSTE)-ACS using optical coherence tomography (OCT; 
primary, secondary, and exploratory endpoints) and intravascular ultrasound (IVUS; 
exploratory endpoints only - see Section 4.1 of the protocol). 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 8 of 94 
CONFIDENTIAL 
 
 
Objective(s)/Endpoint(s) 
 
Objectives 
Endpoints 
Primary 
 To evaluate the effect of evolocumab 
on fibrous cap thickness (FCT) in 
subjects with non-ST-elevation acute 
coronary syndrome (NSTE-ACS) who 
are taking maximally tolerated statin 
therapy. 
 Absolute change in minimum FCT in a 
matched segment of artery as 
determined by optical coherence 
tomography (OCT) from baseline to 
week 50. 
Secondary 
 To evaluate the effects of evolocumab 
on coronary plaque morphology in 
subjects with NSTE-ACS who are 
taking maximally tolerated statin 
therapy. 
 Coronary artery segment-based: 
 
Percent change in minimum FCT 
in a matched segment of artery as 
determined by OCT from baseline 
to week 50. 
 
Absolute change in mean 
minimum FCT for all images 
assessed in an individual subject 
as determined by OCT from 
baseline to week 50. 
 
Absolute change in the maximum 
lipid arc in a matched segment of 
artery as determined by OCT from 
baseline to week 50. 
 Plaque-based: 
 
Absolute change in minimum FCT, 
maximum lipid arc, and lipid core 
length in lipid rich plaques defined 
as minimum FCT < 120 μm and 
lipid arc > 90° in at least 
3 consecutive images as 
determined by OCT from baseline 
to week 50. 
Safety 
 To evaluate the safety and tolerability 
of evolocumab treatment in subjects 
with NSTE-ACS who are taking 
maximally tolerated statin therapy. 
 Subject incidence of 
treatment-emergent adverse events 
and serious adverse events. 
 
Hypotheses 
The primary hypothesis is that low-density lipoprotein cholesterol (LDL-C) lowering with 
evolocumab 420 mg monthly (QM) will result in a greater increase from baseline in 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 9 of 94 
CONFIDENTIAL 
 
 
minimum FCT at week 50 than placebo in subjects taking maximally tolerated statin 
therapy. 
Overall Design 
This is a phase 3, double-blind, placebo-controlled, randomized study evaluating the 
effect of evolocumab on coronary atherosclerotic plaques as assessed by OCT at 
baseline and at week 50 in subjects with an NSTE-ACS.  The trial duration of 1 year was 
chosen based on the results of several historical trials.  Subjects will be randomized 
1:1 into 2 treatment groups no more than 7 days after the signing of the informed 
consent:  evolocumab 420 mg subcutaneously (SC) QM or placebo SC QM.  The 
randomization will be stratified by current statin use (> 4 weeks or ≤ 4 weeks duration) at 
screening.  Investigators will up-titrate statin therapy to the maximally tolerated dose, in 
accordance with local guidelines, for subjects prior to randomization. 
Number of Subjects 
Approximately 150 subjects will be enrolled in the study. 
Summary of Subject Eligibility Criteria 
Key Inclusion Criteria 
 
Age ≥ 18 years at screening. 
 
Clinical indication for coronary angiography during admission due to NSTE-ACS with 
interventional treatment of culprit plaque. 
 
LDL-C level via local lab assessment based on statin use at screening: 
 
No statin use:  ≥ 130 mg/dL 
 
Low- or moderate-intensity statin use:  ≥ 80 mg/dL 
 
High-intensity statin use:  ≥ 60 mg/dL 
 
On maximally tolerated statin therapy in accordance with standard of care per local 
guidelines prior to randomization. 
 
Tolerates placebo run-in injection at screening. 
 
Meet all the following criteria at the qualifying coronary angiogram: 
 
Angiographic evidence of coronary artery disease (CAD) with ≥ 20% reduction of 
lumen diameter by angiographic visual estimation, in addition to the culprit 
plaque. 
 
Left main coronary artery must not have a > 50% reduction in lumen diameter by 
visual angiographic estimation. 
 
Targeted vessel: 
 
may not be the culprit vessel for the current or a previous myocardial 
infarction (MI). 
 
has not undergone prior percutaneous coronary intervention (PCI) or 
coronary artery bypass grafting (CABG), and may not be a bypass graft. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 10 of 94 
CONFIDENTIAL 
 
 
 
may not be a candidate for PCI or CABG currently or over the next 
12 months, in the opinion of the investigator. 
 
must be accessible by the OCT catheter. 
 
Targeted segment: 
 
must have up to 50% but not > 50% reduction in lumen diameter by visual 
angiographic estimation and must be at least 40 mm in length. 
 
must contain at least 1 image with an FCT of ≤ 120 µm and at least 1 image 
with a lipid arc of > 90° as determined by the imaging core laboratory. 
 
distal plaques of up to 50% stenosis by visual angiographic estimation are 
permitted, provided that such stenosis is not a target for PCI or CABG. 
For a full list of eligibility criteria, please refer to Section 6.1 to Section 6.2. 
Treatments 
Evolocumab QM will be administered on day 1 through week 48 with a personal injector 
or prefilled autoinjector/pens (AI/Pens). 
Subcutaneous evolocumab and placebo will be administered at the study site or in an 
appropriate non-clinic setting (eg, at home).  Observed, in-clinic dosing must occur at 
day 1 and should occur at week 4, and week 24.  At home dosing by the subject should 
occur for all remaining dose administrations.  Subjects who do not wish to self-inject at 
home may return to the clinic for injection. 
Evolocumab or matching placebo will be administered in accordance with instructions in 
the IPIM and the Information for Use (IFU).  The subject (or designee) must have 
demonstrated competency, as per site judgment, at administration of SC injections 
before self-administration is permitted.  The first self-administered dose by the subject 
(or designee) must be administered at the site under the supervision of a healthcare 
provider.   
It is suggested that the evolocumab administration is done by the subject under site staff 
supervision at each of the regular study visits (except day 1) to reinforce proper use of 
the injection device.  If evolocumab or matching placebo is to be administered during the 
study visit, administration must occur after all other procedures have been completed. 
Procedures 
Written informed consent must be obtained from all subjects or legally acceptable 
representatives before any study-specific procedures are performed.  Subjects will be 
assessed for eligibility and medical as well as medication history will be obtained.  
Subjects will undergo clinically-indicated coronary angiography for further clinical 
evaluation.  Subjects who require a PCI because of qualifying angiography will have 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 11 of 94 
CONFIDENTIAL 
 
 
baseline OCT and IVUS performed following the PCI.  OCT and IVUS must not be 
performed in vessels that underwent an intervention.  Prior to performing the baseline 
OCT and IVUS examinations, investigators should ensure that subjects’ initial screening 
LDL-C results are available.  If angiographic criteria are met, the subject will have 
baseline OCT and IVUS completed.  Subjects should undergo all labs and receive a 
3.5 mL placebo injection by SC administration to assess SC injection tolerability, at 
screening. 
At randomization, an Interactive Voice Response System/Interactive Web Response 
System (IVRS/IWRS) will allocate subjects to receive either evolocumab SC QM or 
placebo SC QM.  Day 1 of the treatment period (ie, first dose of investigational product) 
must happen within 7 days of the signing of the informed consent.  Investigational 
product will be administered monthly (every 4 weeks ± 3 days).  Final administration of 
evolocumab or placebo will occur at week 48. 
Subjects must fast overnight when fasting lipid samples are to be obtained (ie, 
day 1, week 24, and week 50).  If the subject is not fasting for the day 1 visit, no visit 
procedures are performed and the visit should be rescheduled within the applicable 
protocol window.  If subject is not fasting after day 1, all procedures except fasting labs 
and investigational product administration, if applicable, will be performed and another 
visit should be scheduled within the visit window for fasting labs and investigational 
product administration. 
During the week 4, 12, 24, 36, and 50 visits, adverse events, serious adverse events, 
and concomitant medications will be recorded.  Physical exams, laboratory tests and 
other procedures will be performed at the time points indicated in the Schedule of 
Activities (Table 2-1).   
Final follow-up OCT and IVUS should take place at 50 ± 2 weeks (ie, 48 to 52 weeks) 
after initial baseline image acquisition.  In any case, it is critical that the follow-up OCT 
and IVUS be obtained for all subjects, regardless of whether they discontinued study 
drug prematurely or are outside the 50 ± 2 weeks window. 
End of study (EOS) for all subjects is by contact (eg, phone call) from the site at 
week 52 for any potential adverse events or serious adverse events.  End of study 
phone call must be ≥ 2 weeks after the follow-up OCT and IVUS or ≥ 4 weeks after the 
last dose of treatment period investigational product administration, whichever is later. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 12 of 94 
CONFIDENTIAL 
 
 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 9.2 and the Schedule of Activities in Table 2-1. 
Statistical Considerations 
The planned total sample size is 150 subjects (75 randomized to evolocumab 
420 mg SC QM and 75 randomized to placebo SC QM).  This sample size will provide 
sufficient power (90%) to determine whether there is a treatment effect of evolocumab 
relative to placebo in the primary endpoint.  The primary endpoint for the study is the 
absolute change in minimum fibrous cap thickness (FCT) from baseline to week 50 in a 
matched segment of artery as determined by optical coherence tomography (OCT).  
Hypothesis testing of the primary endpoint will be the primary objective of the final 
analysis.  There will be no interim analysis for this study.  The final analysis will be 
conducted after all subjects have either completed all the scheduled study visits or have 
early terminated from the study.  At that time, the database will be cleaned and locked 
followed by unblinding of the study.   
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor Name:  Amgen Inc. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 13 of 94 
CONFIDENTIAL 
 
 
2. 
Study Schema and Schedule of Activities 
2.1 
Study Schema 
Figure 2-1.  Study Schema 
-1   0        4          8        12       16       20       24       28       32       36       40       44       48  50  52
Evolocumab 420 mg   QM     (n = 75) 
Placebo   QM     (n = 75) 
End of Study
Screening
On-site visit
Phone visit
In-clinic IP administration
Non-clinic IP administration
Lipid assessment
OCT and IVUS
Weeks
Visits
IP
Lipids
OCT/IVUS
 
IP = investigational product; IVUS = intravascular ultrasound; OCT = optical coherence tomography; QM = every 4 weeks ± 3 days for each visit/dose 
Note:  To minimize the chances of performing unnecessary invasive procedures, investigators should ensure that initial screening lipid results are available prior to 
performing the baseline OCT and IVUS examination.   
Note:  Subjects may administer study drug at the clinic on non-visit days if preferred. 
 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 14 of 94 
CONFIDENTIAL 
 
 
2.2 
Schedule of Activities 
Table 2-1.  Schedule of Activities 
PROCEDURE 
Screening 
Treatment Period (± 7 days) 
End of Studyb 
(+ 7 days) 
Day 1a 
Week 4 
Week 12b 
(Phone 
Visit) 
Week 24 
Week 36b 
(Phone 
Visit) 
Week 50 
Week 52 
(Phone Visit) 
GENERAL AND SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Physical examination  
X 
X 
 
 
 
 
X 
 
Medical history  
X 
 
 
 
 
 
 
 
Vital signs 
X 
X 
 
 
 
 
X 
 
Personal injector or AI/Pen  
instructions and training 
 
X 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
Serious adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse device effects 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapies review 
X 
X 
X 
X 
X 
X 
X 
X 
LABORATORY ASSESSMENTS 
Urine/Serum pregnancy test  
(females of childbearing potential 
only)c 
X 
X 
 
 
X 
 
X 
 
Page 1 of 2 
Abbreviations and footnotes are defined on last page of table. 
 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 15 of 94 
CONFIDENTIAL 
 
 
Table 2-1.  Schedule of Activities 
PROCEDURE 
Screening 
Treatment Period (± 7 days) 
End of Studyb 
(+ 7 days) 
Day 1a 
Week 4 
Week 12b 
(Phone 
Visit) 
Week 24 
Week 36b 
(Phone 
Visit) 
Week 50 
Week 52 
(Phone Visit) 
Chemistry 
X 
 
 
 
 
 
 
 
Lipid testingd 
X 
 
 
 
 
 
 
 
Fasting lipid testinge 
 
X 
 
 
X 
 
X 
 
STUDY-SPECIFIC ASSESSMENTS (eg, DISEASE-SPECIFIC ASSESSMENTS, RADIOLOGICAL ASSESSMENTS) 
OCT 
X 
 
 
 
 
 
Xf 
 
IVUS 
X 
 
 
 
 
 
Xf 
 
BIOMARKER ASSESSMENTS 
Biomarker collection 
(blood/plasma) 
 
X 
 
 
 
 
X 
 
STUDY TREATMENT 
Placebo run-ing 
X 
 
 
 
 
 
 
 
Statin optimizationh 
X 
 
 
 
 
 
 
 
Amgen investigational product 
dispensation 
 
 
X 
 
X 
 
 
 
Observe investigational product 
self-administration at hospital/clinic 
(retraining, if applicable)i 
 
X 
X 
 
X 
 
 
 
Amgen investigational product 
administration 
 
Investigational product administered once every 4 weeks (QM) 
beginning day 1 and ending week 48j 
 
Page 2 of 2 
AI = autoinjector; ApoA1 = apolipoprotein A1; ApoB = apolipoprotein B; HDL-C = high-density lipoprotein cholesterol; IVUS = intravascular ultrasound; 
LDL-C = low-density lipoprotein cholesterol; Lp(a) = lipoprotein(a); OCT = optical coherence tomography; QM = every 4 weeks ± 3 days; TC = total cholesterol; 
TG = triglyceride; VLDL-C = very low-density lipoprotein cholesterol 
a Day 1 is the first administration day of investigational product.  Must be within 7 days the signing of informed consent. 
b Subjects to participate in a phone visit.  End of study phone call must be ≥ 2 weeks after the follow-up OCT and IVUS or ≥ 4 weeks after the last dose of treatment 
period investigational product administration, whichever is later. 
c Urine/serum pregnancy test for females of childbearing potential is assessed by local lab, prior to coronary catherization (as applicable). 
 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 16 of 94 
CONFIDENTIAL 
 
 
d Local laboratory is used during screening period for TG and LDL-C measurements.  To minimize the chances of performing unnecessary invasive 
procedures, investigators should ensure that subjects’ initial screening LDL-C results are available prior to performing the baseline OCT 
examination.   
e Lipid measurements during treatment period must be performed via central lab.  Collected lipids will consist of TC, HDL-C, VLDL-C, LDL-C, ApoA1, ApoB, TG, 
and Lp(a).  If subject is not fasting on day 1, reschedule; if subject is not fasting after day 1, do all procedures except fasting labs and investigational product 
administration, if applicable; schedule another visit, if possible within the visit window for fasting labs and investigational product administration. 
f Final, follow-up OCT and IVUS should take place 50 ± 2 weeks (ie, 48 to 52 weeks) after initial baseline image acquisition.  End of study phone call must be 
≥ 2 weeks after the follow-up OCT and IVUS or ≥ 4 weeks after the last dose of treatment period investigational product administration, whichever is later. 
g Healthcare professional will deliver the placebo run-in at screening. 
h Statin optimization occurs prior to randomization for all subjects. 
i Personal injector or AI/Pen training will occur at the day 1 visit and each visit thereafter if necessary.  First investigational product administration will 
be either in hospital or in clinic by subject after self-administration training.   
j Investigational product administered QM beginning day 1 and ending week 48.  Week 48 investigational product administration must occur prior to OCT and 
IVUS at week 50.    
 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 17 of 94 
CONFIDENTIAL 
 
 
3. 
Introduction 
3.1 
Study Rationale 
Plaque morphology plays pivotal role for the development of acute coronary syndromes 
(ACS) (Toutouzas et al, 2011; Ino et al, 2011).  Lipid-lowering therapy with statins has 
proven to have beneficial effects on plaque morphology in patients suffering from 
coronary artery disease (CAD) (Takarada et al, 2009).  Treatment with evolocumab in 
addition to optimal statin therapy has been shown to result in a regression of 
atherosclerotic plaque burden (Nicholls et al, 2016).  While treatment with evolocumab is 
associated with a reduction in cardiovascular events (Sabatine et al, 2017), it is 
uncertain whether additional effects on plaque, beyond regression, may contribute to this 
benefit.  The development of advanced imaging techniques permits evaluation of the 
effect of treatment on plaque phenotype features consistent with plaque instability.  This 
study seeks to identify morphologic changes, such as increase in fibrous cap thickness 
(FCT), in atherosclerotic plaques associated with treatment with evolocumab and 
maximally tolerated statin therapy with or without additional lipid-modifying medication in 
patients presenting with non-ST-segment elevation (NSTE)-ACS using optical 
coherence tomography (OCT; primary, secondary, and exploratory endpoints) and 
intravascular ultrasound (IVUS; exploratory endpoints only - see Section 4.1). 
3.2 
Background 
3.2.1 
Cardiovascular Disease 
According to the World Health Organization, cardiovascular disease is the leading cause 
of death and disability, accounting for approximately 31% of all deaths and 46% of 
deaths from noncommunicable diseases worldwide (World Health Organization, 2014).  
Of deaths related to cardiovascular disease, approximately 80% are from myocardial 
infarction or stroke (World Health Organization, 2014).  The morbidity associated with 
myocardial infarction and stroke continues to be serious and multifaceted, the reduction 
of which is an important treatment goal.  Each year, it is estimated that 
935 000 Americans have myocardial infarction or coronary death, 155 000 have a silent 
first myocardial infarction, 610 000 have a new stroke (ischemic or hemorrhagic), and 
185 000 have a recurrent stroke (Mozaffarian et al, 2016). 
Elevated cholesterol, in particular low-density lipoprotein cholesterol (LDL-C), is a 
modifiable independent cardiovascular risk factor (Silverman et al, 2016).  The effects of 
LDL-C on cardiovascular risk likely begin at the level of the arterial wall since low-density 
lipoprotein particles drive atheroma formation and progression 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 18 of 94 
CONFIDENTIAL 
 
 
(Moore and Tabas, 2011).  The formation of flow obstructing lesions and/or acute plaque 
rupture with subsequent thrombogenesis result in clinical sequelae including coronary 
heart, cerebrovascular, and peripheral arterial diseases.  Results from imaging studies 
demonstrated that reductions in LDL-C can slow or halt coronary atheroma progression 
or even reduce their volume (Räber et al, 2015; Nicholls et al, 2016; Nicholls et al, 
2011; Nissen et al, 2006; Nissen et al, 2004).  These data illustrate important biologic 
effects of LDL-C reduction and support a potential mechanism by which lowering LDL-C 
reduces risk of cardiovascular events. 
Many interventional studies evaluated the impact of therapeutic reductions in LDL-C on 
cardiovascular outcomes (Silverman et al, 2016; Cholesterol Treatment Trialists' [CTT] 
Collaboration et al, 2010).  A meta-analysis (Silverman et al, 2016) included 
49 randomized, controlled, cardiovascular outcomes studies and over 312 000 subjects 
to analyze the effects of therapies that act primarily via low-density lipoprotein receptor 
(LDLR) upregulation.  Results from these studies show a strong relationship between 
LDL-C lowering and cardiovascular event reduction for drugs such as statins 
(Cannon et al, 2004; Sacks et al, 1996; Scandinavian Simvastatin Survival Study 
Group, 1994) and ezetimibe (Cannon et al, 2015). 
3.2.2 
Intracoronary Imaging 
Several intracoronary imaging techniques exist to visualize coronary anatomy and 
assess the presence and extent of CAD.  Fluoroscopic angiography allows a 
2-dimensional depiction of the coronary arterial vasculature by delineating the vascular 
lumen.  However, it is limited by its inability to provide detailed assessments of the 
vessel wall, particularly the intima and media, where coronary plaque formation takes 
place.  In addition to fluoroscopy, IVUS and OCT are well-established imaging modalities 
frequently used in clinical practice (Matthews and Frishman, 2017). 
Intravascular ultrasound uses an ultrasound transducer mounted on a coronary catheter.  
It provides cross-sectional, grey-scale images and can cover the entire circumference of 
the coronary artery wall from the inner border to the outer layer, thereby visualizing the 
extent of coronary plaque burden.  With IVUS, large coronary segments can be 
visualized in a standardized and reproducible manner using automated pullback of the 
ultrasound probe (Nair et al, 2002; Nissen et al, 1991).  In addition, IVUS has proven to 
be a valuable tool in clinical trials (Nicholls et al, 2016); however, IVUS image acquisition 
can be limited or impaired due to transducer rotation, guide wires and other mechanical 
hindrances, as well as anatomical and physiological aspects such as the heartbeat, 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 19 of 94 
CONFIDENTIAL 
 
 
tortuous arteries, and bifurcations of side branches (ten Hoff et al, 1989).  While IVUS is 
reproducible for quantitative serial plaque volume measurements, it cannot elucidate all 
features of plaque morphology due to insufficient spatial resolution.  Virtual histology 
data acquired using specialized IVUS catheters may have the ability to provide 
additional information on plaque composition (eg, visualizing calcifications and 
quantification of the necrotic core).  However, IVUS-virtual histology has limited ability to 
assess incremental changes in FCT over time (Puri et al, 2014). 
Optical coherence tomography is based on coherent light; hence, it does not penetrate 
as deeply into the tissue and may therefore not always be able to visualize the entire 
arterial wall, but it provides a higher spatial resolution compared to IVUS.  In addition, 
OCT is not limited by near-field artifacts, a feature commonly seen with 
ultrasound-based imaging techniques.  The practical approach to OCT shares many 
similarities with IVUS, including some of the mechanical challenges regarding image 
acquisition.  Similar to IVUS, coronary catheters carrying the imaging probe are used to 
acquire cross-sectional images, which are usually color-coded in sepia.  These catheters 
can be operated manually or via automated pullback (Bezerra et al, 2009; 
Kume et al, 2005) allowing for a high degree of standardization and reliable 
reproducibility even when imaging large coronary segments (Kini et al, 2017; 
Jamil et al, 2013; Gonzalo et al, 2010).  Optical coherence tomography’s high-resolution 
images enable clear delineation and exact measurements of individual layers of the 
vessel wall, including the thin intima.  Thus, a strength of OCT lies in its ability to assess 
intimal disease (Kubo et al, 2007; Yabushita et al, 2002). 
All imaging techniques have their respective characteristics; they complement each 
other and provide interventional cardiologists with a solid armamentarium to assess 
coronary artery disease.  Thus, it is possible to reveal morphologic differences of culprit 
lesion in STEMI and NSTEMI patients, such as the incidence of plaque rupture as well 
as the length, size, and location of the aperture in those ruptured plaques 
(Ino et al, 2011; Toutouzas et al, 2011).  It is likely that such refined diagnostic tools will 
help physicians select the most appropriate treatment for patients (Bezerra et al, 2013).  
Moreover, the individual cardiovascular risk can be assessed in more detail and 
addressed accordingly (Tanaka et al, 2008).  
In recent years, different features of plaque morphology such as FCT, calcifications, and 
size of necrotic core have been recognized as determining factors for the risk of acute 
coronary syndromes, with FCT being the most important predicting factor 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 20 of 94 
CONFIDENTIAL 
 
