A Multicenter, Open-label, Single-arm, Extension Study to Assess Long-term Safety of Evolocumab Therapy in Patients With Clinically Evident Cardiovascular Disease
Phase: PHASE3
Conditions: Dyslipidemia
Sponsor: Amgen

Product:  Evolocumab 
Protocol Number:  20130295 
Date:  26 February 2020 
Page 1 of 77 
CONFIDENTIAL 
Title:  A Multicenter, Open-label, Single-arm, Extension Study to Assess 
Long-term Safety of Evolocumab Therapy in Patients With Clinically Evident 
Cardiovascular Disease 
Evolocumab (AMG 145) 
Amgen Protocol Number 20130295 
EudraCT number 2015-004780-36 
NCT02867813 
FOURIER-OLE 
Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With 
Elevated Risk Open-label Extension 
Clinical Study Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Phone:  +1-805-447-1000 
Key Sponsor Contact: 
Clinical Research Medical Director
One Amgen Center Drive
Thousand Oaks, CA 91320, USA
Telephone:  
Email:  
Date: 
24 November 2015 
Amendment 1 
20 November 2017 
Amendment 2 
08 April 2019 
Amendment 3 
26 February 2020 
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, 1-800-772-6436.
This protocol was developed, reviewed, and approved in accordance with 
Amgen’s standard operating procedures. 
Approved

Product:  Evolocumab 
Protocol Number:  20130295 
Date:  26 February 2020 
Page 2 of 77 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled “A Multicenter, Open-label, Single-arm, 
Extension Study to Assess Long-term Safety of Evolocumab Therapy in Patients With 
Clinically Evident Cardiovascular Disease,” dated 26 February 2020, 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) and applicable national or regional 
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:  20130295 
Date:  26 February 2020 
Page 3 of 77 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Multicenter, Open-label, Single-arm, Extension Study to Assess Long-term Safety of 
Evolocumab Therapy in Patients With Clinically Evident Cardiovascular Disease 
Study Phase:  3b 
Indication:  Dyslipidemia 
Primary Objective:  The primary objective is to describe the safety and tolerability of long-term 
administration of evolocumab. 
Secondary Objectives:  The secondary objectives are to describe the effects of long-term 
administration of evolocumab on low-density lipoprotein cholesterol (LDL-C) levels and to 
describe the effects of long-term administration of evolocumab in subjects achieving an LDL-C 
level < 40 mg/dL (1.03 mmol/L). 
Exploratory objectives are provided in Section 1.3. 
Hypotheses:  The primary clinical hypothesis is that long-term exposure of evolocumab will be 
safe and well tolerated in subjects with clinically evident atherosclerotic cardiovascular disease 
(CVD). 
Primary Endpoint:  The primary endpoint is the subject incidence of adverse events. 
Secondary Endpoints:  The secondary endpoints are the percent change of LDL-C from 
baseline at each scheduled visit and the achievement of an LDL-C < 40 mg/dL (1.03 mmol/L) at 
each scheduled visit. 
Exploratory endpoints are provided in Section 10.1.1.3. 
Study Design:  This is a multicenter, open-label extension (OLE) study designed to assess the 
long-term safety of evolocumab in subjects who completed the FOURIER study 
(Study 20110118), a randomized placebo-controlled study of evolocumab in subjects with 
clinically evident atherosclerotic CVD on stable effective statin therapy.  Eligible subjects at sites 
participating in this study who have signed the informed consent for this OLE may be enrolled at 
the completion of the FOURIER study.  Enrollment of eligible subjects may be limited at the site 
level to maintain a 1:1 ratio between the following subject populations: 
• 
subjects with ≥ 2 years of study exposure in FOURIER and 
• 
subjects who have less than 2 years of study exposure in FOURIER and did not participate in 
the EBBINGHAUS study (Study 20130385) 
Eligible subjects from EBBINGHAUS may participate in this study regardless of FOURIER study 
exposure. 
This study (FOURIER OLE) requires laboratory assessments at week 12 and thereafter 
approximately every 24 weeks from day 1; the corresponding blood samples will be processed 
using a central laboratory.  To preserve the integrity of FOURIER blinding, no local lipid 
assessments may be performed until either FOURIER is unblinded or at least 12 weeks after a 
subject’s last administration of FOURIER investigational product (evolocumab or placebo), 
whichever is first. 
Upon enrollment in this study (FOURIER OLE), subjects will receive evolocumab 140 mg every 
2 weeks (Q2W) or 420 mg monthly (QM), according to the subject’s preference.  The frequency 
and corresponding dose of administration can be changed at any scheduled time point where 
evolocumab is supplied to the subject, provided the appropriate supply is available.  It is 
recommended that subjects continue the same background lipid-lowering therapy (LLT), including 
statin, as taken during FOURIER. 
This study will continue for 260 weeks (approximately 5 years).  Subjects ending administration of 
evolocumab should continue study assessments until the end of study. 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20130295 
Date:  26 February 2020 
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All subjects will be followed and complete procedures/assessments from enrollment through the 
date of study termination unless the subject has withdrawn consent, irrespective of whether the 
subject is continuing to receive treatment.  All deaths and cardiovascular events of interest will be 
reviewed by an independent external Clinical Events Committee (CEC), using standardized 
definitions. 
Sample Size:  Approximately 5000 subjects will be enrolled, including approximately 
2000 subjects with ≥ 2 years of study exposure in FOURIER. 
Summary of Subject Eligibility Criteria:  Subjects must have completed FOURIER 
(Study 20110118) while still receiving assigned investigational product and provided informed 
consent for this OLE study.  Eligible subjects may not be currently receiving treatment in another 
investigational device or drug study, or have ended treatment on another investigational device or 
drug study(ies) within less than 4 weeks.  Women cannot be pregnant or breastfeeding or 
planning to become pregnant or planning to breastfeed during treatment with evolocumab and 
within 15 weeks after the end of treatment with evolocumab.  Women of childbearing potential 
must be willing to use an acceptable method(s) of effective birth control during treatment with 
evolocumab and for an additional 15 weeks after the end of treatment with evolocumab. 
For a full list of eligibility criteria, please refer to Section 4.1 through Section 4.1.2. 
Investigational Product 
Amgen Investigational Product Dosage and Administration:  Evolocumab will be 
administered using a handheld mechanical (spring-based) prefilled 1.0 mL autoinjector/pen 
(AI/Pen) or an on-body electromechanical injection 3.5 mL personal injector (PI).  
Evolocumab will be administered 140 mg subcutaneous (SC) Q2W (1 administration by prefilled 
AI/Pen) or 420 mg SC QM (3 administrations by prefilled AI/Pen or 1 administration by PI). 
Subjects will choose whether to initiate treatment at the Q2W or QM schedule and will have the 
opportunity to switch between evolocumab Q2W and QM at any scheduled time point where 
evolocumab is supplied to the subject, provided the appropriate supply is available.  Subjects who 
choose QM treatment will initiate treatment using the PI, provided the appropriate supply is 
available.  If the PI is not available, then the AI/Pen may be used.  Subjects will have the 
opportunity to switch between the AI/Pen and PI, at any scheduled time point where 
evolocumab is supplied to the subject, provided the appropriate supply is available. 
Non-investigational Product 
Non-Amgen Non-investigational Product Dosage and Administration:  It is recommended 
that subjects continue the same background LLT, including statin, as taken while in FOURIER.  
Background LLT will not be provided by Amgen unless required by local regulations. 
Procedures:  Mandatory study visits will occur at week 12 and thereafter approximately every 
24 weeks from day 1.  Evolocumab resupply visits will be scheduled quarterly (every 12 weeks).  
Evolocumab will be supplied to the subject at the site.  The method of resupply will be determined 
based on local regulations as well as available infrastructure.  Assessments and procedures 
include vital signs; physical examination; body weight; assessment of targeted concomitant 
therapy, adverse events, device-related adverse effects, serious adverse events, and 
disease-related events; Cambridge Neuropsychological Test Automated Battery (CANTAB) 
assessments (only in subjects from EBBINGHAUS [Study 20130385]); laboratory assessments, 
including fasting lipid panel, apolipoprotein A1, apolipoprotein B, and lipoprotein(a); serum (or 
urine) pregnancy testing (women of childbearing potential only); and evolocumab administration.  
If evolocumab is administered at the site, the administration by SC injection will be done after 
blood draw and vital sign procedures have been completed. 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments (Table 1). 
Statistical Considerations:  The primary and secondary endpoints will use the OLE safety 
analysis set (OLE study only) which includes all subjects who received at least 1 dose of 
open-label evolocumab in the OLE study. 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20130295 
Date:  26 February 2020 
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Statistical analyses in this open-label study will be descriptive in nature.  No statistical inference 
or missing value imputation is planned.  No formal hypotheses will be tested in this study, unless 
specified otherwise, the baseline value is defined as the subject’s baseline value from the parent 
study (FOURIER).  All analyses will be performed on the OLE safety analyses set.  The primary 
analysis of all primary, secondary, and exploratory endpoints will use data from the OLE study 
only.  Additional analyses combining the data from the OLE study and FOURIER/EBBINGHAUS 
study will be performed as applicable.  For all endpoints, results will be summarized by the 
randomized treatment group from the FOURIER study and overall, unless specified otherwise. 
Exposure-adjusted subject incidence rates of all treatment-emergent adverse events, serious 
adverse events, fatal adverse events, adverse events leading to withdrawal from evolocumab, 
device-related adverse events and disease-related events will be tabulated for the overall OLE 
study period using the OLE safety analysis set.  These events will also be presented by yearly 
subject exposure time intervals.  All events, including CEC reviewed events will be tabulated. 
Adverse event data from the OLE study will also be combined with FOURIER study data as an 
additional analysis, and positively reviewed events will not be included in the adverse event 
analysis to remain consistent with FOURIER adverse event reporting.  The analysis will be 
performed using the long-term safety analysis set. 
Summary statistics of the secondary endpoints (percent change of LDL-C from baseline and 
achieving an LDL-C < 40 mg/dL) will be provided. 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen 
Data Element Standards 
Version/Date:  
Version 5, 20 March 2015 
 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20130295 
Date:  26 February 2020 
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Study Design and Treatment Schema 
 