 
(Stone et al, 2011; Virmani et al, 2006).  Some publications suggest that FCT < 65 μm is 
associated with a high risk for future cardiovascular events (Stefanadis et al, 2017; 
Burke et al, 1997). 
3.2.3 
Amgen Investigational Product Background:  Evolocumab 
Recycling of the hepatic cell surface LDLR plays a critical role in regulating serum LDL-C 
levels.  Proprotein convertase subtilisin/kexin type 9 (PCSK9) 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 coronary artery disease (CAD) 
(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 (AMG 145) Investigator’s Brochure for more information on 
evolocumab. 
3.3 
Benefit/Risk Assessment 
The following benefit risk assessment supports the conduct of this clinical trial.  
Reference should be made to the Evolocumab (AMG 145) Investigator’s Brochure for 
further data on evolocumab. 
3.3.1 
Benefits of Evolocumab 
3.3.1.1 
Reduction in Low-density Lipoprotein Cholesterol (LDL-C) 
In the original marketing application, placebo-adjusted reductions in LDL-C of 
approximately 55% to 75% were consistently observed with evolocumab in subjects with 
primary hyperlipidemia (familial or non-familial) or mixed dyslipidemia.  Evolocumab was 
also superior to ezetimibe in these subjects, comparatively reducing LDL-C by 
approximately 35% to 45%.  LDL-C reductions with evolocumab treatment occurred 
regardless of cardiovascular risk level, statin use (none, low, moderate, or high intensity) 
or baseline LDL-C.  The approved evolocumab dosing regimens of 140 mg every 
2 weeks (Q2W) and 420 mg monthly were clinically equivalent.  Effects of evolocumab 
were reversible upon cessation of treatment, with no evidence of rebound.  Reductions 
in LDL-C were maintained during long-term use, without attenuation of effect; to date, 
results from long-term studies show LDL-C reductions of approximately 60% maintained 
over 4 years. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 21 of 94 
CONFIDENTIAL 
 
 
Data on reduction in LDL-C from both Study 20120153 (a 78-week, phase 3 study in 
subjects with clinical signs or symptoms of coronary artery disease [n = 968]) and 
Study 20110118 (a phase 3 study in subjects with or at risk for atherosclerotic 
cardiovascular disease [n = 27 564]), were consistent with that reported in the original 
evolocumab marketing application in subjects with hypercholesterolemia.  In 
Study 20120153, mean reductions from baseline in LDL-C were approximately 60% in 
the evolocumab group and were maintained through end of study (week 78).  In 
Study 20110118, median reductions in LDL-C of 64% to 70% were observed during 
evolocumab treatment and these reductions were maintained over the duration of the 
study (> 36 months) without attenuation of effect.  Of note, Study 20110118 represents 
the lowest on-treatment LDL-C concentrations achieved to date in any cardiovascular 
outcomes study involving a lipid lowering agent, with 25% of subjects achieving 
LDL-C concentrations < 20 mg/dL.   
3.3.1.2 
Regression of Coronary Atherosclerosis 
In Study 20120153, statistically significant regression in coronary atherosclerosis was 
observed at week 78 in comparison with placebo.  Evolocumab, when added to statin 
therapy, reduced percent atheroma volume (PAV) by -1.01% (-1.38%, -0.64%), 
compared with placebo at week 78 (p < 0.0001).  Evolocumab also reduced total 
atheroma volume (TAV) by -4.89% (-7.25%, -2.53%), compared with placebo, at 
week 78 (p < 0.0001).  Evolocumab resulted in more regression in coronary 
atherosclerosis at week 78, compared with placebo, as measured by PAV and TAV; 
atherosclerosis regression was achieved by 17.0% (95% CI:  10.3, 23.5 [p < 0.0001]) 
and 12.5% (95% CI:  5.8, 19.1 [p = 0.0002]) more subjects, respectively, in the 
evolocumab group compared with the placebo group.  In subjects with baseline 
LDL-C ≥ 70 mg/dL, a total of 61.0% (95% CI:  55.9, 66.1) of evolocumab-treated 
subjects experienced atherosclerosis regression, as measured by reduction in PAV, 
compared with 47.1% (95% CI:  41.9, 52.4) in the placebo group.  Reducing LDL-C had 
favorable effects on coronary atherosclerosis even at very low concentrations of LDL-C.  
Adding evolocumab to statin therapy reduced LDL-C from baseline by 60% (at the end 
of the dosing interval) to 68% (2 weeks post-dose), and LDL C reductions were 
maintained through end of study at week 78.  Subjects with baseline LDL-C levels below 
the lowest global targets in use at the time of the study also experienced plaque 
regression while receiving evolocumab.  In addition, post-hoc analysis suggested a 
continuous relationship between achieved LDL-C and reductions in PAV, with evidence 
of regression in PAV extending to on-treatment LDL C levels as low as 7 mg/dL.  In 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 22 of 94 
CONFIDENTIAL 
 
 
conclusion, data from this study show a positive, measurable and statistically significant 
effect of evolocumab on coronary atherosclerosis, beyond what is achievable with 
statins alone. 
3.3.1.3 
Reduction in the Risk of Cardiovascular Events 
In Study 20110118, treatment with evolocumab statistically significantly reduced the risk 
of cardiovascular events.  With a median follow-up period of 26 months, evolocumab 
reduced the risk of cardiovascular death, myocardial infarction, stroke, hospitalization for 
unstable angina, or coronary revascularization, whichever occurred first (primary 
composite endpoint) by 15%, compared with placebo with a hazard ratio (HR) of 
0.85 (95% CI:  0.79, 0.92; p < 0.0001).  Evolocumab reduced the risk of cardiovascular 
death, myocardial infarction, or stroke, whichever occurred first (key secondary 
composite endpoint) by 20%, compared with placebo with a HR of 0.80 (95% CI:  
0.73, 0.88; p < 0.0001).  The treatment effect was driven by reductions in myocardial 
infarction, stroke, and coronary revascularization (primary composite endpoint); and by 
reductions in myocardial infarction and stroke (secondary composite endpoint), without a 
detectable effect on cardiovascular death.  The primary and key secondary treatment 
effects were directionally consistent across subgroups.  There was a clear relationship 
between reductions in LDL-C and lower rates of cardiovascular events.  This relationship 
was observed across the spectrum of post baseline LDL-C levels, and no lower LDL-C 
threshold for this relationship was identified for post-baseline LDL-C levels (mean of 
lowest decile, 16.2 mg/dL [0.42 mmol/L]).  Overall, results from this study provide 
compelling evidence that evolocumab, through effects on lowering LDL-C, reduces the 
risk for cardiovascular events in patients with or at risk of atherosclerotic cardiovascular 
disease who cannot achieve LDL-C control with statins alone. 
3.3.2 
Risks of Evolocumab 
The safety profile provided in the original evolocumab application includes more than 
6800 subjects in > 25 clinical studies with evolocumab.  The adverse drug reactions 
consist of nausea, injection site reactions, influenza, nasopharyngitis, upper respiratory 
tract infection, arthralgia, back pain, rash, and urticaria.  There were no important 
identified risks.  Hypersensitivity was determined to be an important potential risk based 
on the adverse events of rash and urticaria; most events were mild to moderate and 
non-serious.  Evolocumab had a very low rate of immunogenicity (0.1%) which did not 
affect pharmacokinetics, pharmacodynamics, efficacy, or safety. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 23 of 94 
CONFIDENTIAL 
 
 
Study 20110118 was a large clinical outcomes study of 27 564 subjects.  The incidences 
of adverse events of interest were balanced between treatment groups, with the 
exception of injection site reactions and hypersensitivity events (rash and urticaria), 
which are known adverse drug reactions with evolocumab.  These events occurred in a 
slightly higher percentage of evolocumab subjects than placebo subjects, were generally 
mild to moderate, nonserious, and did not lead to treatment discontinuation.  The 
development of anti-evolocumab antibodies post-baseline was infrequent (0.3%).  
Anti-evolocumab antibodies were non-neutralizing and not associated with loss of 
efficacy or any safety concerns.  In addition, there were no trends indicative of clinically 
important treatment-related laboratory abnormalities.  No safety risk of very low LDL-C 
during treatment with evolocumab was identified.  Among the evolocumab-treated 
subjects with post-baseline LDL-C measurements during evolocumab treatment and 
within 30 days after the last dose, who achieved a minimum LDL-C < 40 mg/dL 
(88.4%) and a minimum LDL-C < 25 mg/dL (69.9%), overall incidences of adverse 
events were similar between the evolocumab and placebo groups regardless of 
achieved LDL-C concentrations.  In subjects not known to have pre-existing diabetes 
mellitus at baseline, a comparable proportion in each treatment group 
(8.1% evolocumab, 7.7% placebo) developed positively adjudicated new onset diabetes 
mellitus.  No evidence of neurocognitive safety risk was observed based on review of 
adverse events from Study 20110118 and objective data from its neurocognitive 
sub-study (Study 20130385).  Study 20130385 used a validated, objective assessment 
of higher-level executive function (Cambridge Neuropsychological Text Automated 
Battery [CANTAB]) and demonstrated non-inferiority of evolocumab compared with 
placebo.  Neither analysis showed evidence for concern in subjects who achieved 
LDL-C levels < 40 mg/dL and < 25 mg/dL at least once. 
Study 20120153 included a total of 968 subjects (484 evolocumab, 484 placebo) in the 
safety analysis set.  The overall adverse event incidences were similar to those reported 
in the original evolocumab application and no new safety risks were identified.  The 
incidence, type and severity of events were comparable between the evolocumab and 
placebo groups. 
In the integrated safety set (which included Study 20110118 and Study 20120153), a 
slightly higher incidence of potential events of hypersensitivity were observed in the 
evolocumab group compared to the control group.  Most of the adverse events were 
non-serious, reported as grade 1 and 2, and none were fatal.  Within the potential 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 24 of 94 
CONFIDENTIAL 
 
 
hypersensitivity events, events of rash and urticaria were considered adverse drug 
reactions for evolocumab and part of the safety profile.  Overall, no new risks or change 
in the nature of the risk have been identified from the combined 28 532 evolocumab 
subjects in the integrated analysis set. 
3.3.3 
Conclusion 
Overall, this structured benefit-risk assessment provides compelling evidence of the 
benefit of evolocumab, with minimal evidence of any significant hazard, even in patients 
that achieved at least one LDL-C value < 40 mg/dL.  Adding evolocumab to high- to 
moderate-intensity statin therapy significantly reduced cardiovascular events.  
Evolocumab provided robust, consistent, and predictable LDL-C reduction across all 
populations and patient subgroups studied, regardless of cardiovascular risk, statin use 
(none, low, moderate, or high intensity), or baseline LDL-C.  In addition, these analyses 
suggest a consistent relationship between lower achieved LDL-C and lower 
cardiovascular event rates to LDL-C levels as low as 16.2 mg/dL (mean LDL-C in lowest 
decile). 
The safety data for evolocumab to date indicated no important identified risks.  
Hypersensitivity is an important potential risk; the incidence of hypersensitivity events is 
low and adverse events are mild to moderate in severity. 
Based on the above evidence, the benefit-risk profile of evolocumab is favorable for 
use in: 
 
adults with hyperlipidemia, alone or in combination with other lipid-lowering 
therapies, as an adjunct to diet to reduce LDL-C. 
 
adults and adolescents aged 12 years and over with HoFH to reduce LDL-C, TC, 
ApoB, and non-HDL-C in combination with other lipid-lowering therapies (eg, statins, 
low-density lipoprotein [LDL] apheresis). 
 
adults with coronary artery disease for regression of coronary atherosclerosis. 
 
patients with established atherosclerotic cardiovascular disease to reduce the risk of 
cardiovascular events. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 25 of 94 
CONFIDENTIAL 
 
 
4. 
Objectives, Endpoints, and Hypotheses 
4.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 To evaluate the effect of evolocumab 
on fibrous cap thickness (FCT) in 
subjects with non-ST-elevation acute 
coronary syndrome (NSTE-ACS) who 
are taking maximally tolerated statin 
therapy. 
 Absolute change in minimum FCT in a 
matched segment of artery as 
determined by optical coherence 
tomography (OCT) from baseline to 
week 50. 
Secondary 
 To evaluate the effects of evolocumab 
on coronary plaque morphology in 
subjects with NSTE-ACS who are 
taking maximally tolerated statin 
therapy. 
 Coronary artery segment-based: 
 
Percent change in minimum FCT 
in a matched segment of artery as 
determined by OCT from baseline 
to week 50. 
 
Absolute change in mean 
minimum FCT for all images 
assessed in an individual subject 
as determined by OCT from 
baseline to week 50. 
 
Absolute change in the maximum 
lipid arc in a matched segment of 
artery as determined by OCT from 
baseline to week 50. 
 Plaque-based: 
 
Absolute change in minimum FCT, 
maximum lipid arc, and lipid core 
length in lipid rich plaques defined 
as minimum FCT < 120 μm and 
lipid arc > 90° in at least 
3 consecutive images as 
determined by OCT from baseline 
to week 50. 
Safety 
 To evaluate the safety and tolerability 
of evolocumab treatment in subjects 
with NSTE-ACS who are taking 
maximally tolerated statin therapy. 
 Subject incidence of 
treatment-emergent adverse events 
and serious adverse events. 
  
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 26 of 94 
CONFIDENTIAL 
 
 
Objectives 
Endpoints 
Exploratory 
 To evaluate the effects of evolocumab 
on lipid parameters in subjects with 
NSTE-ACS who are taking maximally 
tolerated statin therapy. 
 To evaluate the effects of evolocumab 
on features of coronary plaques in 
subjects with NSTE-ACS who are 
taking maximally tolerated statin 
therapy using different imaging 
techniques. 
 Absolute and percent changes in lipid 
parameters by visit from baseline. 
 Absolute change in number of 
microchannels in matched segments 
of all lesions assessed in an individual 
subject as determined by OCT from 
baseline to week 50. 
 Absolute change in macrophage 
composition in matched segments of 
all lesions assessed in an individual 
subject as determined by OCT from 
baseline to week 50. 
 Absolute change in lipid content in 
matched segments of all lesions 
assessed in an individual subject as 
determined by IVUS from baseline to 
week 50. 
The primary estimand consists of: 
 
The target population, which is the adult subjects with NSTE-ACS who are taking 
maximally tolerated statin therapy with or without additional lipid-modifying 
medication. 
 
The primary variable, which is the absolute change in minimum FCT in a matched 
segment of artery as determined by OCT from baseline to week 50. 
 
The summary measure, which is the mean treatment difference of the primary 
variable means between evolocumab and placebo. 
 
The intercurrent events, all randomized subjects who receive at least 1 dose of 
investigational product regardless of adherence to treatment. 
 
4.2 
Hypothesis 
The primary hypothesis is that low-density lipoprotein cholesterol (LDL-C) lowering with 
evolocumab 420 mg monthly (QM) will result in a greater increase from baseline in 
minimum FCT at week 50 than placebo in subjects taking maximally tolerated statin 
therapy. 
5. 
Study Design 
5.1 
Overall Design 
This is a phase 3, double-blind, placebo-controlled, randomized study evaluating the 
effect of evolocumab on coronary atherosclerotic plaques as assessed by OCT at 
baseline and at week 50 in subjects with NSTE-ACS.  The trial duration of 1 year was 
chosen based on the results of several historical trials (Dai et al, 2017; Hou et al, 2016; 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 27 of 94 
CONFIDENTIAL 
 
 
Kataoka et al, 2014; Komukai et al, 2014; Nishio et al, 2014; Hattori et al, 2012; 
Takarada et al, 2009).  Subjects will be randomized 1:1 into 2 treatment groups no more 
than 7 days after the signing of the informed consent:  evolocumab 420 mg 
subcutaneously (SC) QM or placebo SC QM.  The randomization will be stratified by 
current statin use (> 4 weeks or ≤ 4 weeks duration) at screening.  Investigators will 
up-titrate statin therapy to the maximally tolerated dose, in accordance with local 
guidelines, for subjects prior to randomization. 
The overall study design is described by a study schema in Section 2.1.  The endpoints 
are defined in Section 4.1. 
5.2 
Number of Subjects 
Approximately 150 subjects will be enrolled in the study, with 75 subjects randomized to 
receive evolocumab 420 mg SC QM and 75 subjects randomized to receive matching 
placebo SC QM. 
Subjects in this clinical investigation shall be referred to as “subjects”.  For the sample 
size justification, see Section 10.1. 
5.2.1 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
5.2.2 
Number of Sites 
Approximately 37 investigative sites globally will be included in the study.  Sites that do 
not enroll a subject within 3 months of site initiation may be closed. 
5.3 
End of Study 
5.3.1 
End of Study Definition 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s), for the purposes of conducting the primary analysis, whether the 
study concluded as planned in the protocol or was terminated early. 
The primary completion date is the date when all randomized subjects have either 
completed the assessments at week 50 or have early terminated from the study. 
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 28 of 94 
CONFIDENTIAL 
 
 
End of Study:  The end of study (EOS) date is defined as the date when the last subject 
across all sites is assessed or receives an intervention for evaluation in the study (ie, last 
subject last visit), following any additional parts in the study (eg, long-term follow-up), as 
applicable. 
5.3.2 
Study Duration for Subjects 
Including the initial screening, study treatment period (double-blind), and the safety/EOS 
follow-up, the maximum planned length of participation in the study for an individual 
subject is 53 weeks.  Subjects should be randomized no more than 1 week after the 
signing of informed consent. 
5.4 
Justification for Investigational Product Dose 
Selection of the proposed dose regimen (420 mg SC QM) was based on analysis of 
pharmacokinetic and pharmacodynamic data obtained from our interim phase 2 analysis 
(Studies 20110109, 20110110, 20110231, 20110233, and 20110271), bolstered by a 
single dose study of evolocumab in healthy volunteers (Study 20080397), and confirmed 
in phase 3 and registrational studies. 
The no-observed-adverse-effect level (NOAEL) observed in a 6-month cynomolgus 
monkey toxicology study (300 mg/kg weekly SC) provides significant exposure multiples 
(86 x for exposure [area under the curve] and 254 x for maximum concentration) over the 
anticipated human exposures. 
5.5 
Patient Input on Study Design 
Patient input on study design was not obtained. 
6. 
Study Population 
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 
System (IVRS)/Interactive Web Response System (IWRS). 
Eligibility criteria will be evaluated during screening. 
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Appendix 3). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be provided. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 29 of 94 
CONFIDENTIAL 
 
 
6.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
101 
Provided informed consent prior to initiation of any study-specific 
activities/procedures. 
102 
Age ≥ 18 years at screening. 
103 
Clinical indication for coronary angiography during admission due to 
non-ST-segment elevation acute coronary syndrome (NSTE-ACS) with 
interventional treatment of culprit plaque. 
104 
An eligible LDL-C level via local lab assessment based on statin use at screening 
(see Section 9.1.1): 
 
No statin use:  ≥ 130 mg/dL 
 
Low- or moderate-intensity statin use (see Table 7-1):  ≥ 80 mg/dL 
 
High-intensity statin use (see Table 7-1):  ≥ 60 mg/dL 
105 
On maximally tolerated statin therapy in accordance with standard of care per 
local guidelines prior to randomization.  See Section 7.1.4 for details. 
106 
Tolerates placebo run-in injection at screening. 
107 
Meets all the following criteria at the qualifying coronary angiogram: 
 
Angiographic evidence of coronary artery disease (CAD) with ≥ 20% 
reduction of lumen diameter by angiographic visual estimation, in addition to 
the culprit plaque. 
 