CANTAB = Cambridge Neuropsychological Test Automated Battery; D = day; EOS = end of study; Q2W = every 2 weeks; QM = monthly; W = week 
a Assessments do not need to be repeated except when the day 1 visit of this open-label extension study occurs > 90 days after the FOURIER EOS visit. 
b Subjects may be contacted by phone. 
c. Subject will be contacted by phone at least 30 days (+ 3 days) after last evolocumab administration, unless they are continuing their participation in the study after 
ending evolocumab prior to study completion. 
d CANTAB assessments will only be performed for subjects from the EBBINGHAUS study. 
 
 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20130295 
Date:  26 February 2020 
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Study Glossary 
Abbreviation or Term 
Definition/Explanation 
AI/Pen 
autoinjector/pen 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ApoA1 
apolipoprotein A1 
ApoB 
apolipoprotein B 
AST 
aspartate aminotransferase 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
CEC 
Clinical Events Committee 
CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
CVD 
cardiovascular disease 
CYP 
cytochrome P450 
day 1 
defined as the first day that protocol-specified investigational 
product/protocol-required therapies are administered to the subject 
DILI 
drug-induced liver injury  
EBBINGHAUS 
Study 20130385; a substudy of FOURIER 
eCRF 
electronic case report form 
EDC 
electronic data capture 
electronic source data 
(eSource) 
source data captured initially into a permanent electronic record 
used for the reconstruction and evaluation of a study 
end of study 
defined as when the last subject is assessed or receives an 
intervention for evaluation in the study; if the study includes multiple 
parts (eg, safety follow-up or survival assessment), the end of study 
would include these additional parts 
end of study (primary 
completion) 
defined as the date when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary 
endpoint(s), whether the study concluded as planned in the protocol 
or was terminated early 
end of treatment 
defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject 
EOS 
end of study for individual subject; defined as the last day that 
protocol-specified procedures are conducted for an individual subject 
FOURIER 
Study 20110118; the parent study for this open-label extension study 
FOURIER OLE 
open-label extension study of the FOURIER study (ie, the study 
described by this protocol) 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HCV 
hepatitis C virus 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20130295 
Date:  26 February 2020 
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Abbreviation or Term 
Definition/Explanation 
HDL-C 
high-density lipoprotein cholesterol 
HeFH 
heterozygous familial hypercholesterolemia 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IFU 
instructions for use 
IPIM 
Investigational Product Instruction Manual 
IRB/IEC 
institutional review board/independent ethics committee 
LDL-C 
low-density lipoprotein cholesterol 
LDLR 
low-density lipoprotein receptor 
LLT 
lipid-lowering therapy 
Lp(a) 
lipoprotein(a) 
MI 
myocardial infarction 
OLE 
open-label extension 
PAL 
Paired Associates Learning 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
PI 
personal injector 
Q2W 
every 2 weeks 
QM 
monthly; defined as every 4 weeks 
RTI 
Reaction Time 
SC 
subcutaneous 
source data 
information from an original record or certified copy of the original 
record containing patient information for use in clinical research.  
The information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained 
in source documents (original records or certified copies).  (ICH 
Guideline [E6]).  Examples of source data include subject 
identification, randomization identification, and stratification value. 
SWM 
Spatial Working Memory 
TIA 
transient ischemic attack 
TBL 
total bilirubin 
ULN 
upper limit of normal 
US 
United States 
VLDL-C 
very low-density lipoprotein cholesterol 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20130295 
Date:  26 February 2020 
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CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................. 3 
Study Design and Treatment Schema .............................................................................. 6 
Study Glossary .................................................................................................................. 7 
1. 
OBJECTIVES ......................................................................................................... 13 
1.1 
Primary ....................................................................................................... 13 
1.2 
Secondary .................................................................................................. 13 
1.3 
Exploratory ................................................................................................. 13 
2. 
BACKGROUND AND RATIONALE ........................................................................ 13 
2.1 
Cardiovascular Disease .............................................................................. 13 
2.2 
Amgen Investigational Product Background ............................................... 16 
2.3 
Rationale .................................................................................................... 16 
2.4 
Clinical Hypotheses .................................................................................... 17 
3. 
EXPERIMENTAL PLAN ......................................................................................... 17 
3.1 
Study Design .............................................................................................. 17 
3.2 
Number of Sites .......................................................................................... 18 
3.3 
Number of Subjects .................................................................................... 18 
3.4 
Replacement of Subjects ............................................................................ 19 
3.5 
Estimated Study Duration ........................................................................... 19 
3.5.1 
Study Duration for Subjects ........................................................ 19 
3.5.2 
End of Study ............................................................................... 19 
4. 
SUBJECT ELIGIBILITY .......................................................................................... 19 
4.1 
Inclusion and Exclusion Criteria ................................................................. 19 
4.1.1 
Inclusion Criteria ......................................................................... 19 
4.1.2 
Exclusion Criteria ........................................................................ 19 
5. 
SUBJECT ENROLLMENT ..................................................................................... 21 
5.1 
Treatment Assignment ............................................................................... 21 
6. 
TREATMENT PROCEDURES ............................................................................... 21 
6.1 
Classification of Products and/or Medical Devices ..................................... 21 
6.2 
Investigational Product - Evolocumab ........................................................ 22 
6.2.1 
Dosage, Administration, and Schedule ...................................... 22 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ...................................... 24 
6.3 
Non-Amgen Non-investigational Products - Background 
Lipid-lowering Therapy ............................................................................... 24 
6.3.1 
Dosage, Administration, and Schedule ...................................... 24 
6.3.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ...................................... 24 
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Protocol Number:  20130295 
Date:  26 February 2020 
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6.4 
Hepatotoxicity Stopping and Rechallenge Rules ........................................ 25 
6.4.1 
Criteria for Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ................................. 25 
6.4.2 
Criteria for Conditional Withholding of Amgen 
Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ................................. 26 
6.4.3 
Criteria for Rechallenge of Amgen Investigational 
Product and Other Protocol-required Therapies After 
Potential Hepatotoxicity .............................................................. 27 
6.5 
Concomitant Therapy ................................................................................. 27 
6.6 
Medical Devices ......................................................................................... 28 
6.7 
Product Complaints .................................................................................... 28 
6.8 
Excluded Treatments, Medical Devices, and/or Procedures 
During Study Period ................................................................................... 28 
7. 
STUDY PROCEDURES ......................................................................................... 29 
7.1 
Schedule of Assessments .......................................................................... 29 
7.2 
General Study Procedures ......................................................................... 32 
7.2.1 