Left main coronary artery must not have a > 50% reduction in lumen diameter 
by visual angiographic estimation. 
 
Targeted vessel: 
 
may not be the culprit vessel for the current or a previous myocardial 
infarction (MI). 
 
has not undergone prior percutaneous coronary intervention (PCI) or 
coronary artery bypass grafting (CABG), and may not be a bypass graft. 
 
may not be a candidate for PCI or CABG currently or over the next 
12 months, in the opinion of the investigator. 
 
must be accessible by the OCT catheter. 
 
Targeted segment: 
 
must have up to 50% but not > 50% reduction in lumen diameter by visual 
angiographic estimation and must be at least 40 mm in length. 
 
must contain at least 1 image with a FCT of ≤ 120 µm and at least 
1 image with a lipid arc of > 90° as determined by the imaging core 
laboratory 
 
distal plaques of up to 50% stenosis by visual angiographic estimation are 
permitted, provided that such stenosis is not a target for PCI or CABG. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 30 of 94 
CONFIDENTIAL 
 
 
6.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply. 
Disease Related 
201 
ST-segment elevation myocardial infarction (STEMI) or left bundle branch block 
(LBBB). 
202 
ACS likely to be caused by a non-atherosclerotic process, in the opinion of the 
investigator (ie, type 2 myocardial infarction, which is characterized by an 
imbalance between myocardial oxygen demand and supply). 
203 
Clinically significant heart disease which in the opinion of the investigator is likely 
to require coronary bypass surgery, PCI (does not apply to PCI of non-STEMI 
(NSTEMI) during initial screening angiogram), surgical or percutaneous valve 
repair and/or replacement during the course of the study. 
204 
Any cardiac surgery within 6 weeks prior to screening. 
Diagnostic Assessments 
205 
Triglycerides ≥ 400 mg/dL (4.5 mmol/L) at screening. 
206 
Moderate to severe renal dysfunction, defined as an estimated glomerular 
filtration rate (eGFR) < 30 mL/min/1.73m2 at screening. 
Other Medical Conditions 
207 
Malignancy except non-melanoma skin cancers, cervical, or breast ductal 
carcinoma in situ within the last 5 years. 
208 
Intolerant to statins as determined by principal investigator. 
Prior/Concomitant Therapy 
209 
Previously received or receiving evolocumab or any other therapy to inhibit 
PCSK9. 
210 
Previously received a cholesterol ester transfer protein (CETP) inhibitor (ie, 
anacetrapib, dalcetrapib, evacetrapib), mipomersen, lomitapide, or has 
undergone LDL-apheresis in the last 12 months prior to LDL-C screening. 
Prior/Concurrent Clinical Study Experience 
211 
Currently receiving treatment in another investigational device or drug study, or 
less than 30 days since ending treatment on another investigational device or 
drug study(ies).  Other investigational procedures while participating in this study 
are excluded. 
Other Exclusions 
212 
Baseline OCT does not meet OCT imaging criteria as determined by the imagine 
core laboratory technical standards. 
213 
Female subject is pregnant or breastfeeding or planning to become pregnant or 
breastfeed during treatment and for an additional 15 weeks after the last dose of 
investigational product.  (Females of childbearing potential should only be 
included in the study after a confirmed menstrual period and a negative highly 
sensitive urine or serum pregnancy test.) 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 31 of 94 
CONFIDENTIAL 
 
 
214 
Female subjects of childbearing potential unwilling to use 1 acceptable method of 
effective contraception during treatment and for an additional 15 weeks after the 
last dose of investigational product.  Refer to Appendix 5 for additional 
contraceptive information. 
215 
Female subject who has not used an acceptable method(s) of birth control for at 
least 1 month prior to screening, unless the female subject is sterilized or 
postmenopausal. 
216 
Known sensitivity to any of the products or components 
(eg, carboxymethylcellulose) to be administered during dosing. 
217 
Not be available to complete all protocol-required study visits or procedures, 
and/or to comply with all required study procedures to the best of the subject’s 
and investigator’s knowledge. 
218 
Unreliability based on the investigator's (or designee’s) knowledge (eg, alcohol or 
other drug abuse, inability or unwillingness to adhere to the protocol, or 
psychosis).   
219 
History or evidence of any other clinically significant disorder, condition, or 
disease (with the exception of those outlined above) 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. 
6.3 
Lifestyle Restrictions 
6.3.1 
Meals and Dietary Restrictions 
Subjects should adhere to the National Cholesterol Education Program Adult Treatment 
Panel 3, therapeutic lifestyles changes diet or an equivalent diet. 
6.4 
Subject Enrollment 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form, and all other 
subject information and/or recruitment material, if applicable (see Appendix 3). 
All subjects must personally sign and date the IRB/IEC and Amgen approved informed 
consent before commencement of study-specific procedures. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment case report form (CRF). 
Each subject who enters into the screening period for the study (defined as when the 
subject signs the IRB/IEC approved informed consent form) 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. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 32 of 94 
CONFIDENTIAL 
 
 
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 be the same as the randomization number assigned 
for the study. 
6.5 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
criteria, medical history, prior therapies, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
not be rescreened during the same index or NSTE-ACS admission period. 
7. 
Treatments 
Study treatment is defined as any investigational product(s), non-investigational 
product(s), placebo, or medical device(s) intended to be administered to a study subject 
according to the study protocol. 
Note that in several countries, investigational product and non-investigational product 
are referred to as investigational medicinal product and non-investigational medicinal 
product, respectively. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of each treatment shown in Section 7.1 below. 
7.1 
Treatment Procedures 
7.1.1 
Investigational Products 
7.1.1.1 
Dosage Formulation:  Evolocumab 
Evolocumab and matching placebo will be manufactured and packaged by Amgen Inc. 
and distributed using Amgen clinical investigational product distributions procedures. 
Evolocumab and placebo SC will be supplied as 1 personal injector or 3 AI/Pens.  
Evolocumab will be presented as follows: 
 
A personal injector as a single use, disposable, on-body electro-mechanical injection 
device that is co-packaged with a prefilled Crystal Zenith cartridge containing 3.5 mL 
deliverable volume of 120 mg/mL evolocumab or an identical volume of placebo  
 
An AI/Pen as a single use, disposable, handheld mechanical (spring-based) for fixed 
dose, subcutaneous injection of 140 mg evolocumab in 1.0 mL deliverable volume or 
an identical volume of placebo 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 33 of 94 
CONFIDENTIAL 
 
 
Evolocumab and placebo should be stored refrigerated and protected from light 
according to the storage and expiration information provided on the label 
(where required).  Evolocumab should be handled per the instructions provided in the 
IPIM and the clinical instructions for use (IFU) for the personal injector and AI/Pens.  
The personal injector (or AI/Pens) should be inspected for investigational product quality, 
expiry, and damage before using.  Damaged, expired, or degraded product should not 
be used and any issues with the personal injector (or AI/Pens) should be reported to 
Amgen.  Further details are provided in the IPIM and clinical IFU. 
The investigator may be required to record the box number of evolocumab on the 
subject’s Drug Administration CRF.   
7.1.1.2 
Evolocumab:  Dosage, Administration, and Schedule 
Evolocumab or matching placebo will be administered SC on day 1 through week 
48. Investigational product will be administered monthly (QM defined as 
every 4 weeks + 3 days). 
Subcutaneous evolocumab and placebo will be administered at the study site (ie, 
in-clinic) or in an appropriate non-clinic setting (eg, at home).  Observed, in-clinic dosing 
must occur at day 1 and should occur at week 4, and week 24.  At home dosing by the 
subject should occur for all remaining dose administrations.  Subjects who do not wish to 
self-inject at home may return to the clinic for injection. 
Evolocumab or matching placebo will be administered in accordance with instructions in 
the IPIM and the IFU.  The subject (or designee) must have demonstrated competency, 
as per site judgment, at administration of SC injections before self-administration is 
permitted.  The first self-administered dose by the subject (or designee) at day 1 must be 
administered at the site under the supervision of a healthcare provider.  If evolocumab or 
matching placebo is to be administered during the study visit, administration must occur 
after all other procedures have been completed.   
If evolocumab is administered at the study site, the date and completion time of 
administration, the body location of the injection, whether the injection was fully or 
partially administered, and box number are to be recorded on each subject’s CRF. 
When evolocumab is administered at a non-investigator site location (eg, at home), at a 
minimum, the dates the devices were dispensed and the used devices returned, the 
number of devices returned, box numbers, and for each device whether it was returned 
fully or partially used are to be recorded on each subject’s CRF. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 34 of 94 
CONFIDENTIAL 
 
 
It is suggested that the investigational product administration is done by the subject 
under site staff supervision at each of the regular study visits (except day 1) to ensure 
continued proper use of the injection device.  Investigational product administration at a 
scheduled visit (eg, day 1, week 4, and week 24), if applicable, is to be performed after 
all study-related procedures. 
Details of preparing evolocumab, the injection procedures, and device disposal are 
included in the IPIM and IFU provided by Amgen before the start of the study. 
The effects of overdose of this product are not known. 
7.1.2 
Non-investigational Products 
Not applicable for this study. 
7.1.3 
Medical Devices 
The investigational medical devices provided by Amgen for use in this study are the 
personal injector, or the spring based prefilled AI/pen.  Personal injector or AI/Pen 
training by study site staff to each subject will occur at the day 1 visit and each visit 
thereafter if necessary.   
The personal injector with prefilled cartridge assembly is a single-use, disposable, 
on-body electro-mechanical injection device that is co-packaged with a prefilled Crystal 
Zenith cartridge assembly containing 3.5 mL deliverable volume of 
120 mg/mL evolocumab.  Additional details are provided in the IPIM. 
An AI/Pen is a single use, disposable, handheld mechanical (spring-based) for fixed 
dose, SC injection of 140 mg evolocumab in 1.0 mL deliverable volume or an identical 
volume of placebo. 
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard care. 
Non-investigational medical devices (eg, syringes, sterile needles), 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. 
7.1.4 
Other Protocol-required Therapies 
All other protocol-required therapies including, background lipid-lowering therapy, that 
are commercially available are not provided or reimbursed by Amgen (except if required 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 35 of 94 
CONFIDENTIAL 
 
 
by local regulation).  The investigator will be responsible for obtaining supplies of these 
protocol-required therapies. 
Subjects must receive maximally tolerated statin therapy with or without additional 
lipid-modifying medication during the study.  Statin therapy must be initiated or 
up-titrated to the maximally tolerated dose prior to randomization for all subjects; local 
guidelines should be taken into consideration when determining optimal treatment.  All 
lipid therapies (doses and regimen) should remain unchanged for the duration of study 
participation (up to 52 weeks).  All subjects should receive high-intensity statin therapy 
with atorvastatin ≥ 40 mg daily or equivalent (Table 7-1; criteria modified from American 
College of Cardiology/American Heart Association [ACC/AHA] guidelines), in 
accordance with local guidelines.  If not receiving atorvastatin ≥ 40 mg or equivalent, the 
investigator must attest in eCRF that higher dose statin therapy has been considered but 
is not appropriate for this subject (eg, dose not tolerated, dose not available in that 
country, other significant concern). 
If making any changes to this therapy after randomization, the reason for the change 
must be provided in the CRF and the Amgen medical monitor or designee should be 
consulted before making the change. 
Other regulatory-approved lipid regulating therapies (eg, ezetimibe) used at screening 
should remain unchanged for the duration of study participation (up to 52 weeks). 
Beyond the week 52 assessment, use of statins and other lipid regulating therapies will 
be at the discretion of the investigator. 
Table 7-1.  Acceptable Background Statin Therapy 
 
High-intensity  
Statin Therapy 
Moderate-intensity Statin 
Therapy 
Low-intensity  
Statin Therapy 
Atorvastatin 
≥ 40 mg QD 
10 mg to  
< 40 mg QD 
< 10 mg QD 
Rosuvastatin 
≥ 20 mg QD 
5 mg to  
< 20 mg QD 
< 5 mg QD 
Simvastatina 
≥ 80 mg QD 
20 mg to  
< 80 mg QD 
< 20 mg QD 
Pravastatin 
- 
≥ 40 mg QD 
< 40 mg QD 
Lovastatin 
- 
≥ 40 mg QD 
< 40 mg QD 
Fluvastatin 
- 
80 mg QD 
< 80 mg QD 
Pitavastatin 
- 
≥ 2 mg QD 
< 2 mg QD  
QD = once daily 
a Use of simvastatin 80 mg was associated with myopathy and is not commonly recommended for use.  
Simvastatin 80 mg is not available in all countries participating in this study.  Approval of simvastatin 
80 mg by the local regulatory authority is required for subjects using simvastatin 80 mg in this study. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 36 of 94 
CONFIDENTIAL 
 
 
Statins are not provided or reimbursed by Amgen (except if required by local regulation). 
Additional details regarding these protocol-required therapies are provided in the IPIM. 
7.1.5 
Other Treatment Procedures 
There are no other treatment procedures for this study. 
7.1.6 
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 drug(s), device(s) or combination product(s) provisioned and/or 
repackaged/modified by Amgen.  Drug(s) or device(s) includes investigational product.   
Examples of potential product complaints that need to be reported to Amgen include, but 
are not limited to: 
 
Broken container or cracked container 
 
Misuse of the personal injector (or AI/Pen) due to misunderstanding of the clinical 
IFU or error on part of the user, or other inability to appropriately use the product 
(eg, due to malfunction of the personal injector [or AI/Pen]) 
 
Missing, illegible, incorrect, and/or suspect labels 
 
Change in investigational product appearance (eg, color change or visible presence 
of foreign material) 
 
Unexpected quantity or volume (eg, number of tablets or amount of fluid in the 
personal injector [or AI/Pen]), or evidence of tampering or stolen material 
Any product complaint(s) associated with an investigational product(s), 
non-investigational product(s), device(s), or combination product(s) supplied by Amgen 
are to be reported according to the instructions provided in the IPIM. 
7.1.7 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
The following treatments are not permitted during the study: 
 
Non-study investigational therapies 
 
Any lipid lowering therapies not taken at the time of screening and enrollment  
Please contact the Amgen medical monitor or designee if any of these therapies should 
be initiated during the study.  Note that a change in background lipid-lowering therapy 
(including statins), does not necessarily require ending investigational product. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 37 of 94 
CONFIDENTIAL 
 
 
The following treatments are not recommended in subjects treated with statins 
metabolized by cytochrome P450 (CYP) 3A4 (eg, simvastatin or atorvastatin) because of 
their potential impact on metabolism of certain statins: 
 
Medications or foods that are known potent inhibitors of CYP 3A4 (eg, itraconazole, 
ketoconazole, and other antifungal azoles, macrolide antibiotics erythromycin, 
clarithromycin, and the ketolide antibiotic telithromycin, human immunodeficiency 
virus or hepatitis C virus (HCV) protease inhibitors, antidepressant nefazodone and 
grapefruit juice in large quantities (> 1 quart daily [approximately 1 L]) should not be 
used during the study. 
7.2 
Method of Treatment Assignment 
Subjects will be randomized in a 1:1 allocation ratio, evolocumab to placebo, 
respectively, in a double-blind manner.  
The randomization will be performed by IVRS/IWRS. 
The randomization number will be provided once eligibility into the study has been 
confirmed.  A site representative will make the randomization call to the IVRS/IWRS to 
assign a randomization number to the subject.  The randomization call to the IVRS is 
accomplished by entering the pertinent information detailed in the IVRS/IWRS user 
manual.  A confirmation fax/electronic-mail (e-mail) will be sent to the site to verify that 
the correct information has been entered and confirm the randomization number 
assigned. 
The randomization will be stratified by current statin use (> 4 weeks or ≤ 4 weeks) at 
screening.  
The randomization date is to be documented in the subject’s medical record and on the 
enrollment CRF. 
7.3 
Blinding 
This is a double-blind study.  Treatment assignment will be blinded to all subjects, site 
personnel, and Amgen as described below. 
7.3.1 
Site Personnel Access to Individual Treatment Assignments 
A subject’s treatment assignment is to only be unblinded when knowledge of the 
treatment is essential for further clinical management of the subject on this study.  
Unblinding at the study site for any other reason will be considered a protocol deviation.  
The Amgen Trial Manager must be notified before the blind is broken unless 
identification of the study treatment is required for a medical emergency in which the 
knowledge of the specific blinded study treatment will affect the immediate management 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 38 of 94 
CONFIDENTIAL 
 
 
of the subject’s condition.  In this case, the Amgen Trial Manager must be notified within 
24 hours after breaking the blind.  The date and reason that the blind was broken must 
be recorded in the source documentation and CRF, as applicable. 
7.3.2 
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 is not to 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 7.3.1). 
7.4 
Dose Modification 
7.4.1 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
7.4.1.1 
Amgen Investigational Product:  Evolocumab 
There will be no investigational product dose adjustments in this study.  If, in the opinion 
of the investigator, a subject is unable to tolerate investigational product, that subject will 
discontinue investigational product but will return for all other study procedures and 
measurements until the end of the study. 
If a subject is late for administration of investigational product, administration should 
occur as soon as possible.  A QM dose of investigational product should not be 
administered within less than 7 days of a previous dose.  If a subject arrives for a visit 
and investigational product was administered within less than 7 days prior, the dose 
should not be administered but all other study procedures should be conducted and 
administration of investigational product should occur as soon as possible at least 
7 days after the previous administration. 
If a subject completely misses a dose of SC investigational product, the subject should 
continue in the study and the next dose of investigational product should be 
administered per their schedule of administration. 
7.4.1.2 
Non-Amgen Non-Investigational Product:  Background 
Lipid-lowering Therapy  
The reason for dose change of non-Amgen non-investigational product (background 
lipid-lowering therapy) is to be recorded on each subject’s CRF(s). 
Subjects who miss a dose of background lipid-lowering therapy will be advised to refer to 
the product information of that drug and proceed according to the directions in the label.  
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 39 of 94 
CONFIDENTIAL 
 
 
If stopping or altering dosing of statin therapy (or allowable non-statin therapy) is 
medically warranted during the trial, the subject should continue to receive 
investigational product.  These situations should be discussed with the Amgen medical 
monitor as soon as possible.  In addition, if a medical decision is made to withhold 
investigational product during the study, subjects should continue to receive statin (and 
allowable non-statin) background therapy.  The medical monitor should be contacted 
prior to stopping investigational product. 
7.4.2 
Hepatotoxicity Stopping and Rechallenge Rules 
Refer to Appendix 7 for details regarding drug-induced liver injury (DILI) guidelines, as 
specified in the Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation, July 2009.   
If a possible DILI is suspected, investigational product, statin therapy, and other 
applicable lipid-regulating background therapy must be discontinued and the subject 
should be followed according to the recommendations in Appendix 7. 
7.5 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product other protocol-required therapies and/or device 
(personal injector or AI/Pen) during the study are provided in the IPIM. 
7.6 
Treatment Compliance 
Medication will be dispensed for self-administration at home.  Subjects are to report all 
administered doses and missed doses for all study-required medication taken at home to 
their study physician upon collection of adverse events and product/device complaints.  
Non-compliance is to be documented in the medical file and will be reflected in the 
CRF.  Non-compliant subjects are to be re-educated on the importance of adhering to 
the study drug administration schedule and reminded that repeated cycles of 
non-compliance could be a reason for discontinuation of study treatment. 
7.7 
Treatment of Overdose 
There is no specific treatment for evolocumab overdose.  In the event of an overdose, 
the patient should be treated symptomatically and supportive measures instituted as 
required. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 40 of 94 
CONFIDENTIAL 
 
 
7.8 
Prior and Concomitant Treatment 
7.8.1 
Prior Treatment 
Prior therapies that were being taken/used from 30 days prior to enrollment through the 
signing of the informed consent will be collected. 
7.8.2 
Concomitant Treatment 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 7.1.7. 
Concomitant therapies are to be collected from informed consent through the end of 
safety follow-up period. 
It is anticipated that subjects will remain on a stable dose of statin therapy and other 
allowed lipid-regulating therapies from randomization until the EOS. 
The use of antacids is not recommended within the period of 2 hours before and 2 hours 
after dosing with statins. 
8. 
Discontinuation Criteria 
Subjects have the right to withdraw from investigational product and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
and for any reason without prejudice to their future medical care by the physician or at 
the institution. 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, device, and/or other protocol-required therapies, protocol procedures, or the 
study as a whole at any time prior to study completion for the reasons listed in 
Section 8.1, Section 8.2.1, and Section 8.2.2. 
8.1 
Discontinuation of Study Treatment 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss with 
the subject the possibilities for continuation of the Schedule of Activities (see Table 2-1) 
including different options of follow-up (eg, in person, by phone/mail, through 
family/friends, in correspondence/communication with other treating physicians, from the 
review of medical records) and collection of data, including endpoints, adverse events, 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 41 of 94 
CONFIDENTIAL 
 
 
and device-related events, as applicable and must document this decision in the 
subject’s medical records.  Subjects who have discontinued investigational product 
and/or other protocol-required therapies or procedures should not be automatically 
removed from the study.  Whenever safe and feasible, it is imperative that subjects 
remain on-study to ensure safety surveillance and/or collection of outcome data. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
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 Appendix 3. 
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
 
Decision by Sponsor 
 
Lost to follow-up 
 
Death 
 
Ineligibility determined 
 
Protocol deviation 
 
Non-compliance  
 
Adverse event 
 
Subject request 
 
Requirement for alternative therapy not allowed by protocol 
 
Pregnancy 
8.2 
Discontinuation From the Study 
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, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study, and must document the 
subject’s decision to withdraw in the subject’s medical records. 
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly (see 
Appendix 6 for further details).  Refer to the Schedule of Activities (Table 2-1) for data to 
be collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 42 of 94 
CONFIDENTIAL 
 
 
8.2.1 
Reasons for Removal From Invasive Procedures 
Reasons for removal from the invasive procedures include any of the following: 
 
Decision by Sponsor 
 
Lost to follow-up 
 
Death 
 
Ineligibility determined 
 
Protocol deviation 
 
Non-compliance  
 
Adverse event 
 
Subject request 
 
Requirement for alternative therapy not allowed by protocol 
 
Pregnancy 
8.2.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
Decision by sponsor 
 
Withdrawal of consent from study 
 
Death 
 
Lost to follow-up 
8.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
 
The site must attempt to contact the subject and reschedule the missed visit as 
soon as possible and counsel the subject on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the subject wishes to and/or 
is able to continue in the study. 
 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and, if necessary, a certified letter to the subject’s last 
known mailing address or local equivalent methods).  These contact attempts are 
to be documented in the subject’s medical record. 
 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
 
For subjects who are lost to follow-up, the investigator can search publicly 
available records [where permitted]) to ascertain survival status.  This ensures 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 43 of 94 
CONFIDENTIAL 
 
 
that the data set(s) produced as an outcome of the study is/are as 
comprehensive as possible. 
9. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Table 2-1).  
As protocol waivers or exemptions are not allowed if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the subject is to continue or 
discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities (Table 2-1), is essential and required for study conduct. 
9.1 
General Study Periods 
This will be a multi-center, double-blind, randomized, placebo-controlled trial.  The study 
consists of: 
 
Screening 
 
Double-blind treatment period 
 
EOS visit 
Written informed consent must be obtained and will be implemented before 
protocol-specific procedures are carried out.  The risks and benefits of participating in 
the study will be verbally explained to each potential subject prior to entering the study.  
The procedures to be performed during the study are described below and are 
summarized in the Schedule of Activities (Table 2-1). 
9.1.1 
Screening, Enrollment and/or Randomization 
Informed consent must be obtained before completing any screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  After the subject has 
signed the informed consent form, the site will register the subject in the IVRS/IWRS and 
screen the subject in order to assess eligibility for participation.  The screening window is 
up to 1 week. 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria, including acceptability of OCT data set as determined 
by the imaging core laboratory.  The investigator will maintain a screening log to record 
details of all subjects screened and to confirm eligibility or record reasons for screening 
failure, as applicable. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 44 of 94 
CONFIDENTIAL 
 
 
If a subject has not met all eligibility criteria at the time of randomization, the subject will 
be registered as a screen fail IVRS/IWRS.  Subjects cannot undergo rescreening during 
the same admission, (ie, index date [admission]).  Rescreening is only permitted if a 
subject is re-admitted for new occurrence of NSTE-ACS that is not related to the 
NSTE-ACS at index admission.  Screen fail subjects may be eligible for rescreening 
2 times.   
All rescreened subjects must reconsent.  Rescreen subjects must be registered as 
rescreens in IVRS/IWRS.  Once the subject is registered as rescreened, a new 7-day 
screening window will begin.  With the exception of the screening placebo injection, 
rescreened subjects will repeat all screening procedures.  Rescreened subjects will 
maintain the originally assigned subject identification number. 
For procedures regarding LDL-C assessments during screening, these should occur 
between admission for NSTE-ACS and the coronary angiogram.  Subject eligibility 
(Section 6.1; inclusion criterion 104) based on subjects’ statin dose at the time of LDL-C 
blood sample measurement is as follows: 
No statin use 
 LDL-C:  ≥ 130 mg/dL 
Low- or Moderate-intensity statin dose (see Table 7-1) 
 LDL-C:  ≥ 80 mg/dL 
High-intensity statin dose (see Table 7-1) 
 LDL-C:  ≥ 60 mg/dL  
Day 1 of the treatment period (ie, first dose of investigational product) must happen 
within 7 days of the signing of the informed consent. 
9.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (Table 2-1).  On-study visits may be 
completed within 50 weeks and must occur within ± 7 days of their specified date (with 
the exception of the week 50 OCT and IVUS).  The date of the first dose of 
investigational product is defined as day 1.  All subsequent doses and study visits will be 
scheduled based on the day 1 date.  Administration of investigational product is to be 
administered last during each visit that it is required. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 45 of 94 
CONFIDENTIAL 
 
 
Before each study visit where fasting lipid samples are obtained, subjects must be 
fasting overnight.  If the subject is not fasting for the day 1 visit, no visit procedures are 
performed and the visit should be rescheduled within the applicable protocol windows.  If 
subject is not fasting after day 1, all procedures except fasting labs and investigational 
product administration, if applicable, will be performed and another visit should be 
scheduled, within the visit window if possible, for fasting labs and investigational product 
administration. 
The study includes collection of biomarker samples. 
Final, follow-up OCT and IVUS should take place 50 ± 2 weeks (ie, 48 to 52 weeks) after 
initial baseline image acquisition.  It is critical that the follow-up OCT and IVUS be 
obtained for all subjects, regardless of whether they discontinued study drug prematurely 
or are outside the 50 ± 2 weeks window. 
9.1.2.1 
Clinically Indicated Catherization Prior to Week 40 
For subjects requiring coronary angiography prior to week 40, the final OCT and IVUS 
examination should not be performed in these subjects at the time of clinically indicated 
catherization.  Subjects will remain on study drug and complete all required visits and 
procedures, including the week 50 OCT and IVUS. 
For subjects requiring coronary angiography with intervention of the targeted vessel prior 
to week 40, these subjects will continue investigational product and complete all study 
visits and procedures with the exception of the week 50 OCT and IVUS. 
9.1.2.2 
Clinically Indicated Catherization at Week 40 Prior to Week 50 
Any subjects who require cardiac catherization for clinically indicated reasons at 
week 40 or later must have OCT and IVUS examination of the target vessel performed 
at that time.  The week 50 OCT and IVUS will not be required for these subjects.  If PCI 
of a non-target vessel is required, subjects will undergo the final OCT and IVUS after 
PCI is completed.  If PCI of the target vessel is required, the final OCT and IVUS should 
be completed prior to PCI if clinically appropriate.  These subjects will continue 
investigational product and complete all study visits and procedures with the exception 
of the week 50 OCT and IVUS. 
9.1.3 
End of Study 
Subjects will end the study once contacted by the site by phone call at week 52. 
Completion of the study is defined as the last day that protocol-specified procedures are 
conducted for an individual subject.  Subjects who are not deceased, have not 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 46 of 94 
CONFIDENTIAL 
 
 
withdrawn consent, or are not lost to follow-up, should have at minimum an EOS 
assessment for vital status (alive or deceased) and adverse events. 
9.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
time points. 
9.2.1 
General Assessments  
9.2.1.1 
Informed Consent 
All subjects or their legally authorized representative must sign and personally date the 
IRB/IEC approved informed consent before any study-specific procedures are 
performed. 
9.2.1.2 
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.   
9.2.1.3 
Medical History 
The investigator or designee will collect a targeted medical and surgical history on the 
following conditions or indications that started prior to study entry/screening through the 
start of the adverse event reporting period:  cardiovascular disease.  Record all findings 
on the medical history CRF.  The current severity will be collected for each condition that 
has not resolved.  Additionally, patient reported cardiovascular risk factors will be 
collected at the time of randomization. 
9.2.1.4 
Physical Examination  
Physical examination will be performed as per standard of care.  Physical examination 
findings should be recorded on the appropriate CRF (eg, medical history, event). 
9.2.1.5 
Physical Measurements 
9.2.1.5.1 
Height 
Height in centimeters should be measured without shoes. 
9.2.1.5.2 
Weight 
Weight in kilograms should be measured without shoes. 
9.2.2 
Efficacy Assessments 
Disease assessments will be based on intracoronary imaging (OCT and IVUS) and 
LDL-C assessments at scheduled timepoints in the Schedule of Activities (Table 2-1). 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 47 of 94 
CONFIDENTIAL 
 
 
9.2.2.1 
Intracoronary Imaging (OCT and IVUS) 
In order to minimize the chances of performing unnecessary invasive procedures, 
investigators should ensure that subjects’ initial screening LDL-C results are available 
prior to performing the baseline OCT and IVUS examination.  Thereafter, subjects will 
undergo clinically-indicated coronary angiography for further clinical evaluation following 
their hospitalization for NSTE-ACS.  If angiographic criteria are met, the subject will have 
baseline OCT and IVUS completed.  Subjects who require a PCI deemed necessary by 
the qualifying angiogram will have baseline OCT and IVUS imaging performed 
immediately following the PCI.  OCT and IVUS must not be performed in vessels that 
underwent an intervention.   
The accuracy and reproducibility of the imaging endpoints of the study are dependent 
upon Investigator’s commitment to rigorous image acquisition techniques.  The central 
imaging core laboratory will provide a separate imaging guidance document to all 
participating sites.  Adherence to these guidelines will ensure low inter- and 
intra-observer variability and high image quality. 
For each patient, all imaging conditions at baseline must be duplicated at follow-up 
utilizing the same imaging system.  The OCT and IVUS systems must not be changed 
between the baseline and follow-up examinations.  All baseline studies (angiography, 
OCT, IVUS) must be forwarded to the imaging core laboratory for informational review.  
OCT images must be reviewed and approved by the imaging core laboratory before 
subjects return for randomization visit.   
9.2.2.2 
LDL-C 
Low-density lipoprotein cholesterol analysis will be performed by local laboratory 
assessments during the Screening period.  The results will have to be recorded in CRF.  
Treatment period LDL-C analysis will be performed by the central laboratory.  The blood 
samples will be drawn at the time points indicated in the Schedule of Activities 
(Table 2-1). 
9.2.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
(Table 2-1). 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 48 of 94 
CONFIDENTIAL 
 
 
9.2.3.1 
Adverse Events 
9.2.3.1.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
9.2.3.1.1.1 
Adverse Events 
The adverse event grading scale to be used for this study will be the Common 
Terminology Criteria for Adverse Events (CTCAE) or the Amgen Adverse Event Grading 
Scale and is described in Appendix 4. 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after signing the informed consent 
through the EOS are reported using the Event CRF. 
9.2.3.1.1.2 
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 the informed consent 
through 30 days after the last dose of investigational product or EOS (whichever is later) 
are reported using the Event CRF. 
All serious adverse events will be collected, recorded, and reported to the sponsor or 
designee within 24 hours, as indicated in Appendix 4.  The investigator will submit any 
updated serious adverse event data to the sponsor within 24 hours of it being available. 
The criteria for grade 4 in the 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. 
9.2.3.1.1.3 
Serious Adverse Events After the Protocol-required Reporting 
Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after EOS.  However, these serious adverse 
events can be reported to Amgen.  Per local requirements in some countries, 
investigators are required to report serious adverse events that they become aware of 
after EOS.  If serious adverse events are reported, the investigator is to report them to 
Amgen within 24 hours following the investigator’s knowledge of the event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases and handled accordingly based 
on relationship to investigational product.  
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 49 of 94 
CONFIDENTIAL 
 
 
The method of recording, evaluating, and assessing causality of adverse events, 
adverse device effects, and serious adverse events and the procedures for completing 
and transmitting serious adverse event reports are provided in Appendix 4. 
9.2.3.1.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the subject is the 
preferred method to inquire about adverse event occurrence. 
9.2.3.1.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is required to 
proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 8.3).  
Further information on follow-up procedures is given in Appendix 4. 
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Event CRF. 
9.2.3.1.4 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 50 of 94 
CONFIDENTIAL 
 
 
An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB/IEC, if appropriate according to local requirements. 
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.  Aggregate 
analyses may also be unblinded by the Safety Assessment Team (SAT) as appropriate.  
Investigators will receive notification of related serious adverse events reports sent to 
regulatory authorities in accordance with local requirements. 
9.2.3.1.5 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects and, if indicated, female 
partners of male subjects will be collected after the start of study treatment and until 
15 weeks after the last dose of investigational product. 
If a pregnancy is reported, the investigator is to inform Amgen within 24 hours of learning 
of the pregnancy and/or lactation and is to follow the procedures outlined in Appendix 5.  
Amgen Global Patient Safety will follow-up with the investigator regarding additional 
information that may be requested. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events. 
Further details regarding pregnancy and lactation are provided in Appendix 5. 
9.2.3.1.6 
Adverse Device Effects 
In order to fulfill regulatory reporting obligations worldwide, the investigator is 
responsible for the detection and documentation of any adverse device effects that occur 
during the study with such devices.  
An adverse device effect is any adverse event related to the use of a combination 
product or medical device.  Adverse device effects include adverse events resulting from 
insufficient or inadequate IFU, adverse events resulting from any malfunction of the 
device, or adverse events resulting from use error or from intentional misuse of the 
device. 
All adverse device effects are to be reported as adverse events following the same 
reporting periods and procedures. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 51 of 94 
CONFIDENTIAL 
 
 
Product complaints are described in Section 7.1.6. 
Further details regarding adverse device effects can be found in Appendix 4. 
9.2.3.2 
Vital Signs 
The following measurements must be performed:  systolic/diastolic blood pressure and 
heart rate.  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 as possible.  
The position selected for a subject should be the same that is used throughout the study 
and documented on the vital sign CRF.  Record all measurements on the vital signs 
CRF. 
9.2.3.3 
Vital Status 
Vital status must be obtained for all subjects within the limits of local law.  This includes 
subjects who may have discontinued study visits with or without withdrawing consent 
and should include interrogation of public databases, if necessary.  If deceased, the date 
and reported cause of death should be obtained. 
9.2.4 
Clinical Laboratory Assessments 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Table 2-1) for the timing and frequency.  
The investigator is responsible for reviewing laboratory test results and recording any 
clinically relevant changes occurring during the study in the Event CRF.  The investigator 
must determine 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. 
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities 
(Table 2-1).  
Laboratory/analyte results that could unblind the study should not be performed during 
the subject’s participation in the study.  Central laboratory results of the lipid testing will 
be blinded post-treatment until unblinding of the clinical database and will not be 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 52 of 94 
CONFIDENTIAL 
 
 
reported to the investigator post-screening.  In addition, investigators and staff involved 
with this trial and all medical staff involved in the subject’s medical care should refrain 
from obtaining lipid panels between randomization and at least 12 weeks after the 
subject ends the study (to avoid potential unblinding). 
9.2.4.1 
Pregnancy Testing 
A high sensitive (urine or serum) pregnancy test should be completed at screening and 
within 7 days of initiation of investigational product for females of childbearing potential.   
Note:  Females who have undergone a bilateral tubal ligation/occlusion should have 
pregnancy testing per protocol requirements.  (If a female subject, or the partner of a 
male subject, becomes pregnant it must be reported on the Pregnancy Notification 
Worksheet, see Figure 12-2).  Refer to Appendix 5 for contraceptive requirements.  
An additional pregnancy test should be performed also at week 24 and week 50. 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 
9.2.5 
Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention. 
Biomarker development can be useful in developing markers to identify disease 
subtypes, guide therapy, and/or predict disease severity. 
Amgen may attempt to develop test(s) designed to identify subjects most likely to 
respond positively or negatively to evolocumab to investigate and further understand 
cardiovascular disease. 
Blood samples are to be collected for biomarker development at the time points 
specified in the Schedule of Activities (Table 2-1).  
10. 
Statistical Considerations 
10.1 
Sample Size Determination 
The planned total sample size is 150 subjects (75 randomized to evolocumab 
420 mg SC QM and 75 randomized to placebo SC QM).  This sample size will provide 
sufficient power (90%) to determine whether there is a treatment effect of evolocumab 
relative to placebo in the primary endpoint. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 53 of 94 
CONFIDENTIAL 
 
 
The assumptions in the sample size calculation are based on a linear regression 
meta-analysis of 7 historical trials (Dai et al, 2017; Hou et al, 2016; Kataoka et al, 2014; 
Komukai et al, 2014; Nishio et al, 2014; Hattori et al, 2012; Takarada et al, 2009) 
weighted by sample sizes. 
The analysis result indicates that every 1 mg/dL reduction in LDL-C is estimated to be 
associated with 1.4785 µm increase in FCT in 12-month follow-up.  Assuming a 
50 mg/dL reduction in LDL-C, the predicted mean increase (95% CI) in FCT from the 
meta-analysis was 73.92 (50.97, 96.88) µm.  For this study, the assumed treatment 
effect is at least 50.97 µm increase in FCT, which is approximated from the lower bound 
95% CI of the expected change in FCT from the regression model, based on a 
conservative assumption of 50 mg/dL reduction in LDL-C from baseline to week 50. 
The SD of FCT measurement at baseline or at the end of various length of follow-up was 
reported in a wide range (10.6 to 124 µm) based on 15 to 134 subjects per arm in the 
historical trials.  The SD of change in FCT was only reported in 2 of the 7 trials, ranging 
from 22 to 86 µm.  The assumed common SD for this study is 86 µm to be conservative. 
Assuming 1 out of 6 subjects will not complete both baseline and week 50 OCT 
assessments, and therefore be excluded in the primary analysis, the sample size of 
150 subjects will provide approximately 125 subjects in the primary analysis to ensure 
90% power to test the study hypothesis. 
The sample size calculation was performed using a 2-sided t-test with a 
0.05 significance level.  The sample size calculation was derived using East® software 
(version 6.4). 
10.2 
Analysis Sets, Subgroups, and Covariates 
10.2.1 
Analysis Sets 
Full Analysis Set:  The full analysis set (FAS) includes all randomized subjects who 
received at least 1 dose of investigational product.  
10.2.2 
Covariates 
Baseline covariates will include, but are not limited to the following: 
 
Age 
 
Sex 
 
Baseline LDL-C 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 54 of 94 
CONFIDENTIAL 
 
 
10.2.3 
Subgroups 
Subgroup analysis of the primary endpoint will be conducted for, but not limited to the 
following variables: 
 
Age (< median, ≥ median; < 65 years of age, ≥ 65 years of age) 
 
Sex 
 
Baseline LDL-C (< median, ≥ median) 
10.2.4 
Handling of Missing and Incomplete Data 
Subjects may be missing specific data points for various reasons.  In general, data may 
be missing due to a subject's early withdrawal from study, a missed visit, or 
non-evaluability of a data point or endpoint at a particular time.  The frequency and 
pattern of missing data for efficacy endpoints will be assessed through descriptive 
summaries of the measurements over time.  The reason of missing the final OCT 
measurement will be tabulated.  For subjects with missing post-baseline FCT, the 
missing primary endpoint will be imputed using multiple imputation 
(see Section 10.3.2.2). 
10.3 
Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock.  Below 
is a summary of the timing and methods for the planned statistical analyses.  To 
preserve study integrity, the final analysis will be conducted and reported following the 
EOS, as defined in Section 5.3.1. 
10.3.1 
Planned Analyses 
10.3.1.1 
Final Analysis 
There will be no interim analysis for this study.  The final analysis will be conducted after 
all subjects have either completed all the scheduled study visits or have early terminated 
from the study.  At that time, the database will be cleaned, processed, locked, and a 
snapshot will be taken; the study will also be unblinded.  Based on the snapshot, efficacy 
and safety analyses will be performed. 
10.3.2 
Methods of Analyses 
10.3.2.1 
General Considerations 
Summary statistics for continuous variables will include the number of subjects, mean, 
median, SD or standard error, minimum, and maximum.  For categorical variables, the 
frequency and percentage will be given. 
Statistical inferences will be provided for analyses of primary and secondary efficacy 
endpoints.  Unless specified otherwise, all statistical tests are 2-sided with a significance 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 55 of 94 
CONFIDENTIAL 
 
 
level of 0.05; no statistical inference and imputation will be conducted for analyses of 
safety of exploratory endpoints. 
Multiplicity Adjustment Method 
In order to preserve the family wise type 1 error rate at 0.05 for testing the primary and 
secondary endpoints, the primary analysis of primary endpoint will be tested first.  If the 
treatment effect from the primary analysis of the primary endpoint is significant at a 
significance level of 0.05, the secondary endpoints will be tested with significance level 
of 0.05 using the Hochberg method 
10.3.2.2 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
The primary analysis method of the primary endpoint is to use the 
analysis of covariance (ANCOVA) model, including terms for treatment 
group, stratification factor (current statin use [> 4 weeks or ≤ 4 weeks] 
at randomization), and baseline FCT as covariates.  Least square 
means and corresponding 95% confidence intervals will be calculated 
for each treatment group and for the difference between the treatment 
groups.  For subjects with missing post-baseline FCT, the missing 
primary endpoint will be imputed using multiple imputation (details 
provided in SAP).  FAS will be used. 
A sensitivity analysis of the primary endpoint will be conducted using 
nonparametric method and FAS. 
Secondary 
ANCOVA model including terms for treatment group, stratification 
factor (current statin use [> 4 weeks or ≤ 4 weeks] at randomization), 
and respective baseline value as covariates. 
Exploratory 
Will be described in the statistical analysis plan finalized before 
database lock 
 