Enrollment and Baseline Procedures (Day 1) ............................ 34 
7.2.2 
Treatment ................................................................................... 35 
7.2.3 
Safety Follow-up/End of Study Visit ........................................... 36 
7.3 
Cambridge Neuropsychological Test Automated Battery Tests ................. 37 
7.3.1 
Spatial Working Memory ............................................................ 37 
7.3.2 
Paired Associates Learning ........................................................ 38 
7.3.3 
Reaction Time ............................................................................ 38 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 39 
8.1 
Subjects’ Decision to Withdraw .................................................................. 39 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 40 
8.3 
Reasons for Removal From Treatment or Study ........................................ 40 
8.3.1 
Reasons for Removal From Treatment ...................................... 40 
8.3.2 
Reasons for Removal From Study ............................................. 40 
8.4 
Lost to Follow-up ........................................................................................ 40 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 41 
9.1 
Definition of Safety Events ......................................................................... 41 
9.1.1 
Disease-related Events .............................................................. 41 
9.1.2 
Adverse Events .......................................................................... 41 
9.1.3 
Serious Adverse Events ............................................................. 42 
9.2 
Safety Event Reporting Procedures ........................................................... 43 
9.2.1 
Reporting Procedures for Disease-related Events ..................... 43 
9.2.2 
Adverse Events .......................................................................... 44 
9.2.2.1 
Reporting Procedures for Adverse Events 
That Do Not Meet Serious Criteria ........................... 44 
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Date:  26 February 2020 
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9.2.2.2 
Reporting Procedures for Serious Adverse 
Events ...................................................................... 45 
9.2.2.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 46 
9.2.2.4 
Reporting a Safety Endpoint as a Study 
Endpoint ................................................................... 47 
9.2.2.5 
Serious Adverse Events That Are Not To 
Be Reported in an Expedited Manner ...................... 47 
9.3 
Pregnancy and Lactation Reporting ........................................................... 47 
10. 
STATISTICAL CONSIDERATIONS ....................................................................... 48 
10.1 
Study Endpoints, Analysis Sets, and Covariates ........................................ 48 
10.1.1 
Study Endpoints ......................................................................... 48 
10.1.1.1 
Primary Endpoint ..................................................... 48 
10.1.1.2 
Secondary Endpoints ............................................... 48 
10.1.1.3 
Exploratory Endpoints .............................................. 48 
10.1.2 
Analysis Sets .............................................................................. 49 
10.1.3 
Covariates and Subgroups ......................................................... 49 
10.2 
Sample Size Considerations ...................................................................... 49 
10.3 
Planned Analyses ....................................................................................... 50 
10.3.1 
Interim Analyses ......................................................................... 50 
10.3.2 
Primary Analysis ......................................................................... 50 
10.4 
Planned Methods of Analysis ..................................................................... 50 
10.4.1 
General Considerations .............................................................. 50 
10.4.2 
Primary Endpoint ........................................................................ 51 
10.4.3 
Secondary Endpoints ................................................................. 51 
10.4.4 
Exploratory Endpoints ................................................................ 51 
10.4.5 
Additional Safety Analyses ......................................................... 52 
11. 
REGULATORY OBLIGATIONS ............................................................................. 52 
11.1 
Informed Consent ....................................................................................... 52 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 52 
11.3 
Subject Confidentiality ................................................................................ 53 
11.4 
Investigator Signatory Obligations .............................................................. 54 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................... 54 
12.1 
Protocol Amendments and Study Termination ........................................... 54 
12.2 
Study Documentation and Archive ............................................................. 54 
12.3 
Study Monitoring and Data Collection ........................................................ 55 
12.4 
Investigator Responsibilities for Data Collection ........................................ 56 
12.5 
Language.................................................................................................... 56 
12.6 
Publication Policy ....................................................................................... 56 
12.7 
Compensation ............................................................................................ 57 
13. 
REFERENCES ....................................................................................................... 58 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20130295 
Date:  26 February 2020 
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14. 
APPENDICES ........................................................................................................ 60 
List of Tables 
Table 1.  Schedule of Assessments ................................................................................ 30 
Table 2.  Confidence Interval Width for Adverse Event Rates ........................................ 50 
List of Appendices 
Appendix A.  Additional Safety Assessment Information ................................................ 61 
Appendix B.  Sample Serious Adverse Event Report Form ............................................ 63 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................... 66 
Appendix D.  Recommended Lipid-lowering Background Therapy ................................. 68 
Appendix E.  Drugs With Known Major Interactions With Statin Background 
Therapy .................................................................................................... 69 
Appendix F.  Cambridge Neuropsychological Test Automated Battery Tests ................. 70 
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1. 
OBJECTIVES 
1.1 
Primary 
The primary objective is to describe the safety and tolerability of long-term administration 
of evolocumab. 
1.2 
Secondary 
The secondary objectives are the following: 
• 
to describe the effects of long-term administration of evolocumab on low-density 
lipoprotein cholesterol (LDL-C) levels 
• 
to describe the effects of long-term administration of evolocumab in subjects 
achieving an LDL-C level < 40 mg/dL (1.03 mmol/L) 
1.3 
Exploratory 
The exploratory objectives in subjects who completed the EBBINGHAUS study 
(Study 20130385) are the following: 
• 
to evaluate long-term change over time in executive function, as assessed by the 
Cambridge Neuropsychological Test Automated Battery (CANTAB) Spatial Working 
Memory (SWM) strategy index of executive function 
• 
to evaluate long-term change over time in working memory, as assessed by the 
CANTAB SWM test between-errors score 
• 
to evaluate long-term change over time in memory function, as assessed by the 
CANTAB Paired Associates Learning (PAL) test 
• 
to evaluate long-term change over time in psychomotor speed, as assessed by the 
CANTAB Reaction Time (RTI) test 
The exploratory objectives in all subjects are: 
• 
to describe the effects of long-term evolocumab administration on non-high-density 
lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol, 
lipoprotein(a) (Lp[a]), triglycerides, HDL-C, very low-density lipoprotein cholesterol 
(VLDL-C), and apolipoprotein A1 (ApoA1) levels. 
• 
to describe the effects of long-term administration of evolocumab on subject 
incidence of death and cardiovascular events of interest. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Cardiovascular Disease 
Collectively, cardiovascular diseases (CVD) are regarded as a worldwide epidemic; 
although CVD mortality has declined over the last 2 decades (primarily in developed 
countries), it still represents the leading cause of death and disability in the world, as well 
as over 10% of the global total disease burden.  In 2008, the World Health Organization 
estimated 57 million deaths worldwide, of which 36 million were due to 
noncommunicable causes.  Cardiovascular diseases accounted for over 17 million of 
Approved 
 