10.3.2.3 
Safety Analyses 
10.3.2.3.1 
Adverse Events 
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 investigational product or other 
protocol-required therapies, and significant treatment-emergent adverse events will also 
be provided.  Subject incidence of device-related events, if applicable, will be tabulated 
by system organ class and preferred term. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 56 of 94 
CONFIDENTIAL 
 
 
10.3.2.3.2 
Laboratory Test Results 
The analyses of safety laboratory endpoints will include summary statistics at each 
scheduled visit for each treatment group.  Shifts in grades of safety laboratory values 
between the worst on-study value from baseline to the EOS will be tabulated for each 
treatment group. 
10.3.2.3.3 
Vital Signs 
The analyses of vital signs will include summary statistics at each measurement time 
point for each treatment group. 
10.3.2.3.4 
Physical Measurements 
The analyses of physical measurements will include summary statistics at each 
measurement time point for each treatment group. 
10.3.2.3.5 
Exposure to Investigational Product 
The patient-month exposure to investigational product, the categorical representation of 
dose received, and the total quantity of investigational product used by treatment group 
will be summarized using descriptive statistics. 
10.3.2.3.6 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving therapies of interest including statins will be 
summarized for each treatment group as coded by the World Health Organization Drug 
(WHODRUG) dictionary. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 57 of 94 
CONFIDENTIAL 
 
 
11. 
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. 
Bezerra HG, Attizzani GF, Sirbu V, et al.  Optical coherence tomography versus 
intravascular ultrasound to evaluate coronary artery disease and percutaneous coronary 
intervention.  JACC Cardiovasc Interv.  2013;6:228-236. 
Bezerra HG, Costa MA, Guagliumi G, Rollins AM, Simon DI.  Intracoronary optical 
coherence tomography:  a comprehensive review clinical and research applications.  
JACC Cardiovasc Interv.  2009;2:1035-1046. 
Burke AP, Farb A, Malcolm GT, Liang YH, Smialek J, Virmani R.  Coronary risk factors 
and plaque morphology in men with coronary disease who died suddenly.  
N Engl J Med.  1997;336:1276-1282. 
Cannon CP, Blazing MA, Giugliao RP, et al.  Ezetimibe Added to Statin Therapy after 
Acute Coronary Syndromes.  N Engl J Med.  2015;372:2387-2397. 
Cannon CP, Braunwald E, McCabe CH, et al.  Intensive versus moderate lipid lowering 
with statins after acute coronary syndromes.  N Engl J Med.  2004;350:1495-1504. 
Cholesterol Treatment Trialists' (CTT) Collaboration, Baigent C, Blackwell L, et al.  
Efficacy and safety of more intensive lowering of LDL cholesterol:  a meta-analysis of 
data from 170,000 participants in 26 randomised trials.  Lancet.  2010;376:1670-1681. 
Dai J, Hou J, Xing L, et al.  Is age an important factor for vascular response to statin 
therapy?  A serial optical coherence tomography and intravascular study.  Coron Artery 
Dis.  2017;28:209-217. 
Evolocumab (AMG 145) Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc.  
Gonzalo N, Tearney GJ, Serruys PW, et al.  Second-generation optical coherence 
tomography in clinical practice.  High-speed data acquisition is highly reproducible in 
patients undergoing percutaneous coronary intervention.  Rev Esp Cardiol.  
2010;63:893-903. 
Hattori K, Ozaki Y, Ismail TF, et al.  Impact of statin therapy on plaque characteristics as 
assessed by serial OCT, grayscale and integrated backscatter-IVUS.  JACC 
Cardioavasc Imaging.  2012;5:169-177. 
Hou J, Xing L, Jia H, et al.  Comparison of Intensive Versus Moderate Lipid-Lowering 
Therapy on Fibrous Cap and Atheroma Volume of Coronary Lipid-Rich Plaque Using 
Serial Optical Coherence Tomography and Intravascular Ultrasound Imaging.  Am J 
Cardiol.  2016;117:800-806. 
Ino Y, Kubo T, Tanaka A, et al.  Difference of culprit lesion morphologies between ST-
segment elevation myocardial infarction and non-ST-segment elevation acute coronary 
syndrome: an optical coherence tomography study.  JACC Cardiovasc Interv.  
2011;4:76-82. 
International Committee of Medical Journal Editors, Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals:  Writing and Editing for Biomedical 
Publication.  2013.  http://www.icmje.org/ 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 58 of 94 
CONFIDENTIAL 
 
 
Jamil Z, Tearney G, Bruining N, et al.  Interstudy reproducibility of the second 
generation, Fourier domain optical coherence tomography in patients with coronary 
artery disease and comparison with intravascular ultrasound:  a study applying 
automated contour detection.  Int J Cardiovasc Imaging.  2013;29:39-51. 
Kataoka Y, Puri R, Hammadah M, et al.  Frequency-domain optical coherence 
tomographic analysis of plaque microstructures at nonculprit narrowings in patients 
receiving potent statin therapy.  Am J Cardiol.  2014;114:549-554. 
Kini AS, Vengrenyuk Y, Yoshimura T, et al.  Fibrous Cap Thickness by Optical 
Coherence Tomography In Vivo.  J Am Coll Cardiol.  2017;69:644-657. 
Komukai K, Kubo T, Kitabata H, et al.  Effect of atorvastatin therapy on fibrous cap 
thickness in coronary atherosclerotic plaque as assessed by optical coherence 
tomography:  the EASY-FIT study.  J Am Coll Cardiol.  2014;64:2207-2217. 
Kubo T, Imanishi T, Takarada S, et al.  Assessment of culprit lesion morphology in acute 
myocardial infarction:  ability of optical coherence tomography compared with 
intravascular ultrasound and coronary angioscopy.  J Am Coll Cardiol.  
2007;50:933-999. 
Kume T, Akasaka T, Kawamoto T, et al.  Assessment of coronary intima-media 
thickness by optical coherence tomography:  comparison with intravascular ultrasound.  
Circ J.  2005;69:903-907. 
Matthews SD and Frishman WH.  A Review of the Clinical Utility of Intravascular 
Ultrasound and Optical Coherence Tomography in the Assessment and Treatment of 
Coronary Artery Disease.  Cardiol Rev.  2017;25:68-76. 
Moore KJ and Tabas I.  Macrophages in the pathogenesis of atherosclerosis.  Cell.  
2011;145:341-355. 
Mozaffarian D, Benjamin EJ, Go AS, et al.  Statistical update.  Heart disease and stroke 
statistics - 2016 update.  A Report From the American Heart Association.  Circulation.  
2016;133:e38-e360. 
Nair A, Kuban BD, Tuzcu EM, Schoenhagen P, Nissen SE, Vince DG.  Coronary plaque 
classification with intravascular ultrasound radiofrequency data analysis.  Circulation.  
2002;106:2200-2206. 
Nicholls SJ, Puri R, Anderson T, et al.  Effect of Evolocumab on Progression of Coronary 
Disease in Statin-Treated Patients:  the GLAGOV randomized clinical trial.  JAMA.  
2016;316:2373-2384. 
Nicholls SJ, Ballantyne CM, Barter PJ, et al.  Effect of two intensive statin regimens on 
progression of coronary disease.  N Engl J Med.  2011;365:2078-2087. 
Nishio R, Shinke T, Otake H, et al.  Stabilizing effect of combined eicosapentaenoic acid 
and statin therapy on coronary thin-cap fibroatherroma.  Atherosclerosis.  
2014;234:114-119. 
Nissen SE, Nicholls SJ, Sipahi I, et al.  Effect of very high-intensity statin therapy on 
regression of coronary atherosclerosis:  the ASTEROID trial.  JAMA.  
2006;295:1556-1565. 
Nissen SE, Tuzcu EM, Schoenhagen P, et al.  Effect of intensive compared with 
moderate lipid-lowering therapy on progression of coronary atherosclerosis:  a 
randomized controlled trial.  JAMA.  2004;291:1071-1080. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 59 of 94 
CONFIDENTIAL 
 
 
Nissen SE, Gurley JC, Grines CL, et al.  Intravascular ultrasound assessment of lumen 
size and wall morphology in normal subjects and patients with coronary artery disease.  
Circulation.  1991;84:1087-1099. 
Puri R, Libby P, Nissen SE, et al.  Long-term effects of maximally intensive statin 
therapy on changes in coronary atheroma composition: insights from SATURN.  Eur 
Heart J Cardiovasc Imaging.  2014;15:380-388. 
Räber L, Taniwaki M, Zaugg S, et al.  Effect of high-intensity statin therapy on 
atherosclerosis in non-infarct-related coronary arteries (IBIS-4): a serial intravascular 
ultrasonography study.  Eur Heart J.  2015;36:490-500. 
Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al.  
Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease.  N Engl J 
Med.  2017;376:1713-1722. 
Sacks FM, Pfeffer MA, Moye LA, et al.  The effect of pravastatin on coronary events 
after myocardial infarction in patients with average cholesterol levels.  Cholesterol and 
Recurrent Events Trial investigators.  N Engl J Med.  1996;335:1001-1009. 
Scandinavian Simvastatin Survival Study Group.  Randomised trial of cholesterol 
lowering in 4444 patients with coronary heart disease:  the Scandinavian Simvastatin 
Survival Study (4S).  Lancet.  1994;344:1383-1389. 
Silverman MG, Ference BA, Im K, et al.  Association between lowering LDL-C and 
cardiovascular risk reduction among different therapeutic interventions:  A systematic 
review and meta-analysis.  JAMA.  2016;316:1289-1297. 
Stefanadis C, Antoniou CK, Tsiachris D, Pietri P.  Coronary atherosclerotic vulnerable 
plaque:  current perspectives.  J Am Heart Assoc.  2017;6:e005543. 
Stone GW, Maehara A, Lansky AJ, et al.  A prospective natural-history study of coronary 
atherosclerosis.  N Engl J Med.  2011;364:226-235. 
Takarada S, Imanishi T, Kubo T, et al.  Effect of statin therapy on coronary fibrous-cap 
thickness in patients with actue coronary syndrome:  assessment by optical coherence 
tomography study.  Atherosclerosis.  2009;202:491-497. 
Tanaka A, Imanishi T, Kitabata H, et al.  Distribution and frequency of thin-capped 
fibroatheromas and ruptured plaques in the entire culprit coronary artery in patients with 
acute coronary syndrome as determined by optical coherence tomography.  
Am J Cardiol.  2008;102:975-979. 
ten Hoff H, Korbijn A, Smith TH, Klinkhamer JF, Bom N.  Imaging artifacts in 
mechanically driven ultrasound catheters.  Int J Card Imaging.  1989;4:195-199. 
Toutouzas K, Karanasos A, Tsiamis E, et al.  New insights by optical coherence 
tomography into the differences and similarities of culprit ruptured plaque morphology in 
non-ST-elevation myocardial infarction and ST-elevation myocardial infarction.  Am 
Heart J.  2011;161:1192-1199. 
Virmani R, Burke AP, Farb A, Kolodgie FD.  Pathology of the vulnerable plaque.  
J Am Coll Cardiol.  2006;47:C13-18. 
World Health Organization (WHO).  Global Status Report on Noncommunicable 
Diseases.  Geneva 2014; http://www.who.int/nmh/publications/ncd-status-report-
2014/en/. 
Yabushita H, Bouma BE, Houser SL, et al.  Characterization of human atherosclerosis 
by optical coherence tomography.  Circulation.  2002;106:1640-1645. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 60 of 94 
CONFIDENTIAL 
 
 
12. 
Appendices 
 
 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 61 of 94 
CONFIDENTIAL 
 
 
12.1 
Appendix 1.  List of Abbreviations and Definitions of Terms 
 
Abbreviation or Term 
Definition/Explanation 
ACC 
American College of Cardiology 
AHA 
American Heart Association 
AI 
autoinjector 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANA 
anti-nuclear antibody 
ANCOVA 
analysis of covariance 
ApoA1 
apolipoprotein A1 
ApoB 
apolipoprotein B 
AST 
aspartate aminotransferase 
BIL 
bilirubin 
CAD 
coronary artery disease 
CABG 
coronary artery bypass grafting 
CANTAB 
Cambridge Neuropsychological Text Automated Battery 
CBC 
complete blood count 
CETP 
cholesterol ester transfer protein 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
COA 
clinical outcome assessment 
CPK 
creatine phosphokinase 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTT 
Cholesterol Treatment Trialists’ 
CYP 
cytochrome P450 
DILI 
drug-induced liver injury  
EC 
Executive Committee 
ECG 
electrocardiogram 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
e-mail 
electronic mail 
Electronic Source Data 
(eSource)  
source data captured initially into a permanent electronic record 
used for the reconstruction and evaluation of a trial. 
End of Follow-up 
defined as when the last subject completes the last 
protocol-specified assessment in the study   
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 62 of 94 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
End of Study (EOS) for 
Individual Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject 
End of Study (EOS) (end of 
trial) 
defined as the date when the last subject is assessed or 
receives an intervention for evaluation in the study (ie, last 
subject last visit), following any additional parts in the study (eg, 
long-term follow-up), as applicable 
End of Treatment 
defined as the last assessment for the protocol-specified 
treatment phase of the study for an individual subject 
FAS 
full analysis set 
FCT 
fibrous cap thickness 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
HCV 
hepatitis C virus 
HDL-C 
high-density lipoprotein cholesterol 
HIPAA 
Health Insurance Portability and Accountability Act 
HoFH 
homozygous familial hypercholesterolemia 
HR 
hazard ratio 
HRT 
hormonal replacement therapy 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
ID 
identification 
IEC 
Independent Ethics Committee 
IFU 
instructions for use 
index date 
date subject is admitted to a hospital for a specific condition 
INR 
international normalized ratio 
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IUS 
intrauterine hormonal-releasing system 
Interactive Voice Response 
System (IVRS) 
telecommunication technology that is linked to a central 
computer in real time as an interface to collect and process 
information   
IVUS 
intravascular ultrasound 
Interactive Web Response 
System (IWRS) 
web based technology that is linked to a central computer in real 
time as an interface to collect and process information  
LBBB 
left bundle branch block 
LDH 
lactate dehydrogenase 
LDL 
low-density lipoprotein 
LDL-C 
low-density lipoprotein cholesterol 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 63 of 94 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
LDLR 
low-density lipoprotein receptor 
LKM1 
liver kidney microsomal antibody-1 
Lp(a) 
lipoprotein(a) 
MI 
myocardial infarction 
NASH 
nonalcoholic fatty liver disease including steatohepatitis 
NOAEL 
no-observed-adverse-effect level 
NSTE-ACS 
non-ST-segment elevation acute coronary syndrome 
NSTEMI 
non-ST-segment elevation myocardial infarction 
OCT 
optical coherence tomography 
PAV 
percent atheroma volume 
PCI 
percutaneous coronary intervention 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
POR 
Proof of Receipts 
Q2W 
every 2 weeks 
QM 
monthly (every 4 weeks with a window of ± 3 days for each visit 
or dose) 
SAT 
Safety Assessment Team 
SEC 
Self-Evident Corrections 
SC 
subcutaneous 
SD  
standard deviation 
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. 
SUSAR 
suspected unexpected serious adverse reactions 
STEMI 
ST-segment elevation myocardial infarction 
Study Day 1 
defined as the first day that protocol-specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject 
TAV 
total atheroma volume 
TC 
total cholesterol 
TBL 
total bilirubin 
ULN 
upper limit of normal 
US 
United States 
VLDL-C 
very low-density lipoprotein cholesterol 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 64 of 94 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
WHODRUG 
World Health Organization Drug 
 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 65 of 94 
CONFIDENTIAL 
 
 
12.2 
Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 12-1 will be performed by the local laboratory, or the central 
laboratory.  
Whenever the local laboratory is used to make either a study treatment decision or 
response evaluation, the results must be entered into the case report form (CRF). 
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 6.1 to Section 6.2 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
Table 12-1.  Analyte Listing 
Laboratory:  
Chemistry 
Laboratory:  
Coagulation 
Laboratory:  
Hematology 
Other Labs 
Creatinine 
hs-Troponin (I/T) 
- 
- 
Serum or Urine Pregnancy 
Lipid Testing 
 Total cholesterol 
 HDL-C 
 LDL-C 
 Triglycerides 
 VLDL-C 
 Non-HDL-C 
 ApoA1 
 ApoB 
 ApoB/ApoA1 ratio 
 Total Cholesterol/HDL-C 
ratio 
 Lp(a) 
 
 
 
Biomarkers 
Apo = apolipoprotein; HDL-C = high-density lipoprotein cholesterol; hs = high sensitive; LDL-C = low-density 
lipoprotein cholesterol; Lp(a) = lipoprotein(a); VLDL-C = very low-density lipoprotein cholesterol 
Laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded.  Central 
laboratory results of the lipid testing will be blinded post-treatment until unblinding of the 
clinical database and will not be reported to the investigator post-screening.  In addition, 
investigators and staff involved with this trial and all medical staff involved in the 
subject’s medical care should refrain from obtaining lipid panels between randomization 
and at least 12 weeks after the subject ends the study (to avoid potential unblinding). 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 66 of 94 
CONFIDENTIAL 
 
 
12.3 
Appendix 3.  Study Governance Considerations 
Executive Committee 
An Executive Committee (EC) has been formed to advise Amgen on trial design and for 
assistance in the communication of trial results.  The EC will be blinded.  Details will be 
provided in a committee charter. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
 
Applicable ICH laws and regulations 
The protocol, protocol amendments, informed consent form, Investigator’s Brochure, and 
other relevant documents (eg, subject recruitment advertisements) must be submitted to 
an Institutional Review Board/Independent Ethics Committee (IRB/IEC) by the 
investigator and reviewed and approved by the IRB/IEC.  A copy of the written approval 
of the protocol and informed consent form must be received by Amgen before 
recruitment of subjects into the study and shipment of Amgen investigational product. 
Amgen may amend the protocol at any time.  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 must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
 
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 
 
Notifying the IRB/IEC of serious adverse events occurring at the site, deviations 
from the protocol or other adverse event reports received from Amgen, in 
accordance with local procedures 
 
Overall conduct of the study at the site and adherence to requirements of 
Title 21 of the United States (US) Code of Federal Regulations (CFR), ICH 
guidelines, the IRB/IEC, and all other applicable local regulations 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 67 of 94 
CONFIDENTIAL 
 
 
Informed Consent Process 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the sample 
informed consent form are to be communicated formally in writing from the Amgen Trial 
Manager to the investigator.  The written informed consent form is to be prepared in the 
language(s) of the potential patient population. 
The investigator or his/her delegated representative will explain to the subject, or his/her 
legally authorized representative, the aims, methods, anticipated benefits, and potential 
hazards of the study before any protocol-specific screening procedures or any 
investigational product(s) is/are administered, and answer all questions regarding the 
study.   
Subjects must be informed that their participation is voluntary.  Subjects or their legally 
authorized representative defined as an individual or other body authorized under 
applicable law to consent, on behalf of a prospective subject, to the subject’s 
participation in the clinical study will then be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study site.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
informed consent form. 
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 unless it is a local requirement.  The 
investigator shall then inform the primary care physician.  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 informed consent form is to be signed and personally dated by the 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 68 of 94 
CONFIDENTIAL 
 
 
subject or a legally acceptable representative and by the person who conducted the 
informed consent discussion.  Subject withdrawal of consent or discontinuation from 
study treatment and/or procedures must also be documented in the subject’s medical 
records; refer to Section 8. 
Subjects must be re-consented to the most current version of the informed consent 
form(s) during their participation in the study.  
The original signed informed consent form is to be retained in accordance with 
institutional policy, and a copy of the informed consent form(s) must be provided to the 
subject or the subject’s legally authorized representative.  
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.  (Refer to ICH GCP guideline, Section 4.8.9). 
Subjects who are rescreened are required to sign a new informed consent form. 
The informed consent form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each subject the objectives of the exploratory 
research.  Subjects will be told that they are free to refuse to participate and may 
withdraw their specimens at any time and for any reason during the storage period.  A 
separate signature will be required to document a subject’s agreement to allow any 
remaining specimens to be used for exploratory research.  Subjects who decline to 
participate will not provide this separate signature. 
Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
Subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
On the CRF demographics page, in addition to the unique subject identification number, 
include the age at time of enrollment. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 69 of 94 
CONFIDENTIAL 
 
 
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 age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are to 
be kept in confidence by the investigator, except as described below. 
In compliance with governmental regulations/ICH 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. 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
International Committee of Medical Journal Editors, 2013 (ICMJE) Recommendations for 
the Conduct of Reporting, Editing, and Publications of Scholarly Work in Medical 
Journals, which states: 
Authorship credit is to be based on:  (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the article 
or revising it critically for important intellectual content; (3) final approval of the version to 
be published; and (4) agreement to be accountable for all aspects of the work in 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 70 of 94 
CONFIDENTIAL 
 
 
ensuring that questions related to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved.  Authors need to meet conditions 1, 2, 3, and 4. 
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals must 
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 must qualify for authorship, and all those who qualify 
are to be listed. 
Each author must 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. 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
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 
Data Quality Assurance 
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, centrally or 
adjudicated data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.   
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 71 of 94 
CONFIDENTIAL 
 
 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
Clinical monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and 
that the study is being conducted in accordance with the currently approved protocol and 
any other study agreements, ICH GCP, and all applicable regulatory requirements per 
the sponsor’s monitoring plan.  
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. 
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. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research & Development Compliance 
and Audit 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. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Amgen (or designee) will perform Self-Evident Corrections (SEC) to obvious data errors 
in the clinical trial database.  SECs will be documented in the CRF Standard Instructions 
and the CRF Specific Instructions, both of these will be available through the electronic 
data capture (EDC) system.  Examples of obvious data errors that may be corrected by 
Amgen (or designee) include deletion of obvious duplicate data (ie, the same results 
sent twice with the same date with different visit), and updating a specific response if the 
confirming datum is provided in the “other, specify” field (eg, for race, reason for ending 
study). 
Case report forms must be completed in English.  TRADENAMES® (if used) for 
concomitant medications may be entered in the local language.  Consult the 
country-specific language requirements. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 72 of 94 
CONFIDENTIAL 
 
 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
Source Documents 
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 provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
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.  Source documents may also include data captured in the 
Interactive Voice Response System (IVRS)/Interactive Web Response System (IWRS) 
system (if used, such as subject identification [ID] and randomization number) and CRF 
entries if the CRF is the site of the original recording (ie, there is no other written or 
electronic record of data, such as paper questionnaires for a clinical outcome 
assessment [COA]). 
Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 
Elements to include: 
 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of pre-study documentation, and all correspondence to and from the 
IRB/IEC and Amgen 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 73 of 94 
CONFIDENTIAL 
 
 
 
Investigational product-related correspondence including Proof of Receipts 
(POR), Investigational Product Accountability Record(s), Return of Investigational 
Product for Destruction Form(s), Final Investigational Product Reconciliation 
Statement, as applicable 
 
Non-investigational product(s), and/or medical device(s) or combination 
product(s) documentation, as applicable 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Study and Site Closure 
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP.  
Both Amgen and the Investigator reserve the right to terminate the Investigator’s 
participation in the study according to the Clinical Trial Agreement.  The investigator is to 
notify the IRB/IEC in writing of the study’s completion or early termination and send a 
copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
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 Informed Consent that 
is available as a separate document. 
 
 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 74 of 94 
CONFIDENTIAL 
 
 
12.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting 
Definition of Adverse Event 
Adverse Event Definition 
 
An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment.   
 
Note:  An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a treatment, combination 
product, medical device or procedure. 
Events Meeting the Adverse Event Definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, electrocardiogram [ECG], radiological scans, vital 
signs measurements), including those that worsen from baseline, that are 
considered clinically significant in the medical and scientific judgment of the 
investigator (ie, not related to progression of underlying disease). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication.  Overdose per se will not be reported as an 
adverse event/serious adverse event unless it is an intentional overdose taken with 
possible suicidal/self-harming intent.  Such overdoses are to be reported 
regardless of sequelae. 
 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an adverse event or serious adverse event.  Such instances will be 
captured in the efficacy assessments.  However, the signs, symptoms, and/or 
clinical sequelae resulting from lack of efficacy will be reported as adverse event or 
serious adverse event if they fulfill the definition of an adverse event or serious 
adverse event.  
Events NOT Meeting the Adverse Event Definition 
 
Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that 
leads to the procedure is the adverse event. 
 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 75 of 94 
CONFIDENTIAL 
 
 
Definition of Serious Adverse Event 
A Serious Adverse Event is defined as any untoward medical occurrence 
that, meets at least 1 of the following serious criteria: 
Results in death (fatal) 
Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting.  Complications that occur during 
hospitalization are an adverse event.  If a complication prolongs hospitalization or 
fulfills any other serious criteria, the event is serious.  When in doubt as to whether 
“hospitalization” occurred or was necessary, the adverse event is to be considered 
serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an adverse event. 
Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious 
adverse event reporting is appropriate in other situations such as important 
medical events that may not be immediately life-threatening or result in death or  
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 76 of 94 
CONFIDENTIAL 
 
 
A Serious Adverse Event is defined as any untoward medical occurrence 
that, meets at least 1 of the following serious criteria: 
Other medically important serious event (continued) 
hospitalization but may jeopardize the subject or may require medical or surgical 
intervention to prevent 1 of the other outcomes listed in the above definition.  
These events are typically to be considered serious. 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
Definition of Adverse Device Effect 
The detection and documentation procedures for adverse device effects described in 
this protocol apply to all Amgen medical devices provided for use in the study (see 
Section 7.1.3 for the list of Amgen medical devices). 
Adverse Device Effect Definition 
An adverse device effect is any adverse event related to the use of a combination 
product or 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. 
Recording Adverse Events and Serious Adverse Events 
Adverse Event and Serious Adverse Event Recording 
 
When an adverse event, or serious adverse event occurs, it is the responsibility of 
the investigator to review all documentation (eg, hospital progress notes, 
laboratory, and diagnostics reports) related to the event. 
 
The investigator will then record all relevant adverse event/serious adverse event 
information in the Event CRF. 
o Additionally, the investigator is required to report a fatal disease-related event 
on the Event CRF. 
 
The investigator must assign the following adverse event attributes: 
o Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms); 
o Dates of onset and resolution (if resolved); 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 77 of 94 
CONFIDENTIAL 
 
 
Adverse Event and Serious Adverse Event Recording 
o Severity (or toxicity defined below); 
o Assessment of relatedness to evolocumab/placebo, or devices; and 
o Action taken. 
 
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record as a single event with the worst severity on the Event CRF. 
 
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to Amgen in lieu of completion of the Event CRF page. 
 
If specifically requested, the investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the 
medical records.  In this case, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records before 
submission to Amgen. 
 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious 
adverse event. 
Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The investigator will make an assessment of severity for each adverse event and 
serious adverse event reported during the study.  The assessment of severity will be 
based on: 
The Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 
which is available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
When an adverse event cannot be graded by CTCAE version 4.0, the following 
severity grade may be used: 
The Amgen Standard Grading Scale as show below: 
Grade 
Definition 
MILD 
Aware of sign or symptom, but easily tolerated 
MODERATE 
Discomfort enough to cause interference with usual activity 
SEVEREa 
Incapacitating with inability to work or do usual activity 
a An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of a serious adverse event, NOT when it is rated as severe. 
 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 78 of 94 
CONFIDENTIAL 
 
 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between investigational 
product, protocol-required therapies, device(s), and/or study-mandated procedure 
and each occurrence of each adverse event/serious adverse event. 
 
Relatedness means that there are facts or reasons to support a relationship 
between investigational product and the event. 
 
The investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
 
The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 
 
For each adverse event/serious adverse event, the investigator must document in 
the medical notes that he/she has reviewed the adverse event/serious adverse 
event and has provided an assessment of causality. 
 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report.  However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the serious adverse event data. 
 
The investigator may change his/her opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated 
causality assessment. 
 
The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of Adverse Event and Serious Adverse Event 
 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 
Amgen to elucidate the nature and/or causality of the adverse event or serious 
adverse event as fully as possible.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 
care professionals. 
 
If a subject is permanently withdrawn from protocol-required therapies because of 
a serious adverse event, this information must be submitted to Amgen. 
 
If a subject dies during participation in the study or during a recognized follow-
up period, the investigator will provide Amgen with a copy of any post-mortem 
findings including histopathology. 
 
New or updated information will be recorded in the originally completed Event 
CRF. 
 
The investigator will submit any updated serious adverse event data to Amgen 
within 24 hours of receipt of the information. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 79 of 94 
CONFIDENTIAL 
 
 
Reporting of Serious Adverse Event 
Serious Adverse Event Reporting via Electronic Data Collection Tool 
 
The primary mechanism for reporting serious adverse event will be the electronic 
data capture (EDC) system via the Safety Report Form.  
 
If the EDC system is unavailable for more than 24 hours, then the site will report 
the information to Amgen using an Electronic Serious Adverse Event Contingency 
Form (paper form; see Figure 12-1) within 24 hours of the investigator’s knowledge 
of the event. 
 
The site will enter the serious adverse event data into the electronic system as 
soon as it becomes available. 
 
After the study is completed at a given site, the EDC system will be taken off-line to 
prevent the entry of new data or changes to existing data. 
 
If a site receives a report of a new serious adverse event from a study subject or 
receives updated data on a previously reported serious adverse event after the 
EDC has been taken off-line, then the site can report this information on an 
Electronic Serious Adverse Event Contingency Form (paper form; 
see Figure 12-1). 
Adverse Device Effects:  Recording, Evaluating and Reporting 
 
Any adverse event resulting from an adverse device effect that occur during the 
study will be documented in the subject’s medical records, in accordance with the 
investigator’s normal clinical practice, and on the Event CRF page. 
 
It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by Amgen) at the time of the initial 
report and describes any corrective or remedial actions taken to prevent recurrence 
of the incident. 
 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 80 of 94 
CONFIDENTIAL 
 
 
Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Form 
 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 81 of 94 
CONFIDENTIAL 
 
 
 
Approved 
 
 
Alil0Bt 
Study# 20160184 
evolocumab 
Electronic Serious Adverse Event Contingency Report Form 
For Restricted Use 
~ 
Site Nlianl,er 
I 
.Subjod I[) Hurnb&1 
~ 
~ 
I I I I I I I I I I I I I I I ~ 
6. CONCOMITANT MEDICATIONS (elJ, i:hemoth~pyl Aro{ Medications.? 0 No O Yes If yes, j:lease 00011lete: 
Medication NarneM 
still Dil1& 
---· Slojl Dilts ___ _ CO.~u'!E"'"'I ~':} -
Rou!,a 
Freq. 
Treatment Mad 
------------------
- ~ 
.... ~ - Yll!,f' 
C!rt 
~.£, 
Yu .-
D1r 
llla't', 
., .. . 
tb/' 1 Ym./ 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
I 
7. RE:LEVANT MEDICAL HIST ORY ,iinclude dides allergies and any relevilfilt priOI' lheraovl 
8. RE:LEVANT LABORATORY VALUJE S {include baseline values) Aey Relevant laboratory vah>es? 0 No D Yes If yes, please OOIT'fllete: 
I Tm 
Dill9 I Unit 
'" 
..,.., 
Y·•~ 
9. OTHER RELEVANT T ESTS (diagnostics and procedures) 
Aro{ Otller Relevarnt !ea-is? ONo D Yes If yes, please aomplete: 
--------- IOabJi ________ _! 
' 
D..,. 
Wl:r.r. 
Y•II" 
I 
Addi.1ional Tests 
Res.oi lts 
, 
Units 
AMGEN® 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 82 of 94 
CONFIDENTIAL 
 
 
 
Approved 
 
 
AMCJllt 
Study# 20160184 
evoloc1.1mab 
Electronic Serious Adverse Event Contingency Report Form 
For Restricted Use 
~ 
W,W 
,, 
Site Niaooer 
I 
Subjsct ID Number 
W,W 
~ 
~ 
I I I I I I I I I I I I I I I ~ ~ 
10. CASE OESCmPTION (Provide aamdive details ofevenra listed in section 3} Provide additior.al pages if neoe9518ry. For each 
e..ent in section J, whE!ff! relationslvo=Yes. olease orovide ralionel:e. 
Signa1we oi" l~~s 1i~.or er De;ijlllee -
Title 
Daie 
1 ~ rifirm. by ~:1m'f.lg ~ 
f'~O.rt i!wDt t.!ilil mtwmatio.-ri oo thir )~ indU'Cl'."'lg ~.001.1" •• Jh,i~ rmd 
=\ity =
mont,. ,;.sh~·f"<'O',ii•dtaAmg,o.., 1'1 ~
im10.s6gatorf,,rt,'1i,-m,11/y, <Xby 
Cl' fJ_'J"f11ffi1i1d ;\.fpdl:caf k:Y.!.m Q~;;;l'bv cJ-11;• il"11'c'.rt.'.:nrtor fO£ i!T.'.'J: .stu·d~•. 
~ 
7.(J 
E~Da.\e: 1 Felimaty2ll16 
AMGEN® 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 83 of 94 
CONFIDENTIAL 
 
 
12.5 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy 
and Lactation Information 
Study-specific contraception requirements for females of childbearing potential are 
outlined in Section 6.2. 
Female subjects of childbearing potential must receive pregnancy prevention counseling 
and be advised of the risk to the fetus if they become pregnant during treatment and for 
15 weeks after the last dose of protocol-required therapies. 
Additional medications given during the study may alter the contraceptive requirements.  
These additional medications may require female subjects to use highly effective 
methods of contraception and for an increased length of time.  In addition, male subjects 
may also be required to use contraception.  The investigator must discuss these 
contraceptive changes with the subject. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered female of childbearing potential: 
 
Premenopausal female with 1 of the following: 
o Documented hysterectomy; 
o Documented bilateral salpingectomy; or 
o Documented bilateral oophorectomy. 
Note:  Site personnel documentation from the following sources is acceptable:  
1) review of subject’s medical records; 2) subject’s medical examination; or 
3) subject’s medical history interview. 
 
Premenarchal female 
 
Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state 
in women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
o Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study.  Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 84 of 94 
CONFIDENTIAL 
 
 
Contraception Methods for Female Subjects 
Acceptable Methods of Effective Contraception 
 
Combined (estrogen and progestogen containing) or progestogen-only hormonal 
methods given via oral, intravaginal, transdermal, injectable, or implantable route 
 
Intrauterine device (IUD) 
 
Intrauterine hormonal-releasing system (IUS) 
 
Bilateral tubal ligation/occlusion 
 
Vasectomized partner (provided that partner is the sole sexual partner of the 
female subject of childbearing potential and that the vasectomized partner has 
received medical assessment of the surgical success) 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during 
the entire period of risk associated with the study treatments; the reliability of 
sexual abstinence must be evaluated in relation to the duration of the trial and 
the preferred and usual lifestyle of the subject) 
 
Male or female condom with or without spermicide 
 
Cap, diaphragm, or sponge with spermicide 
 
Double barrier method:  the male uses a condom and the female may choose 
either a cap, diaphragm, or sponge with spermicide (a female condom is not an 
option due to the risk of tearing when both partners use a condom) 
Unacceptable Methods of Birth Control for Female Subjects 
Birth control methods that are considered unacceptable in clinical trials include: 
 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
 
Withdrawal (coitus interruptus) 
 
Spermicides only 
 
Lactational amenorrhea method 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
 
Investigator will collect pregnancy information on any female subject who becomes 
pregnant while taking protocol-required therapies through 15 weeks after the end of 
treatment with evolocumab. 
 
Information will be recorded on the Pregnancy Notification Worksheet 
(see Figure 12-2).  The worksheet must be submitted to Amgen Global Patient 
Safety within 24 hours of learning of a subject’s pregnancy.  (Note:  Sites are not 
required to provide any information on the Pregnancy Notification Worksheet that 
violates the country or regions local privacy laws.) 
 
After obtaining the female subject’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy and infant 
health information and complete the pregnancy questionnaire for any female subject 
who becomes pregnant while taking protocol-required therapies through 15 weeks 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 85 of 94 
CONFIDENTIAL 
 
 
after the last dose of the study drug.  This information will be forwarded to Amgen 
Global Patient Safety.  Generally, infant follow-up will be conducted up to 12 months 
after the birth of the child (if applicable). 
 
Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.  
 
While pregnancy itself is not considered to be an adverse event or serious adverse 
event, any pregnancy complication or report of a congenital anomaly or 
developmental delay, fetal death, or suspected adverse reactions in the neonate will 
be reported as an adverse event or serious adverse event.  Note that an elective 
termination with no information on a fetal congenital malformation or maternal 
complication is generally not considered an adverse event, but still must be reported 
to Amgen as a pregnancy exposure case. 
 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a serious adverse event. 
 
Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Appendix 4.  While the 
investigator is not obligated to actively seek this information in former study 
subjects, he or she may learn of a serious adverse event through spontaneous 
reporting.  
 
Any female subject who becomes pregnant while participating will discontinue study 
treatment (see Section 8.1 for details). 
Male Subjects With Partners Who Become Pregnant or Were Pregnant at the Time of 
Enrollment 
 
In the event a male subject fathers a child during treatment, and for an additional 
15 weeks after discontinuing protocol-required therapies, the information will be 
recorded on the Pregnancy Notification Worksheet.  The worksheet 
(see Figure 12-2) must be submitted to Amgen Global Patient Safety within 
24 hours of the site’s awareness of the pregnancy.  (Note:  Sites are not required to 
provide any information on the Pregnancy Notification Worksheet that violates the 
country or regions local privacy laws.) 
 
The investigator will attempt to obtain a signed authorization for release of 
pregnancy and infant health information directly from the pregnant female partner to 
obtain additional pregnancy information. 
 
After obtaining the female partner’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy outcome and 
infant health information on the pregnant partner and her baby and complete the 
pregnancy questionnaires.  This information will be forwarded to Amgen Global 
Patient Safety. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 86 of 94 
CONFIDENTIAL 
 
 
 
Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable).  
 
Any termination of the pregnancy will be reported to Amgen Global Patient Safety 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
Collection of Lactation Information 
 
Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 15 weeks following end of 
treatment with evolocumab or placebo. 
 
Information will be recorded on the Lactation Notification Worksheet (see below) 
and submitted to Amgen Global Patient Safety within 24 hours of the investigator’s 
knowledge of event. 
 
Study treatment will be discontinued if female subject breastfeeds during the study 
as described in exclusion criterion 213. 
 
With the female subjects signed authorization for release of mother and infant 
health information, the investigator will collect mother and infant health information 
and complete the lactation questionnaire on any female subject who breastfeeds 
while taking protocol-required therapies through 15 weeks after discontinuing 
protocol-required therapies. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 87 of 94 
CONFIDENTIAL 
 
 
Figure 12-2.  Pregnancy and Lactation Notification Worksheet 
 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 88 of 94 
CONFIDENTIAL 
 
 
 
Approved 
 
 
A~N· !-actation Notification Worksheet 
Fm: Completed Form to the Country-respectwe Salety Fax Line 
SELECT OR TYPE IN A FAX# ~(e_nt_e_r_f_ax_n_um_b_er _____ =2J=
·~I 
1. Case Administrative Information 
Proto colf31udy Number: 2_0_1_6_0_1_B4 _______________ _ 
Study Design 0 lnterventional 
Obsen<ational (If Obser,,ational: D 
Prospective D
R etrospective) 
2. Contact Information 
Print Form 
Investigator Name---------------------
Site# ____________ _ 
Phone(____J ________ 
_ 
F"" L____) ________ 
_ 
Email _____________ _ 
Institution-------------------------------------------
4. Amgen Product Exposure 
Am gen Product 
Dose at ti me of 
Frequency 
Route 
start Date 
breast feeding 
evolocumab 
mm __ 
ldd _!y,m_ 
Was the Amgen product(orsludy drug) discontinued'> D Yes 
D No 
If yes, provide product (or study drug) slop dale: mm __ 
ldd __ 
/yy'fy __ 
Did the subject w~hdraw from the stud{' D 
Yes 
D 
No 
5. Breast Feeding Information 
Did the mother breastfeed or provide the infant with pumped breast milk while actively laking an Amgen product'> D Yes 
D No 
If No, provide stop date: mm ____ 
/dd ___ 
/yy'fy ___ _ 
Infant dale of birth: mrn ____ 
/dd ___ 
/yyyy __ _ 
Infant gender: D Female 
D Male 
Is the infant health{' D Yes 
D No 
D U nk ncmn D NIA 
11 any Adiierse Event was experienced by the mother or the infant, provide brief details··-----------------
Form Completed by: 
Print Name: -----------------
Signature: 
Effective Date: 03 ~ril 2012, ""rsion 2. 
Title: ------------------
Date: 
Page 1 of1 
AMGEN® 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 89 of 94 
CONFIDENTIAL 
 
 
12.6 
Appendix 6.  Sample Storage and Destruction 
Any blood sample collected according to the Schedule of Activities (Table 2-1) 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 
cardiovascular disease, hyperlipidemia and other metabolic disorders, 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 informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
sample types (eg, blood, tumor) 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 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 90 of 94 
CONFIDENTIAL 
 
 
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 
Appendix 3 for subject confidentiality. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 91 of 94 
CONFIDENTIAL 
 
 
12.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and 
Follow-up Assessments 
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 investigational product or other protocol-required therapies, as specified in the 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, 
July 2009. 
Criteria for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity 
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver biomarkers (TBL, INR, and transaminases) has not been 
identified.  
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 (BIL) glucuronidation 
(eg, indinavir, atazanavir) 
 
Alpha-one antitrypsin deficiency 
 
Alcoholic hepatitis 
 
Autoimmune hepatitis 
 
Wilson’s disease and hemochromatosis 
 
Nonalcoholic fatty liver disease including steatohepatitis (NASH) 
 
Non-hepatic causes (eg, rhabdomyolysis, hemolysis) 
If investigational product(s) is/are withheld, the subject is to be followed for possible 
drug-induced liver injury (DILI) according to recommendations in the last section of this 
appendix.  
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 92 of 94 
CONFIDENTIAL 
 
 
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 (see next section in this appendix). 
Table 12-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity 
Analyte 
Temporary Withholding 
Permanent Discontinuation 
TBL 
> 3 x ULN  
at any time 
> 2 x ULN 
 