 

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Date:  26 February 2020 
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these deaths; nearly 80% of which were due to heart attacks and strokes alone 
(responsible for 7.3 and 6.2 million deaths, respectively). 
A large proportion of CVD is preventable and the investment in prevention measures has 
been regarded as the most sustainable solution for dealing with the CVD epidemic.  
Elevated cholesterol is among the leading risk factors for cardiovascular deaths (sixth), 
with an estimated prevalence of 39% globally among all adults (even greater in 
high-income countries).  Cardiovascular disease perhaps represents the single leading 
threat to the health of the world; the unmet medical need in this area is immense 
(World Health Organization, 2011). 
Dyslipidemia is a major modifiable risk factor for the development of CVD.  It is 
estimated that approximately 100 and 34 million Americans have total cholesterol in 
excess of 200 mg/dL (approximately 5.2 mmol/L) and 240 mg/dL (approximately 
6.2 mmol/L), respectively.  In Europe, up to 50% of the population aged 35 to 64 years 
has total cholesterol > 250 mg/dL (6.5 mmol/L) (Tolonen et al, 2005).  This high 
prevalence of dyslipidemia translates into a significant cardiovascular morbidity and 
mortality, as described above.  Dyslipidemia is associated with more than 50% of the 
global cases of coronary heart disease and more than 4 million deaths per year 
worldwide. 
To decrease the morbidity and mortality associated with CVD, over 50 million patients in 
the United States (US), Europe, and Japan are currently treated with dyslipidemia 
therapies.  The rationale for treatment of dyslipidemia, particularly elevated LDL-C, 
extends from extensive clinical study data in both primary and secondary prevention that 
demonstrates the reduction in total cholesterol, non-HDL-C, and most importantly, 
LDL-C through pharmacological therapies, particularly statins, lowers the risk of CVD 
events (Kannel, 1995; Kannel et al, 1979; Kannel et al, 1974).  The most recent 
Cholesterol Treatment Trialists’ Collaboration (2010) meta-analysis which included 
21 randomized controlled studies of statin versus control involving nearly 
170,000 patients showed that for every approximately 1 mmol/L reduction of LDL-C, 
there was an approximately 20% reduction in the risk of major vascular events (coronary 
death, nonfatal myocardial infarction [MI], coronary revascularization, or stroke).  
Importantly, this meta-analysis, which also evaluated 5 studies that compared more 
versus less intensive statin therapy, did not find an LDL-C threshold for risk reduction; 
additional vascular risk reduction is possible in patients with low LDL-C.  The opportunity 
for further cardiovascular risk reduction is also consistently seen in the numerous 
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primary and secondary prevention studies where subjects were treated with statins to 
their LDL-C goal, the results of which have manifested in durable, dramatic changes in 
medical practice and have consequently saved millions of lives. 
Despite achieving their LDL-C goals, approximately two-thirds of patients on lipid 
reduction therapy still have cardiovascular events (Libby, 2005).  While it is unlikely that 
this residual risk is entirely due to the additional LDL-C reduction needed beyond the 
LDL-C goal articulated in recent treatment guidelines (National Cholesterol Education 
Program, 2002; Grundy et al, 2004), Cholesterol Treatment Trialists Collaboration (2010) 
data suggest that novel agents capable of providing additional LDL-C reduction on top of 
statins may further reduce cardiovascular morbidity and mortality.  Furthermore, some 
individuals are intolerant to statin therapy and cannot achieve their respective LDL-C 
goals (eg, Bruckert et al, 2005; Franc et al, 2003).  Nonstatin treatment options are 
currently available (eg, ezetimibe, bile acid sequestrants, plant stanols, niacin) to lower 
LDL-C but their potency is limited, such that LDL-C reductions occur on the order of 
15% to 20%. 
The IMPROVE-IT study evaluated cardiovascular outcomes (cardiovascular death, MI, 
hospital admission for unstable angina, or coronary revascularization) for ezetimibe 
combined with a statin, compared with a statin alone, in approximately 18,000 subjects 
who had been hospitalized for ST segment elevation MI or non-ST segment elevation MI 
or unstable angina less than 10 days before enrollment (Cannon, 2015).  At 1 year, 
mean LDL-C was 70 mg/dL with a statin alone and 53 mg/dL with ezetimibe combined 
with a statin (a 24% reduction in LDL-C).  Over the duration of the study, the addition of 
ezetimibe to a statin significantly reduced the event rate for the primary combined 
endpoint from 34.7% to 32.7% (p = 0.016).  Reductions in individual event rates included 
a 21% relative risk reduction for ischemic stroke and 13% relative risk reduction for MI.  
Thus, despite the fact that mean LDL-C with a statin alone was 70 mg/dL, a level that is 
often used as a goal for lipid-lowering therapy (LLT), significant additional cardiovascular 
benefit was obtained by lowering LDL-C further with the addition of the nonstatin 
therapy, ezetimibe. 
Considering the remaining cardiovascular risk despite the availability of statin therapy 
and given that nonstatin treatment options have modest efficacy and/or are poorly 
tolerated (niacin and bile acid sequestrants), there is an unmet medical need for a 
potent, effective nonstatin agent that will get a significant proportion of patients to their 
LDL-C goal and further reduce cardiovascular risk.  This need is especially evident 
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Product:  Evolocumab 
Protocol Number:  20130295 
Date:  26 February 2020 
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among individuals at high risk for future cardiovascular events; namely, those who have 
already suffered from an MI, nonhemorrhagic stroke, coronary or peripheral arterial 
revascularization procedure or amputation due to atherosclerotic disease. 
Evolocumab has demonstrated consistent, significant, and durable reduction in LDL-C 
with favorable effects on other lipid parameters across a robust clinical development 
program in more than 6000 subjects with primary hyperlipidemia and mixed 
dyslipidemia.  In these studies, evolocumab reduced LDL-C by approximately 55% to 
75% compared with placebo and by approximately 35% to 45% compared with 
ezetimibe.  In subjects with homozygous familial hypercholesterolemia, evolocumab 
reduced LDL-C by approximately 30% compared with placebo.  Reduction of LDL-C was 
maintained with long-term treatment.  The adverse event profile for evolocumab was 
similar overall to that of the control groups, including placebo.  Extensive analyses have 
not identified major safety issues, including for low LDL-C, with evolocumab therapy. 
Recently published data suggest the potential for evolocumab to have beneficial effects 
on outcomes of CVD (Sabatine et al, 2015).  This could potentially be confirmed with the 
results of FOURIER, the clinical outcomes study with evolocumab. 
2.2 
Amgen Investigational Product Background 
Recycling of the hepatic cell surface low-density lipoprotein receptor (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 heart disease (Abifadel et al, 2003).  Evolocumab is a fully human 
monoclonal immunoglobulin G2, developed at Amgen Inc., that specifically binds to 
PCSK9 preventing its interaction with the LDLR.  The inhibition of PCSK9 by 
evolocumab leads to increased LDLR expression and subsequent decreased circulating 
concentrations of LDL-C. 
Refer to the Evolocumab Investigator’s Brochure for more information on evolocumab. 
2.3 
Rationale 