 
OR 
INR 
-- 
> 1.5 x ULN (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 8 x ULN at any time 
> 5 x ULN but < 8 x ULN for ≥ 2 weeks 
> 5 x ULN but < 8 x ULN and unable to 
adhere to enhanced monitoring schedule 
> 3 x ULN with clinical signs or symptoms 
that are consistent with hepatitis (such as 
right upper quadrant pain/tenderness, 
fever, nausea, vomiting, and jaundice) 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values 
> 3 x ULN (when baseline was < ULN) 
 
OR 
 
ALP 
> 8 x ULN at any time 
-- 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject is to be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then evolocumab is to be permanently 
discontinued.  Subjects who clearly meet the criteria for permanent discontinuation (as 
described in Table 12-2) are never to be rechallenged. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 93 of 94 
CONFIDENTIAL 
 
 
Drug-induced Liver Injury Reporting and Additional Assessments 
Reporting 
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 the above, 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 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 Appendix 4. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Table 12-2 or who experience AST or ALT elevations > 3 x upper limit of normal (ULN) 
or 2-fold increases above baseline values for subjects with elevated values before drug 
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, BIL (total and direct), and INR within 24 hours  
 
In cases of TBL > 2 x ULN or INR > 1.5, retesting of liver tests, BIL (total and 
direct), and INR is to be performed every 24 hours until laboratory abnormalities 
improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL.  
The following are to be considered depending on the clinical situation: 
 
Complete blood count (CBC) with differential to assess for eosinophilia 
 
Serum total immunoglobulin G, anti-nuclear antibody (ANA), anti-smooth muscle 
antibody, and liver kidney microsomal antibody-1 (LKM1) to assess for 
autoimmune hepatitis 
 
Serum acetaminophen (paracetamol) levels 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  19 April 2018 
Page 94 of 94 
CONFIDENTIAL 
 
 
 
A more detailed history of:  
o 
Prior and/or concurrent diseases or illness 
o 
Exposure to environmental and/or industrial chemical agents  
o 
Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
o 
Prior and/or concurrent use of alcohol, recreational drugs, and special 
diets 
o 
Concomitant use of medications (including non-prescription medicines 
and herbal and dietary supplements), plants, and mushrooms 
 
Viral serologies 
 
Creatine phosphokinase (CPK), haptoglobin, lactate dehydrogenase (LDH), and 
peripheral blood smear 
 
Appropriate liver imaging if clinically indicated 
 
Appropriate blood sampling for pharmacokinetic analysis if this has not already 
been collected 
 
Hepatology consult (liver biopsy may be considered in consultation with a 
hepatologist) 
Follow the subject and the laboratory tests (ALT, AST, TBL, and INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  The 
“close observation period” is to continue for a minimum of 4 weeks after discontinuation 
of all investigational product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications, and laboratory results must be captured in the corresponding CRFs.  
Approved 
 
 

SAP_001.pdf: 
Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 1 of 27 
CONFIDENTIAL 
 
 
Statistical Analysis Plan 
Protocol Title: 
High-Resolution Assessment of Coronary Plaques 
in a Global Evolocumab Randomized Study 
(HUYGENS)
Short Protocol Title: 
Imaging of Coronary Plaques in Subjects Treated 
With Evolocumab
Protocol Number: 
20160184 
NCT Number: 
Unavailable for first version  
Authors: 
 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive, Thousand Oaks, CA, 
91320, USA 
SAP Date: 
Document Version 
Date 
Original (v1.0) 
28 March 2019 
Amendment 1 (v2.0) 
15 January 2021 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 2 of 27 
CONFIDENTIAL 
 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
28MAR2019 
N/A 
Amendment 1 (v2.0) 
15 January 2021 
Editorial changes were made 
throughout the document to improve 
the overall clarity. 
 
Updated section 1 to reflect the 
planned analysis.  
 
Updated section 5.1.1 regarding the 
definition of Maximum Lipid Arc and 
Lipid Core Length, and added 
definition for Lipid Rich Plaque as per 
clinical team discussion.  
 
Updated section 5.1.2 regarding the 
definition of Number of Microchannels 
and Macrophage Composition, and 
added definition for Lipid Content as 
per clinical team discussion.   
 
Updated section 5.3 to differentiate 
the baseline for Lipid and Lipid-related 
Parameters, Concomitant Medication 
Usage and Medical History, and other 
Baseline Values to reflect true 
baseline for the endpoints.  
 
Updated section 6.2 to reflect FCT 
instead of OCT for clarification. 
 
Updated section 6.3 to change 
 
 
Updated section 6.4 to delete 
Per-Protocol Analysis Set (PPAS) as 
per stats team discussion. 
 
Updated section 8.3 to clarify 
imputation method for secondary 
endpoints.  
 
Updated section 9.2 and section 9.3 
to include COVID-19 Impact related 
descriptive analysis to measure 
COVID impact. 
 
Updated section 9.5 to add COVID-19 
impact analysis into Sensitivity 
Analysis for Primary Endpoint for 
mitigating COVID impact. 
 
Updated method to be used for PROC 
MI from section 9.5.1 as per stats 
team discussion. 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 3 of 27 
CONFIDENTIAL 
 
 
Updated section 9.5.3 to describe the 
analyses for exploratory endpoints for 
clarification. 
 
Updated section 9.6.5 to clarify 
analysis method for statin intensity.  
 
Updated Appendix A to allow for 
additional window for week 50 
assessments impacted due to 
COVID-19 Impact. 
 
Added Appendix B. 
 
Updated Appendix C to reflect the 
changes in statin therapy intensity 
with respect to the latest ACC/AHA 
guideline (2018). 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 4 of 27 
CONFIDENTIAL 
 
 
Table of Contents 
Table of Contents ............................................................................................................ 4 
1. 
Introduction ............................................................................................................. 7 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 7 
2.1 
Objectives and Endpoints ............................................................................ 7 
2.2 
Hypotheses and/or Estimations ................................................................... 8 
3. 
Study Overview ...................................................................................................... 9 
3.1 
Study Design ............................................................................................... 9 
3.2 
Sample Size ................................................................................................ 9 
4. 
Covariates and Subgroups ................................................................................... 10 
4.1 
Planned Covariates ................................................................................... 10 
4.2 
Subgroups ................................................................................................. 10 
5. 
Definitions ............................................................................................................. 11 
5.1 
Endpoint Related Definitions ..................................................................... 11 
5.1.1 
Primary and Secondary Endpoints ............................................ 11 
5.1.2 
Exploratory Endpoints ............................................................... 11 
5.2 
Study Time Points ..................................................................................... 12 
5.3 
Demographics and Baseline Related Definitions ....................................... 13 
5.4 
Other Study Related Definitions ................................................................ 14 
6. 
Analysis Sets ........................................................................................................ 15 
6.1 
Full Analysis Set........................................................................................ 15 
6.2 
OCT Analysis Set (OAS) ........................................................................... 15 
6.3 
Completers Analysis Set (CAS) ................................................................. 15 
6.4 
Safety Analysis Set ................................................................................... 15 
7. 
Planned Analyses ................................................................................................. 16 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 16 
7.2 
Final Analysis ............................................................................................ 16 
8. 
Data Screening and Acceptance ........................................................................... 16 
8.1 
General Principles ..................................................................................... 16 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 16 
8.3 
Handling of Missing and Incomplete Data ................................................. 16 
8.4 
Detection of Bias ....................................................................................... 17 
8.5 
Outliers ..................................................................................................... 17 
8.6 
Distributional Characteristics ..................................................................... 18 
8.7 
Validation of Statistical Analyses ............................................................... 18 
9. 
Statistical Methods of Analysis.............................................................................. 18 
9.1 
General Considerations ............................................................................. 18 
9.2 
Subject Accountability ............................................................................... 19 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 5 of 27 
CONFIDENTIAL 
 
 
9.3 
Important Protocol Deviations ................................................................... 19 
9.4 
Demographic and Baseline Characteristics ............................................... 19 
9.5 
Efficacy Analyses ...................................................................................... 20 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) .................................. 20 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 22 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 22 
9.6 
Safety Analyses ........................................................................................ 22 
9.6.1 
Adverse Events  ........................................................................ 22 
9.6.2 
Laboratory Test Results ............................................................ 23 
9.6.3 
Vital Signs ................................................................................. 23 
9.6.4 
Exposure to Investigational Product .......................................... 23 
9.6.5 
Exposure to Concomitant Medication ........................................ 23 
10. 
Changes From Protocol-specified Analyses.......................................................... 23 
11. 
Literature Citations / References ........................................................................... 24 
12. 
Appendices ........................................................................................................... 25 
Appendix A.  Analytical Study Week Assignments ................................................ 25 
Appendix B. Common Terminology Criteria for AEs (CTCAE) .............................. 26 
Appendix C.  Lipid Modifying Background Therapy Intensity ................................. 27 
List of Tables 
Table 1.  Imputation Rules for Incomplete Dates ........................................................... 17 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 6 of 27 
CONFIDENTIAL 
 
 
List of Abbreviations and Definition of Terms 
 
Abbreviation or Term 
Definition/Explanation 
ACC 
American College of Cardiology 
AHA 
American Heart Association 
ANCOVA 
analysis of covariance 
ApoA1 
apolipoprotein A1 
ApoB 
apolipoprotein B 
CI 
confidence interval 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
FAS 
full analysis set 
FCT 
fibrous cap thickness 
HDL-C 
high-density lipoprotein cholesterol 
IVUS 
intravascular ultrasound 
LDL 
low-density lipoprotein 
LDL-C 
low-density lipoprotein cholesterol 
Lp(a) 
lipoprotein(a) 
MI 
myocardial infarction 
NSTE-ACS 
non-ST-segment elevation acute coronary syndrome 
OCT 
optical coherence tomography 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
QM 
monthly (every 4 weeks with a window of ± 3 days for each visit 
or dose) 
SAT 
Safety Assessment Team 
SEC 
Self-Evident Corrections 
SC 
subcutaneous 
SD  
standard deviation 
UC 
Ultra Centrifugation 
VLDL-C 
very low-density lipoprotein cholesterol 
WHODRUG 
World Health Organization Drug 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 7 of 27 
CONFIDENTIAL 
 
 
1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol for study 20160184, Evolocumab 
dated 19 April 2018. The scope of this plan includes the final analysis that is planned 
and will be executed by the Amgen Global Biostatistical Science department unless 
otherwise specified. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
To evaluate the effect of evolocumab on 
fibrous cap thickness (FCT) in subjects 
with non-ST-elevation acute coronary 
syndrome (NSTE-ACS) who are taking 
maximally tolerated statin therapy.
Absolute change in minimum FCT in a 
matched segment of artery as determined 
by optical coherence tomography (OCT) 
from baseline to week 50. 
Secondary 
To evaluate the effects of evolocumab on 
coronary plaque morphology in subjects 
with NSTE-ACS who are taking maximally 
tolerated statin therapy. 
Coronary artery segment-based:
 
Percent change in minimum FCT in a 
matched segment of artery as 
determined by OCT from baseline to 
week 50. 
 
Absolute change in mean minimum 
FCT for all images assessed in an 
individual subject as determined by 
OCT from baseline to week 50. 
 
Absolute change in the maximum lipid 
arc in a matched segment of artery as 
determined by OCT from baseline to 
week 50. 
 
Plaque-based: 
 
Absolute change in minimum FCT in 
lipid rich plaques defined as minimum 
FCT < 120 
least 3 consecutive images as 
determined by OCT from baseline to 
week 50. 
 
Absolute change in maximum lipid arc 
in lipid rich plaques defined as 
minimum FCT < 120 
> 90° in at least 3 consecutive images 
as determined by OCT from baseline 
to week 50. 
Absolute change in lipid core length in 
Page 1 of 2 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 8 of 27 
CONFIDENTIAL 
 
 
Objectives
Endpoints
Secondary(Continued) 
lipid rich plaques defined as minimum 
FCT < 120 
least 3 consecutive images as 
determined by OCT from baseline to 
week 50. 
Safety 
To evaluate the safety and tolerability 
of evolocumab treatment in subjects 
with NSTE-ACS who are taking 
maximally tolerated statin therapy.
Subject incidence of 
treatment-emergent adverse events 
and serious adverse events. 
Exploratory 
To evaluate the effects of evolocumab on 
lipid parameters in subjects with 
NSTE-ACS who are taking maximally 
tolerated statin therapy 
 
To evaluate the effects of evolocumab on 
features of coronary plaques in subjects 
with NSTE-ACS who are taking maximally 
tolerated statin therapy using different 
imaging techniques. 
Absolute and percent changes in lipid 
parameters by visit from baseline. 
 
Absolute change in number of 
microchannels in matched segments of all 
lesions assessed in an individual subject 
as determined by OCT from baseline to 
week 50. 
 
Absolute change in macrophage 
composition in matched segments of all 
lesions assessed in an individual subject 
as determined by OCT from baseline to 
week 50. 
 
Absolute changes in lipid content in 
matched segments of all lesions 
assessed in an individual subject as 
determined by IVUS from baseline to 
week 50. 
Page 2 of 2 
 
The primary estimand consists of: 
 
The target population, which is the adult subjects with NSTE-ACS who are taking 
maximally tolerated statin therapy with or without additional lipid-modifying 
medication. 
 
The primary variable, which is the absolute change in minimum FCT in a matched 
segment of artery as determined by OCT from baseline to week 50. 
 
The summary measure, which is the mean treatment difference of the primary 
variable means between evolocumab and placebo. 
 
The intercurrent events, all randomized subjects who receive at least 1 dose of 
investigational product regardless of adherence to treatment or commencing 
commercial proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. 
 
2.2 
Hypotheses and/or Estimations 
The primary hypothesis is that low-density lipoprotein cholesterol (LDL-C) lowering with 
evolocumab 420 mg monthly (QM) will result in a greater increase from baseline in 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 9 of 27 
CONFIDENTIAL 
 
 
minimum FCT at week 50 than placebo in subjects taking maximally tolerated statin 
therapy. 
3. 
Study Overview 
3.1 
Study Design 
This is a phase 3, double-blind, placebo-controlled, randomized study evaluating the 
effect of evolocumab on coronary atherosclerotic plaques as assessed by OCT at 
baseline and at week 50 in subjects with an NSTE-ACS. The trial duration of 1 year was 
chosen based on the results of several historical trials. Subjects will be randomized 
1:1 into 2 treatment groups no more than 7 days after the signing of the informed 
consent:  evolocumab 420 mg subcutaneously (SC) QM or placebo SC QM.  The 
randomization will be stratified by current statin use (> 4 weeks or  4 weeks duration) at 
screening. Investigators will up-titrate statin therapy to the maximally tolerated dose, in 
accordance with local guidelines, for subjects prior to randomization.  
3.2 
Sample Size 
The planned total sample size is 150 subjects (75 randomized to evolocumab 
420 mg SC QM and 75 randomized to placebo SC QM). This sample size will provide 
sufficient power (90%) to determine whether there is a treatment effect of evolocumab 
relative to placebo in the primary endpoint. 
The assumptions in the sample size calculation are based on a linear regression 
meta-analysis of 7 historical trials (Dai et al, 2017; Hou et al, 2016; Kataoka et al, 2014; 
Komukai et al, 2014; Nishio et al, 2014; Hattori et al, 2012; Takarada et al, 2009) 
weighted by sample sizes. 
The analysis result indicates that every 1 mg/dL reduction in LDL-C is estimated to be 
associated with 1.4785 µm increase in FCT in 12-month follow-up.  Assuming a 
50 mg/dL reduction in LDL-C, the predicted mean increase (95% CI) in FCT from the 
meta-analysis was 73.92 (50.97, 96.88) µm. For this study, the assumed treatment effect 
is at least 50.97 µm increase in FCT, which is approximated from the lower bound 95% 
CI of the expected change in FCT from the regression model, based on a conservative 
assumption of 50 mg/dL reduction in LDL-C from baseline to week 50. 
The SD of FCT measurement at baseline or at the end of various length of follow-up was 
reported in a wide range (10.6 to 124 µm) based on 15 to 134 subjects per arm in the 
historical trials.  The SD of change in FCT was only reported in 2 of the 7 trials, ranging 
from 22 to 86 µm. The assumed common SD for this study is 86 µm to be conservative. 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 10 of 27 
CONFIDENTIAL 
 
 
Assuming 1 out of 6 subjects will not complete both baseline and week 50 OCT 
assessments, and therefore be excluded in the primary analysis, the sample size of 
150 subjects will provide approximately 125 subjects in the primary analysis to ensure 
90% power to test the study hypothesis. 
The sample size calculation was performed using a 2-sided t-test with a 
0.05 significance level. The sample size calculation was derived using East® software 
(version 6.4).  
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
The following covariates will be used in covariate analyses of the primary endpoint. 
Stratification factor: 
 
current statin use (> 4 weeks or  4 weeks duration at the time of screening) 
Baseline covariates: 
 
Age 
 
Sex 
 
Baseline LDL-C 
 
Type 2 diabetes mellitus (yes, no) 
 
Current tobacco use (yes, no) 
4.2 
Subgroups 
Subgroup analysis of the primary endpoint will be conducted for the following subgroups: 
Subgroup by stratification factor: 
 
Current statin use (> 4 weeks or  4 weeks at the time of screening) 
Subgroup by baseline covariates: 
 
Age (< median,  median; < 65 years of age,  65 years of age) 
 
Sex 
 
Baseline LDL-C (< median,  median)  
 
Current tobacco use (yes, no) 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 11 of 27 
CONFIDENTIAL 
 
 
5. 
Definitions 
5.1 
Endpoint Related Definitions 
5.1.1 
Primary and Secondary Endpoints 
Minimum FCT 
Minimum FCT in µm for a subject is defined as the minimum of all minimum FCT 
measurements within each individual frame across all frames of that subject. 
Mean Minimum FCT 
Mean minimum FCT in µm for a subject is defined as the mean of the minimum FCT 
measurements performed within all individual frames for that subject. 
Maximum Lipid Arc 
Maximum Lipid arc in degree for a subject is defined as the maximum of total lipid arc 
measurements within each individual frame across all frames of that subject. 
Lipid Core Length 
Lipid core length in mm is defined as the longitudinal extent of plaque within the vessel 
wall that continuously meets the criteria defined in the study protocol. The lipid core 
length will be calculated as the number of frames with lipid existence*0.2mm. 
Normalization is also required for lipid core length. 
Lipid Rich Plaque 
Lipid rich plaque serves as identifier for plaque-based secondary endpoints. 
There are three steps to follow to identify frames with lipid rich plaque: 
1. Identify plaque existence using lipid existence or fibrous existence or 
calcium existence at baseline. The gap between two independent plaques 
has to be larger than 5mm (ie, 25 frames) 
2. Among plaques detected in step 1 at baseline, verify if they are lipid rich 
plaque using lipid existence and lipid arc is analyzable and total lipid arc > 
 
3. Obtain frame numbers for each lipid rich plaque detected in step 1 and 2 
5.1.2 
Exploratory Endpoints 
Number of Microchannels 
Number of microchannels per mm is defined as the sum of microchannels measured 
from all frames for one subject with a maximal count of 10 per frame. It will be 
normalized by dividing by the number of frames for each subject and multiplying by 5. 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 12 of 27 
CONFIDENTIAL 
 
 
Macrophage Composition 
Macrophage composition per mm is defined as the sum of macrophage scores from all 
frames for one subject. It will be normalized by dividing by the number of frames for each 
subject and multiplying by 5. 
Lipid Content 
For IVUS datasets perform the following across all IVUS frames from both 
timepoints for a given subject: 
1. Calculate the plaque area as external elastic membrane cross sectional 
area (EEM) minus lumen cross sectional area 
2. Select frame with maximum plaque area and frame with minimum plaque 
area in the 10 mm (20 frames) proximal to frame with maximum plaque area 
3. Use the EEM value of frame with the maximum plaque area divided by the 
EEM value of frame with the minimum plaque area to derive remodeling 
index 
4. Use > 1.05 as cut-
 
5. I
6; otherwise this 
subject data will be excluded for IVUS endpoints 
6. Count all frames with plaque area > 63% of EEM and calculate normalized 
count of frames as 10*(the number of frames with plaque area > 63% of 
EEM)/(total number of frames) at BL and FU, for each subject. Please note 
the unit would be 'mm/cm artery'.                                 
7. Calculate absolute change in mm/cm artery and percent change of 
normalized frame count between the two timepoints (BL and FU) as the 
IVUS endpoints. 
5.2 
Study Time Points 
Enrollment Date  
Enrollment date is defined as the randomization date. 
Randomization Date  
Randomization Date is defined as the date subject was allocated to a treatment group. 
First Dose Date of Investigational Product (First IP Date) 
For each subject, the First Dose Date of Investigational Product is defined as the first 
administration date of the IP as recorded on the IP administration CRF. 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 13 of 27 
CONFIDENTIAL 
 
 
Study Day 1  
Study Day 1 is defined as the date of first investigational product (IP) 
administration or the date of randomization for subjects who are not administered 
any dose of IP.  
Study Day  
For each subject, and for a given date of interest, study day is defined as the number of 
days since Study Day 1: Study day = (date of interest  Study Day 1 date) + 1. If the 
date of interest is prior to the Study Day 1: Study day = (date of interest  Study Day 1 
date), so that the day prior to Study Day 1 is study day -1.  
Last Dose Date of Investigational Product (Last IP Date)  
For each subject, the Last Dose Date of Investigational Product is defined as the date of 
the last administration of the IP.  
Subject-level End of Study (EOS) Date 
End of study for each subject is defined as the date the subject last completed a 
protocol-specified procedure. The date will be recorded on the End of Study CRF page. 
Study End Date 
The Study End Date is the last EOS date of all randomized subjects. 
5.3 
Demographics and Baseline Related Definitions 
Age  
 