This 5-year open-label extension (OLE) study is being conducted to provide additional 
safety data on the long-term administration of evolocumab.  These additional safety data 
include the long-term effects of LDL-C < 40 mg/dL (< 1.03 mmol/L).  A total of 
approximately 5000 subjects will be enrolled.  Approximately 2000 subjects with 2 or 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20130295 
Date:  26 February 2020 
Page 17 of 77 
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more years of study exposure in FOURIER will be enrolled in this OLE to provide safety 
and tolerability for subjects with 7 years of total study exposure (from the start of 
FOURIER to completion of the OLE).  Assuming approximately 50% of these 
2000 subjects were on evolocumab in FOURIER, approximately 1000 subjects will have 
7 years of total evolocumab exposure.  Additionally, subjects participating in the 
EBBINGHAUS study (Study 20130385; a substudy of FOURIER) will be provided the 
opportunity to enroll in the OLE so that additional long-term assessments of cognitive 
function will be performed, using the CANTAB. 
The FOURIER OLE sites will be a subset of FOURIER sites.  The FOURIER OLE study 
population will comprise the following subject groups: 
a) subjects who have at least 2 years of study exposure in FOURIER 
b) subjects from EBBINGHAUS, regardless of study exposure 
c) subjects who have less than 2 years of study exposure in FOURIER and did not 
participate in EBBINGHAUS 
Enrollment of eligible subjects may be limited at the site level, to maintain a 1:1 ratio 
between subject groups “a” and “c” (ie, subjects who have ≥ 2 years of study exposure in 
FOURIER and subjects who have less than 2 years of study exposure in FOURIER and 
did not participate in EBBINGHAUS) or to manage overall recruitment into the OLE. 
2.4 
Clinical Hypotheses 
The primary clinical hypothesis is that long-term exposure of evolocumab will be safe 
and well tolerated in subjects with clinically evident atherosclerotic CVD. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a multicenter, open-label extension study designed to assess the long-term 
safety of evolocumab in subjects who completed the FOURIER study, a randomized 
placebo-controlled study of evolocumab in subjects with clinically evident atherosclerotic 
CVD on stable effective statin therapy.  Eligible subjects at sites participating in 
FOURIER OLE who have signed the FOURIER OLE informed consent may be enrolled 
at the completion of FOURIER.  Enrollment of eligible subjects may be limited at the site 
level to maintain a 1:1 ratio between the following subject populations: 
• 
subjects with ≥ 2 years of study exposure in FOURIER and 
• 
subjects who have less than 2 years of study exposure in FOURIER and did not 
participate in EBBINGHAUS 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20130295 
Date:  26 February 2020 
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In this study, laboratory assessments will be performed at week 12 and thereafter 
approximately every 24 weeks from day 1 (see Section 7.2); the corresponding blood 
samples will be processed using a central laboratory.  To preserve the integrity of 
FOURIER blinding, no local lipid assessments may be performed until either FOURIER 
is unblinded or at least 12 weeks after a subject’s last administration of FOURIER 
investigational product (evolocumab or placebo), whichever is first.  Upon enrollment in 
this study (FOURIER OLE), subjects will receive evolocumab 140 mg every 2 weeks 
(Q2W) or 420 mg monthly (QM), according to their preference.  Frequency and 
corresponding dose of administration can be changed at any scheduled time point where 
evolocumab is supplied to the subject, provided the appropriate supply is available.  It is 
recommended that subjects continue the same background LLT, including statin, as 
taken during FOURIER.  This study will continue for 260 weeks (approximately 5 years).  
Subjects ending administration of evolocumab should continue study assessments until 
the end of study (EOS). 
All subjects will be followed and complete procedures/assessments from enrollment 
through the date of study termination unless the subject has withdrawn consent, 
irrespective of whether the subject is continuing to receive treatment.  All deaths and 
cardiovascular events of interest (MI, stroke, coronary revascularization, hospitalization 
for unstable angina, hospitalization for heart failure, and transient ischemic attack [TIA]) 
will be reviewed by an independent external Clinical Events Committee (CEC), using 
standardized definitions. 
The overall study design is described by a study schema at the end of the 
protocol synopsis section. 
The study endpoints are defined in Section 10.1.1. 
3.2 
Number of Sites 
Approximately 250 centers will participate in this study in North America and Eastern 
Europe.  Sites that do not enroll subjects within 3 to 6 months of site initiation may be 
closed. 
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects.”  Approximately 
5000 subjects will be enrolled, including approximately 2000 subjects with ≥ 2 years of 
study exposure in FOURIER. 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20130295 
Date:  26 February 2020 
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3.4 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
The study will continue for 260 weeks (approximately 5 years). 
3.5.2 
End of Study 
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), whether the study concluded as planned in the protocol or was 
terminated early. 
The primary completion date is the date when the last subject has completed the 
assessments for EOS/safety follow-up. 
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). 
End of Study:  The end of study date is 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, safety follow-up), as applicable. 
4. 
SUBJECT ELIGIBILITY 
4.1 
Inclusion and Exclusion Criteria 
4.1.1 
Inclusion Criteria 
101 
Subject has provided informed consent before initiation of any study-specific 
activities/procedures. 
102 
Subject has completed FOURIER (Study 20110118) while still receiving assigned 
investigational product. 
4.1.2 
Exclusion Criteria 
201 
Investigational product was permanently discontinued during FOURIER for any 
reason, including an adverse event or serious adverse event. 
202 
Subject is currently receiving treatment in another investigational device or drug 
study, or ended treatment on another investigational device or drug study(ies) 
within less than 4 weeks.  Other investigational procedures while participating in 
this study are excluded. 
203 
Subject is not likely to be available to complete protocol-required study visits or 
procedures and/or to comply with required study procedures to the best of the 
subject’s and investigator's knowledge. 
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Date:  26 February 2020 
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204 
Subject has a history or evidence of any other clinically significant disorder, 
condition, or disease that, in the opinion of the investigator or Amgen physician, if 
consulted, would pose a risk to subject safety or interfere with the study 
evaluation, procedures, or completion. 
205 
Subject has a known sensitivity to any of the active substances or excipients 
(eg, sodium acetate) to be administered during dosing. 
206 
Female subject is pregnant or breastfeeding or is planning to become pregnant 
or planning to breastfeed during treatment with evolocumab and within 15 weeks 
after the end of treatment with evolocumab. 
207 
Female subjects of childbearing potential who are not willing to use an 
acceptable method(s) of effective birth control during treatment with evolocumab 
and for an additional 15 weeks after the end of treatment with evolocumab are 
excluded. 
 
Female subjects of non-childbearing potential are not required to use 
contraception during the study and include those who have had a hysterectomy, 
bilateral salpingectomy, bilateral oophorectomy, or who are postmenopausal.  
Postmenopausal is defined as 12 months of spontaneous and continuous 
amenorrhea in a woman ≥ 55 years old; or age < 55 years but no spontaneous 
menses for at least 2 years; or age < 55 years and spontaneous menses within 
the past 1 year, but currently amenorrheic (eg, spontaneous or secondary to 
hysterectomy), and with postmenopausal gonadotropin levels (luteinizing 
hormone and follicle-stimulating hormone [FSH] levels > 40 IU/L), 
postmenopausal estradiol levels (< 5 ng/dL), or according to the definition of 
postmenopausal range for the laboratory involved. 
 
Acceptable methods of effective birth control include true sexual abstinence 
(when this is in line with the preferred and usual lifestyle of the subject; periodic 
abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], 
declaration of abstinence for the duration of a trial, and withdrawal are not 
acceptable methods of contraception), bilateral tubal ligation/occlusion, 
vasectomized partner (provided the vasectomized male has received medical 
assessment of surgical success), use of hormonal birth control methods (oral, 
intravaginal, transdermal, injectable, or implantable), intrauterine devices, 
intrauterine hormonal releasing system, or 2 barrier methods (each partner must 
use one barrier method) and the female partner must use spermicide in addition 
to a barrier method (men must use a condom; women must choose either a 
diaphragm, cervical cap, or contraceptive sponge [a female condom is not an 
option because of  the risk of tearing when both partners use a condom]).  If 
spermicide is not commercially available in the country or region, the 2-barrier 
method without spermicide is acceptable.  Note:  Additional medications given 
during treatment with evolocumab may alter the contraceptive requirements.  
These additional medications may require the use of highly effective methods of 
contraception, an increase in the number of contraceptive methods, a change in 
type of contraceptive methods, and/or an increase in the length of time that 
contraception is to be utilized or length of time that breastfeeding is to be 
avoided.  The investigator is to discuss these contraceptive changes with the 
study subject. 
Approved 
 
 

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5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form (ICF), and all other 
subject information and/or recruitment material, if applicable (see Section 11.2).  All 
subjects must personally sign and date the IRB/IEC- and Amgen-approved ICF before 
commencement of study-specific activities/procedures. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and on the enrollment electronic case report form (eCRF). 
Each subject who signs the IRB/IEC-approved ICF is to be assigned the same subject 
identification number for this OLE study as the parent study (FOURIER) before any 
study procedures are performed.  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. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed. 
5.1 
Treatment Assignment 
All subjects will receive open-label evolocumab. 
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Products and/or Medical Devices 
The Amgen investigational medicinal product used in this study is evolocumab 
(AMG 145).  In several countries, investigational product is referred to as investigational 
medicinal product.  In this document, investigational medicinal product will be referred to 
as investigational product (evolocumab). 
The non-Amgen non-investigational products used in this study include background 
LLTs, including a statin. 
Evolocumab will be provided by prefilled autoinjector/pen (AI/Pen) or personal injector 
(PI). 
Note:  Ancillary devices (ie, medical devices not under study) are described in 
Section 6.6. 
Approved 
 
 

Product:  Evolocumab 
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The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of evolocumab and information about background LLT and the 
investigational medical devices used in this study. 
6.2 
Investigational Product - Evolocumab 
Evolocumab (AMG 145) will be manufactured and packaged by Amgen Inc. and 
distributed using Amgen clinical investigational product distribution procedures.  
Evolocumab will be provided as follows: 
• 
an AI/Pen, as a single-use, disposable, handheld mechanical (spring-based) device 
for fixed dose, subcutaneous (SC) injection of a 1.0-mL deliverable volume of 
140 mg/mL evolocumab 
• 
a PI, as a single-use, disposable, on-body electromechanical injection device that is 
copackaged with a prefilled Crystal Zenith cartridge containing a 3.5-mL deliverable 
volume of 120 mg/mL evolocumab 
Evolocumab 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 instructions for use 
(IFU) for the prefilled AI/Pen or PI. 
The prefilled AI/Pen or PI 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 prefilled AI/Pen or PI should be reported to Amgen.  Further 
details are provided in the IPIM and IFU. 
Evolocumab will be supplied to the subject at the site.  The method of resupply will be 
determined based on local regulations as well as available infrastructure.  The 
investigator may be required to record the box number of evolocumab (prefilled AI/Pen 
or PI) on the subject’s Drug Administration eCRF.  Subjects should return used 
evolocumab for reconciliation by the site. 
6.2.1 
Dosage, Administration, and Schedule 
Evolocumab will be administered SC for approximately 260 weeks in accordance with 
the instructions in the IPIM and IFU.  The subject (or designee, if not a qualified 
healthcare professional) must have demonstrated competency at administration of SC 
injections before self-administration is permitted.  The first self-administered dose by the 
subject (or designee, if not a healthcare professional) may be administered at the site 
under the supervision of a healthcare provider at day 1.  In this study, evolocumab will 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20130295 
Date:  26 February 2020 
Page 23 of 77 
CONFIDENTIAL 
 
 
be administered by self-administration by the subject, designee, or a qualified healthcare 
professional in a non-investigator site setting (eg, at home).  In exceptional 
circumstances, SC administration of evolocumab by a qualified healthcare professional 
in a clinic setting will also be allowed. 
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 eCRF. 
When evolocumab is administered at a non-investigator site location, 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 eCRF. 
It is suggested that the evolocumab administration is done by the subject under site staff 
supervision at each of the regular study visits to ensure continued proper use of the 
injection device.  Evolocumab administration at a scheduled visit, if applicable, is to be 
performed after completion of the blood draws and vital signs. 
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. 
Subjects will have the opportunity to switch between evolocumab Q2W and QM at any 
scheduled time point where evolocumab is supplied to the subject, provided the 
appropriate supply is available.  The first self-administration after switching the dose and 
frequency (140 mg Q2W to 420 mg QM or vice versa) should be done at a regularly 
scheduled visit under the supervision of the investigator or qualified study center staff.  
Subjects who choose QM treatment will initiate treatment using the PI, provided the 
appropriate supply is available.  If the PI is not available, then the AI/Pen may be used. 
If a subject dose of evolocumab is missed, administration should occur as soon as 
possible if there are more than 7 days until the next scheduled dose.  If there are less 
than 7 days before the next scheduled dose, the missed dose should be omitted, and 
the next dose should be administered according to the original schedule. 
Evolocumab will be administered either at 140 mg in 1.0 mL (1 administration by prefilled 
AI/Pen) Q2W or at 420 mg in 3.0 mL or 3.5 mL (3 administrations by prefilled AI/Pen or 
1 administration by PI, respectively) QM.  The 3 injections for the QM administration, if 
applicable, can be administered into different injection sites.  The SC injections should 
be administered in a consecutive fashion with all injections completed within 30 minutes. 
Approved 
 
 