Baseline Lipid and Lipid-related Parameters  
Baseline values for LDL-C, triglycerides and troponin are defined as the concentrations 
measured through local lab at screening. Baseline values for other lipids (eg, total 
cholesterol, HDL-C and VLDL-C), ApoA1, ApoB, Lp(a) and their derived 
parameters (eg, ratio between them) are defined as the concentrations measured 
through central lab on Study Day 1.  
Baseline Laboratory Variables 
Baseline values for laboratory variables are defined as the assessment measured 
at screening. 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 14 of 27 
CONFIDENTIAL 
 
 
Baseline Concomitant Medication Usage and Medical History 
Baseline values for background statin therapy, lipid-modifying concomitant 
medication usage and medical history are defined as the assessment measured at 
screening. For concomitant medication that is not lipid-modifying baseline is 
defined as measurement at study day 1. 
Baseline Image Data 
Baseline values for OCT, IVUS image data are defined as the assessment 
measured at screening. 
Baseline Vital Signs 
Baseline values for vital signs are defined as the last non-missing value collected 
prior to or on Study Day 1. 
Change (absolute change) from Baseline  
The arithmetic difference between a post-baseline value and baseline for a given time 
point:  
Change (absolute change) from baseline = (post-baseline value  baseline value). 
Percent Change from Baseline  
The percent change from baseline for a given variable at a given time point is defined 
as:  
100 x [(value at given time point  baseline value) / baseline value]. 
5.4 
Other Study Related Definitions 
Actual Treatment Group 
receives treatment throughout the study that is different than the randomized treatment 
group assignment, in which case the actual treatment group is the treatment received. 
Investigational Product (IP)  
IP includes AMG 145 SC 420 mg QM and its SC placebo. 
IP Exposure Period in Months  
For each QM subject: IP Exposure Period = [min (Last IP Date + 28 days, EOS Date) - 
First IP Date +1] / 365.25 * 12  


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 15 of 27 
CONFIDENTIAL 
 
 
Study Exposure Period in Months  
For each randomized subject, Study Exposure Period = (EOS date  Randomization 
Date + 1) / 365.25 * 12  
Treatment Emergent Adverse Event (TEAE)  
Events categorized as Adverse Events (AEs) starting on or after first dose of 
investigational product as determined by the flag indicating if the adverse event started 
prior to the first dose of IP on the Events eCRF and up to 30 days after the last dose of 
IP date or EOS date, whichever is earlier. 
Reflexive Approach for LDL-C and VLDL-C  
Reflexive approach for LDL-C and VLDL-C is only applicable for the central lab data. 
When calculated LDL-C is less than 40 mg/dL or triglycerides are > 400 mg/dL, LDL-C 
and VLDL-C will be measured per ultracentrifugation (UC) instead of calculated LDL-C 
and calculated VLDL-C, if available. 
6. 
Analysis Sets 
6.1 
Full Analysis Set 
The full analysis set (FAS) includes all randomized subjects who received at least 1 
dose of IP. In efficacy analyses, subjects will be grouped according to their randomized 
treatment group assignment, regardless of the treatment received 
6.2 
OCT Analysis Set (OAS) 
The OCT analysis set includes subjects in the FAS with a baseline FCT and an FCT 
measurement conducted on or after week 40.  
6.3 
Completers Analysis Set (CAS) 
The Completers Analysis Set (CAS) includes subjects in the OAS who adhered to the 
scheduled IP (ie, EOIP reason is completed IP on eCRF) and had an observed value for 
the primary endpoint. 
6.4 
Safety Analysis Set  
The safety analysis set includes all randomized subjects who have taken at least 1 dose 
of investigational product. For safety analyses, the subjects will be grouped according to 
actual treatment group. 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 16 of 27 
CONFIDENTIAL 
 
 
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
No interim analysis is planned for this study. 
7.2 
Final Analysis 
The final analysis will be conducted after all subjects have either completed all the 
scheduled study visits or have early terminated from the study. At that time, the 
database will be cleaned, processed, locked, and a snapshot will be taken; the study will 
also be unblinded for analyses. Based on the snapshot, efficacy and safety analyses will 
be performed. 
8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses including data from RAVE 
database, imaging data and central lab data (outside of RAVE database). The 
database will be subjected to edit checks outlined in the Data Management Plan 
(DMP).  Additional details will be provided in DMP and Data Acquisition 
Requirements Specifications (DARS). 
8.3 
Handling of Missing and Incomplete Data 
Subjects may be missing specific data points for various reasons. In general, data may 
be missing due to a subject's early withdrawal from study, a missed visit, or 
non-evaluability of a data point or endpoint at a time. All attempts will be made to 
capture missing or partial data for this trial prior to the database lock. The frequency of 
missing data for efficacy endpoints will be assessed through descriptive summaries of 
the measurements over time. For subjects with missing post-baseline FCT, the missing 
primary and secondary endpoints will be imputed using multiple imputation.  


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 17 of 27 
CONFIDENTIAL 
 
 
Adverse event and concomitant medication with completely or partial missing start dates 
will be queried. After the issue is queried, the date is still incomplete with year only or 
year and month only, the start date will be imputed as described below: 
Table 1.  Imputation Rules for Incomplete Dates  
  
Missing 
Imputation 
Exception 
Start date 
(AE and 
concomitant 
medication) 
Day 
1 
Default to Study Day 1 if an event starts the 
same year and month as Study Day 1 
Day / Month 
1-Jan 
Default to Study Day 1 if an event started 
the same year as Day 1 
For historical events (eg, date first taken in the prior statin therapy form) that will be used 
to summarize data derived stratum, the imputation rules are as follows: if the day is 
missing, default to 1; if both month and day are missing, default to Jan 1. If the imputed 
date is on or after the randomization date, default to randomization date minus 1. 
Missing years will not be imputed under any condition. 
8.4 
Detection of Bias 
This study has been designed to minimize potential bias using randomization of subjects 
into treatment groups and the use of blinding. Other factors that may bias the results of 
the study include:  
 
major protocol deviations likely to impact the analysis and interpretation of the 
efficacy endpoints  
 
subject level unblinding before final database lock and formal unblinding  
Important protocol deviations likely to impact the analysis and interpretation of the 
efficacy endpoints will be tabulated in the Clinical Study Report (CSR). Any unblinding of 
individual subjects prior to formal unblinding of the study will be documented in the CSR.  
8.5 
Outliers 
Various methods, including univariate summaries, histograms, scatter plots, box plots, 
and line graphs, may be used to identify outliers in key safety and efficacy variables. The 
primary analyses will include outliers in the data. Sensitivity analyses may be undertaken 
if extreme outliers for a variable are observed. 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 18 of 27 
CONFIDENTIAL 
 
 
8.6 
Distributional Characteristics 
If the distributional assumptions are not met, then alternative methods will be utilized. 
The use of alternative methods will be fully justified in the CSR. 
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.   
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Summary statistics for continuous variables will include the number of subjects, mean, 
median, SD or standard error, minimum, and maximum. For categorical variables, the 
frequency and percentage will be given. 
Statistical inferences will be provided for analyses of primary and secondary efficacy 
endpoints. Unless specified otherwise, all statistical tests are 2-sided with a significance 
level of 0.05; no statistical inference and imputation will be conducted for analyses of 
safety endpoints.  No imputation will be conducted for analyses of exploratory endpoints.  
Even though the p-values will be generated for exploratory endpoints, they are 
descriptive in nature. 
Multiplicity Adjustment Method 
To preserve the family wise type 1 error rate at 0.05 for testing the primary and 
secondary endpoints, the primary analysis of primary endpoint will be tested first. If the 
treatment effect from the primary analysis of the primary endpoint is significant at a 
significance level of 0.05, the secondary endpoints will be tested with significance level 
of 0.05 using the Hochberg method. 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 19 of 27 
CONFIDENTIAL 
 
 
9.2 
Subject Accountability 
The number of subjects screened, randomized to IP, receiving IP, and completing the 
study will be summarized. Study discontinuation and IP discontinuation will be tabulated 
separately by reasons for discontinuation, including due to COVID-19 Impact if 
applicable. The number of subjects included in and excluded from each analysis set 
and reason for exclusion will also be summarized. 
 will be presented. 
The number and percentage of subjects randomized will be tabulated by study 
site. 
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
nd updated during the IPD reviews throughout the study 
prior to database lock. These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the study. Eligibility deviations are defined in the 
protocol. 
The number of subjects reporting Protocol Deviations due to COVID-19 Impact will 
be summarized in a table. A Protocol Deviation listing of subjects impacted due to 
COVID-19 Impact will also be provided. 
9.4 
Demographic and Baseline Characteristics 
All baseline tables will be summarized by randomized treatment group and for all 
subjects in the FAS. Baseline tables will summarize the following (but not limited to): 
baseline characteristics, demographics, cardiovascular medical history, and lipid 
parameters. Difference in stratum assignment between randomized stratum and 
data-derived stratum will be tabulated. 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 20 of 27 
CONFIDENTIAL 
 
 
9.5 
Efficacy Analyses 
Endpoint 
Primary 
Analysis 
Sensitivity Analysis 
Multiplicity 
Adjustment 
Primary Endpoint 
To preserve the 
family wise type 1 
error rate at 0.05 for 
testing the primary 
and secondary 
endpoints, the 
primary analysis of 
primary endpoint will 
be tested first.  If the 
treatment effect from 
the primary analysis 
of the primary 
endpoint is significant 
at a two-sided 
significance level of 
0.05, the secondary 
endpoints will be 
tested with two-sided 
significance level of 
0.05 using the 
Hochberg method. 
 
Absolute change in minimum 
FCT from baseline to week 50 
Multiple 
Imputation 
 
ANCOVA 
(FAS) 
Quade Test (FAS) 
COVID-19 Impact 
Analysis 
Secondary Endpoints 
Coronary artery based: 
 
Percent change in minimum 
FCT in a matched segment 
of the artery as determined 
by OCT from baseline to 
week 50. 
 
Absolute change in mean 
minimum FCT for all images 
accessed in an individual 
subject as determined by 
OCT from baseline to week 
50. 
 
Absolute change in the 
maximum lipid arc in a 
matched segment of artery 
as determined by OCT from 
baseline to week 50. 
Plaque-based: 
 
Absolute change in 
minimum FCT, maximum 
lipid arc, and lipid core 
length in lipid rich plaques 
defined as minimum FCT  
120 m 
Multiple 
imputation 
 ANCOVA 
(FAS) 
NA 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) 
Primary Analysis: 
To assess the primary endpoint of absolute change in minimum FCT from baseline to 
week 50, an ANCOVA (Analysis of Covariance) model on the FAS will be used, 
including terms for treatment group, stratification factor (current statin use [> 4 weeks or 
seline minimum FCT as covariates. Least square means 
and corresponding 95% confidence intervals (CI) will be calculated for each treatment 
group and for the difference between treatment groups. For subjects with missing 
post-baseline minimum FCT, the post-baseline minimum FCT value will be imputed 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 21 of 27 
CONFIDENTIAL 
 
 
using multiple imputation. The imputation model will include treatment group, 
stratification factor, baseline LDL-C, baseline minimum FCT, age as covariates. At least 
five imputations will be conducted, and each complete dataset after imputation will be 
analyzed using the ANCOVA model. SAS PROC MIANALYZE will be used to combine 
the results from individual ANCOVA models.  
Sensitivity Analysis 
1) Non-parametric analysis (Quade test) will be performed on FAS as sensitivity 
analysis. The missing data will be imputed using multiple imputation. The 
imputation model and the analysis approach of combining results from 
multiple imputed datasets will be same as the primary analysis. 
2) COVID-19 Impact sensitivity analysis:  
To determine the impact of COVID-19, a sensitivity analyses will be 
conducted. All the available post-baseline FCT values will be considered in 
the analysis, irrespective of the analysis visit window (ie, the post-baseline 
FCT values after week 56 will also be considered for the analysis). The 
ANCOVA model for COVID-19 Impact analysis will include the covariates of 
treatment group, stratification factor (current statin use [> 4 weeks or 
 4 weeks] at screening), baseline minimum FCT as covariates. The 
imputation method, model and analysis approach will be same as the 
primary analysis. 
Covariate and Subgroup Analysis 
In addition to the primary analysis, covariate adjusted analysis of the primary efficacy 
endpoint will be performed as supportive analyses using the baseline covariates in 
Section 4.1, in their original format, one at a time, in the ANCOVA model used in the 
primary analysis. 
Subgroup analyses on the primary efficacy endpoint will be conducted using the 
subgroups specified in Section 4.2, in the ANCOVA model used in the primary analysis. 
Subgroup by treatment interactions will be tested and the p-value of the interaction term 
will be reported.  
For covariate and subgroup analyses, the data-derived stratification factor from the CRF 
will be used.  


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 22 of 27 
CONFIDENTIAL 
 
 
Supplementary Analysis: 
The following additional analyses will also be performed to evaluate the robustness of 
the primary analysis result: 
 
The primary analysis will be repeated using OAS  
 
The primary analysis will be repeated using CAS  
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
The secondary efficacy endpoints will be analyzed using the similar method as used in 
primary analysis of the primary efficacy endpoint but adjusting for corresponding 
baseline variable. The Hochberg method for multiplicity adjustment will be used to 
maintain the overall error rate at 0.05.  
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 
The exploratory endpoints will be analyzed using ANCOVA. The model will include 
change or percent change from baseline for each exploratory endpoint as 
dependent variable, and terms for treatment group, stratification factor (current 
eeks] at screening) and corresponding baseline 
values as covariates. The p-values displayed will be considered as descriptive. 
The analysis will be carried out on observed data and missing data will not be 
imputed. 
9.6 
Safety Analyses 
9.6.1 
Adverse Events  
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class, high level term and preferred term. Tables of fatal adverse events, serious 
adverse events and adverse events leading to withdrawal from investigational product 
will also be provided. Subject incidence of TEAEs related to a device, if applicable, will 
be tabulated by system organ class and preferred term. 
The latest version of Medical Dictionary for Regulatory Activities (MedDRA) will be used 
to code all events categorized as adverse events to a system organ class and a 
preferred term. 
The subject incidence of adverse events will be summarized for all treatment-emergent 
adverse events, serious adverse events, and adverse events leading to withdrawal of 
investigational product.  


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 23 of 27 
CONFIDENTIAL 
 
 
Subject incidence of all treatment-emergent adverse events, serious adverse events, 
adverse events leading to withdrawal of investigational product, and fatal adverse events 
will be tabulated by system organ class and preferred term in alphabetical order.   
Subject incidence of adverse events associated with injectable protein therapies: 
 
Injection site reactions 
 
Hypersensitivity or allergic reactions  
will be summarized by category and preferred term.  
9.6.2 
Laboratory Test Results 
Descriptive statistics will be provided for actual values and changes from baseline in 
selected laboratory parameters at each protocol-specified scheduled visit. Laboratory 
analytes are provided in the protocol (Appendix 2). 
9.6.3 
Vital Signs 
Systolic and diastolic blood pressure and heart rate will be summarized by treatment 
group using descriptive statistics at each scheduled visit.  
9.6.4 
Exposure to Investigational Product 
The exposure to investigational product will be summarized by treatment group using 
descriptive statistics.  
9.6.5 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving medications of interest (MOI) will be 
summarized by preferred term or category for each treatment group as coded by the 
World Health Organization Drug (WHODRUG) dictionary. Statin intensity will be 
summarized by treatment group at each targeted scheduled visit date. 
10. 
Changes From Protocol-specified Analyses 
There are no changes to the protocol-specified analyses. 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 24 of 27 
CONFIDENTIAL 
 
 
11. 
Literature Citations / References 
Dai J, Hou J, Xing L, et al.  Is age an important factor for vascular response to statin 
therapy?  A serial optical coherence tomography and intravascular study.  Coron Artery 
Dis.  2017; 28:209-217. 
Hou J, Xing L, Jia H, et al.  Comparison of Intensive Versus Moderate Lipid-Lowering 
Therapy on Fibrous Cap and Atheroma Volume of Coronary Lipid-Rich Plaque Using 
Serial Optical Coherence Tomography and Intravascular Ultrasound Imaging.  Am J 
Cardiol.  2016; 117:800-806. 
Hattori K, Ozaki Y, Ismail TF, et al. Impact of statin therapy on plaque characteristics as 
assessed by serial OCT, grayscale and integrated backscatter-IVUS. JACC Cardioavasc 
Imaging. 2012; 5:169-177. 
Kataoka Y, Puri R, Hammadah M, et al.  Frequency-domain optical coherence 
tomographic analysis of plaque microstructures at nonculprit narrowings in patients 
receiving potent statin therapy.  Am J Cardiol.  2014; 114:549-554. 
Komukai K, Kubo T, Kitabata H, et al.  Effect of atorvastatin therapy on fibrous cap 
thickness in coronary atherosclerotic plaque as assessed by optical coherence 
tomography:  the EASY-FIT study.  J Am Coll Cardiol.  2014; 64:2207-2217. 
Nishio R, Shinke T, Otake H, et al.  Stabilizing effect of combined eicosapentaenoic acid 
and statin therapy on coronary thin-cap fibroatherroma.  Atherosclerosis.  2014; 
234:114-119. 
Takarada S, Imanishi T, Kubo T, et al.  Effect of statin therapy on coronary fibrous-cap 
thickness in patients with actue coronary syndrome:  assessment by optical coherence 
tomography study.  Atherosclerosis.  2009; 202:491-497. 
 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 25 of 27 
CONFIDENTIAL 
 
 
12. 
Appendices 
Appendix A.  Analytical Study Week Assignments 
Selected endpoints will be summarized by scheduled study visits in descriptive 
analyses.Since the actual visits may not exactly coincide with their scheduled visit day, 
the actual visit day is mapped to the study visit generally by non-overlapping consecutive 
intervals covering the entire time continuum. The mapping intervals for all distinct 
schedules are summarized in the following table: 
Analytical Study Week
Screening 
Day 1 
Week 4 
Week 24 
Week 50 
Scheduled Visit Day 
 
1 
29 
169 
351 
Physical Examination 
[-7, 1) 
1 
 
 
> 176 
Vital Signs 
[-7, 1) 
1 
 
 
> 176 
Fasting Lipid Testing 
 
1 
 
(1, 259] 
> 259 
OCT 
[-7, 1) 
 
 
 
(280, 393] 
IVUS 
[-7, 1) 
 
 
 
(280, 393] 
Biomarker collection 
(blood/plasma) 
 
 
 
 
> 176 
Statin Therapy 
[-7, 1) 
1 
29 
169 
351 
Handling multiple records assigned to an analytical study week: 
If there is more than one record in a study week interval, the analytical record for that 
specific study week will be defined as the record closest to the scheduled visit day of 
that specific study week (7 x study week + 1). If two records are equidistant from the 
scheduled day, then the earlier record will be chosen. If there are multiple records on the 
same day, the last record will be used. 
Concomitant medication records will be selected when the start day or end day 
euqal to the scheduled visit day, or the concomitant medication usage time period 
includes the scheduled visit day.  


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 26 of 27 
CONFIDENTIAL 
 
 
Appendix B. Common Terminology Criteria for AEs (CTCAE) 
Refer to the NCI Common Terminology Criteria for Adverse Events (CTCAE) for 
adverse event grading and information. The CTCAE is available at the following 
link: http://evs.nci.nih.gov/ftp1/CTCAE/About.html 


Product:  Evolocumab 
Protocol Number:  20160184 
Date:  15 January 2021 
Page 27 of 27 
CONFIDENTIAL 
 
 
Appendix C.  Lipid Modifying Background Therapy Intensity 
Based on ACC/AHA guidelines (2018) 
HIGH-INTENSITY 
STATIN THERAPY 
MODERATE-INTENSITY 
STATIN THERAPY 
LOW-INTENSITY 
STATIN THERAPY 
Atorvastatin 
 40 mg QD 
10   40 mg QD 
 10 mg QD 
Rosuvastatin 
 20 mg QD 
5   20 mg QD 
 5 mg QD 
Simvastatin 
 80 mg QD 
20   80 mg QD 
 20 mg QD 
Pravastatin 
 40 mg QD 
 40 mg QD 
Lovastatin 
 40 mg QD 
 40 mg QD 
Fluvastatin XL 
80 mg QD 
 80 mg QD 
Fluvastatin 
40 mg BID 
 40 mg BID 
Pitavastatin 
1  4 mg QD 
 1 mg QD 
UNKNOWN-INTENSITY STATIN THERAPY if dose frequency is other or dose unit 
is other and therefore total daily dose in mg cannot be derived; NO STATIN 
THERAPY if subject does not use any statin at baseline. 
High-intensity lipid lowering regimen is defined as: 
 
Atorvastatin  40 mg QD 
 
Rosuvastatin  20 mg QD 
 
Simvastatin  80 mg QD 
 
Combination of any statin therapy and Ezetimibe 10 mg QD 
Note protocol cited an older categorization of statin intensity based on