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6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
No dose adjustments of evolocumab will be allowed in this study. 
If, in the opinion of the investigator, a subject is unable to tolerate evolocumab, that 
subject will discontinue evolocumab but should continue to return for all other study 
procedures and measurements until the EOS. 
The decision to rechallenge the subject after therapy changes should be discussed and 
agreed unanimously by the subject, investigator, and Amgen.  If signs or symptoms 
recur with rechallenge of evolocumab, then evolocumab should be permanently 
discontinued. 
Stopping and rechallenge rules due to hepatotoxicity are provided in Section 6.4. 
6.3 
Non-Amgen Non-investigational Products - Background 
Lipid-lowering Therapy 
Non-Amgen non-investigational products, including background LLT, will also be used in 
this study.  Additional details regarding the products are provided in the IPIM. 
6.3.1 
Dosage, Administration, and Schedule 
It is recommended that subjects continue the same background LLT, including statin, as 
taken while in FOURIER (Study 20110118).  All background LLT adjustments must be 
clearly documented and recorded on the appropriate eCRF page and in the source 
documents.  The dose, start date/time, stop date/time, and frequency of non-Amgen 
non-investigational product are to be recorded on each subject’s eCRF.  Background 
LLT will not be provided by Amgen unless required by local regulations.  
Recommendations for background LLT are provided in Appendix D. 
All other drugs that are allowed per protocol and that are prescribed for the subject must 
be commercially available and used at dosages approved by local regulatory authorities.  
These therapies will not be provided or reimbursed by Amgen (except if required by local 
regulation). 
Subjects should consult the investigator if they miss a dose of background statin. 
6.3.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
The investigator should consult the local product label for information on dose 
adjustments, delays, withholding, restarting, or permanent discontinuation of background 
LLT, including statins. 
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If a subject has elevated ad hoc laboratory values (Section 6.4) and is receiving 
background LLT, including statins, that may result in such elevations (eg, ezetimibe, 
fenofibrate, or niacin), the additional therapies should be evaluated for a potential role in 
the elevated laboratory values and considered for discontinuation.  If a subject has 
elevations in triglycerides > 500 mg/dL (5.65 mmol/L) and is concomitantly receiving a 
bile acid binding resin, the bile acid binding resin should be evaluated for 
discontinuation. 
The decision to rechallenge the subject after therapy changes should be discussed and 
agreed unanimously by the subject, investigator, and Amgen.  If signs or symptoms 
recur with rechallenge of statin background therapy, the statin may be substituted by 
another statin in consultation with the Amgen medical monitor, if possible, or the statin 
therapy may be discontinued.  If signs or symptoms recur with rechallenge of other 
applicable lipid background therapy, this therapy may be discontinued. 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or signs/symptoms of hepatitis (as described below) may meet the criteria for 
withholding or permanent discontinuation of evolocumab, statins, and other applicable 
lipid background therapies as specified in the Guidance for Industry Drug-induced Liver 
Injury:  Premarketing Clinical Evaluation (July 2009).  Hepatic laboratory assessments 
are not required for this study.  However, the following guidelines apply for elevations 
noted during ad hoc tests. 
6.4.1 
Criteria for Permanent Discontinuation of Amgen Investigational 
Product and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity 
Amgen investigational product (evolocumab), statins, and other applicable lipid 
background therapies should be discontinued permanently and the subject should be 
followed according to the recommendations in Appendix A (Additional Safety 
Assessment Information) for possible drug-induced liver injury (DILI), if ALL of the 
criteria below are met: 
• 
TBL ≥ 2 x ULN 
• 
AND increased AST or ALT > 3 x ULN if baseline values were less than the ULN 
• 
AND ALP < 2 x ULN 
• 
AND no other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT and/or 
TBL values include, but are not limited to: 
− 
hepatobiliary tract disease 
Approved 
 
 

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− 
viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus, cytomegalovirus, 
herpes simplex virus, varicella, toxoplasmosis, and parvovirus) 
− 
right-sided heart failure, hypotension, or any cause of hypoxia to the liver causing 
ischemia 
− 
exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants, and mushrooms 
− 
heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation 
(eg, indinavir, atazanavir) 
− 
alpha-one antitrypsin deficiency 
− 
alcoholic hepatitis 
− 
autoimmune hepatitis 
− 
Wilson’s disease and hemochromatosis 
− 
nonalcoholic fatty liver disease, including steatohepatitis 
− 
nonhepatic causes (eg, rhabdomyolysis, hemolysis) 
6.4.2 
Criteria for Conditional Withholding of Amgen Investigational 
Product and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity 
For subjects who do not meet the criteria for permanent discontinuation of evolocumab 
outlined above and have no underlying liver disease, the following rules are 
recommended for withholding of evolocumab, statins, and other applicable lipid 
background therapies: 
• 
elevation of either AST or ALT according to the following: 
− 
> 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 
(eg, right upper quadrant pain/tenderness, fever, nausea, vomiting, jaundice) 
• 
OR TBL > 3 x ULN at any time 
• 
OR ALP > 8 x ULN at any time 
Evolocumab, statins, and other applicable lipid background therapies should be withheld 
pending investigation into alternative causes of DILI.  If evolocumab is withheld, the 
subject is to be followed according to recommendations in Appendix A for possible DILI.  
Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL is discovered and the laboratory abnormalities resolve 
to normal or baseline (Section 6.4.3). 
Approved 
 
 

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6.4.3 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then evolocumab, statins, and other 
applicable lipid background therapies should be permanently discontinued.  Subjects 
who clearly meet the criteria for permanent discontinuation (as described in 
Section 6.4.1) should never be rechallenged. 
6.5 
Concomitant Therapy 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.8. 
Targeted concomitant therapy and medications will be recorded on the eCRF.  The 
following groups of concomitant medications will be recorded: 
• 
cardiovascular medications 
• 
analgesics/antipyretics 
• 
anticoagulants/antiplatelets 
• 
antibiotics 
• 
antidepressants 
• 
vitamins 
• 
hormone replacement therapy 
• 
oral corticosteroids 
For antibiotics, the therapy name, indication for use, class of medication, date first taken, 
and route of administration will be collected.  For other targeted concomitant 
medications, the investigator, or designee, should record whether the therapy was being 
taken at the time points indicated in the schedule of assessments (Table 1).  
Concomitant therapies are to be collected from informed consent through the end of 
safety follow-up period. 
For concomitant therapy being taken to treat an event, collect therapy name, indication, 
dose, unit, frequency, start date, and stop date. 
Subjects should adhere to the National Cholesterol Education Program Adult Treatment 
Panel III therapeutic lifestyles changes diet or an equivalent diet.  Subjects will be 
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required to refrain from unaccustomed intensive exercise (eg, heavy lifting or long runs) 
48 hours prior to each visit. 
6.6 
Medical Devices 
Evolocumab will be provided by prefilled AI/Pen or PI (Section 6.2). 
Other medical devices, which are not considered test articles, may be used in the 
conduct of this study as part of standard care.  These devices that are commercially 
available are not usually provided or reimbursed by Amgen (except, for example, if 
required by local regulation).  The investigator will be responsible for obtaining supplies 
of these devices. 
6.7 
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 or devices 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 or devices provisioned and/or repackaged/modified by Amgen.  
Drug or devices includes evolocumab, AI/Pen, and PI. 
Any product complaint(s) associated with an investigational product (evolocumab) or 
devices supplied by Amgen are to be reported according to the instructions provided in 
the IPIM. 
6.8 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
Treatment with any investigational therapies other than study-provided evolocumab is 
not permitted during the study. 
Medications or foods that are known potent inhibitors of cytochrome P450 (CYP) 3A 
(eg, itraconazole, ketoconazole, and other antifungal azoles, macrolide antibiotics 
erythromycin, clarithromycin, and the ketolide antibiotic telithromycin, human 
immunodeficiency virus [HIV] or hepatitis C virus [HCV] protease inhibitors, 
antidepressant nefazodone, and grapefruit juice in large quantities [> 1 quart daily; 
approximately 1 L]) are not recommended during the study because of their potential 
impact on metabolism of certain statins (see Appendix E). 
If a subject is enrolled and subsequently requires a treatment that is not recommended 
based on their particular statin (eg, a strong CYP3A4 inhibitor in a subject on 
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atorvastatin), the treating physician should give consideration to using an equivalent 
concomitant drug, eg, a drug that does not inhibit CYP3A4 so that the subject can 
continue taking statin background therapy.  If this is not possible, it may be necessary to 
withdraw or change statin background therapy while the concomitant drug is required. 
There is no need to discontinue treatment with evolocumab should a subject require a 
nonrecommended drug (eg, a strong CYP3A4 inhibitor) since monoclonal antibody 
therapeutics are not metabolized through CYP and, thus, are unaffected by the use of 
CYP inhibitors. 
The use of antacids is not recommended within the period of 2 hours before and 2 hours 
after dosing with statins. 
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments 
Eligible subjects who have signed the ICF and meet the inclusion/exclusion criteria 
requirements for this FOURIER OLE study will be enrolled at the completion of the 
FOURIER study.  Subject identification numbers will be the same as those in FOURIER.  
Assessments done for the FOURIER/EBBINGHAUS (as applicable) EOS visit do not 
need to be repeated for this study, unless day 1 in this study (FOURIER OLE) occurs 
> 90 days after the FOURIER EOS visit.  Baseline data for participating subjects will be 
carried over from the FOURIER study. 
 
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Table 1.  Schedule of Assessments 
 
Treatment Period (± 14 days) 
Safety 
Follow-up 
Time Point 
Day 1a Wk12 Wk24 Wk48 
Wk72 
Wk96 
Wk120 
Wk144 
Wk168 
Wk192 
Wk216 
Wk240b Wk260 
EOSc 
GENERAL AND SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted concomitant therapy 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Device-related adverse effects 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disease-related events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
Xd 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital signse 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Body weight 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Coronary revascularization 
procedure and death 
informationf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NEUROCOGNITIVE ASSESSMENTS 
CANTAB SWM testg 
Xd 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
CANTAB PAL testg 
Xd 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
CANTAB RTI testg 
Xd 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
LABORATORY ASSESSMENTSh 
Fasting lipid panel 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
ApoA1, ApoB, Lp(a) 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Pregnancy testi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
FSHj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
DOSING 
Administration at study sitek 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Dispense/reconcile 
evolocumabl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Footnotes defined on next page of the table 
 
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ApoA1 = apolipoprotein A1; ApoB = apolipoprotein B; CANTAB = Cambridge Neuropsychological Test Automated Battery; eCRF = electronic case report form; 
EOS = end of study; FSH = follicle-stimulating hormone; Lp(a) = lipoprotein(a); PAL = Paired Associates Learning; Q2W = every 2 weeks; QM = monthly; 
RTI = Reaction Time; SWM = Spatial Working Memory; Wk = week 
Mandatory study visits will occur at week 12 and thereafter approximately every 24 weeks from day 1.  Resupply visits will be scheduled quarterly (every 12 weeks). 
a Day 1 is the day of first administration of evolocumab in this study (FOURIER open-label extension). 
b Subjects may be contacted by telephone at week 240. 
c Subject will be contacted by phone at least 30 days (+ 3 days) after last evolocumab administration, unless they are continuing their participation in the study after 
ending evolocumab prior to study completion. 
d FOURIER/EBBINGHAUS (as applicable) EOS assessments should not be duplicated, except when day 1 occurs > 90 days after the FOURIER EOS visit. 
e Vital signs include sitting blood pressure and heart rate. 
f  Coronary revascularization procedure and death information for cardiovascular events of interests must be collected in the eCRF.  Sites will be prompted 
for this information when necessary. 
g CANTAB assessments will only be performed in subjects from the EBBINGHAUS study.  In addition to the scheduled assessments, all CANTAB assessments should 
be performed if a subject from the EBBINGHAUS study reports a neurocognitive adverse event.  Assessment should be conducted at appropriate time after the 
subject has been allowed to eat and drink. 
h To preserve the integrity of FOURIER blinding and database locking, no local lipid assessments may be performed until either FOURIER is unblinded or at least 
12 weeks after the subject’s last administration of FOURIER investigational product (evolocumab or placebo), whichever is earlier.  Subjects must be fasting for 
≥ 9 hours before each study visit where fasting lipid samples are obtained.  Blood samples for these assessments will be processed at a central laboratory.  
Additional laboratory assessments that may be deemed necessary to evaluate (serious) adverse events will be processed locally. 
i Serum (or urine) pregnancy test will be performed in women of childbearing potential only.  Additional on-treatment pregnancy testing may be performed at the 
investigator’s discretion or per local regulatory requirements. 
j Only if needed to establish postmenopausal status (see Exclusion Criterion 207). 
k Administration at the study site is recommended if the study visit is within the dosing schedule for the subject. 
l Evolocumab will be supplied to the subject at the site.  Subjects will administer evolocumab on a Q2W or QM schedule and will have the opportunity to switch 
between Q2W and QM at any scheduled time point when evolocumab is supplied to the subject, provided the appropriate supply is available.  Subjects should 
continue evolocumab for the entire 260-week treatment period.  The first self-administration after switching the device should be done at a regularly 
scheduled visit under the supervision of the investigator or qualified study center staff. 
 
 
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7.2 
General Study Procedures 
Mandatory study visits will occur at week 12 and thereafter approximately every 
24 weeks from day 1.  Evolocumab resupply visits will be scheduled quarterly (every 
12 weeks).  Evolocumab will be supplied to the subject at the site.  The method of 
resupply will be determined based on local regulations as well as available 
infrastructure.  Assessments and procedures will be conducted per the schedule of 
assessments (Table 1) and include vital signs; physical examinations; body weight; 
assessment of targeted concomitant therapy, adverse events, device-related adverse 
effects, serious adverse events, and disease-related events; CANTAB assessments 
(only in subjects from EBBINGHAUS); laboratory assessments, including fasting lipid 
panel, ApoA1, ApoB, and Lp(a); serum (or urine) pregnancy testing (women of 
childbearing potential); and evolocumab administration. 
Time gaps between the completion of FOURIER and day 1 of this OLE study should be 
minimized.  It is recommended that the day 1 FOURIER OLE visit occurs on the same 
day as the FOURIER EOS visit.  If this is not possible (eg, last evolocumab dose in 
FOURIER is less than 7 days from the first dose in this study), the day 1 visit should 
occur no later than 90 days after the FOURIER EOS visit.  All on-study visits and dosing 
should be scheduled from FOURIER OLE study day 1 (day of first administration of 
evolocumab in this study).  When it is not possible to perform the study visit at the 
specified time point, the visit should be performed within the visit window in the schedule 
of assessments (Table 1).  If a study visit is missed or late, including visits outside the 
visit window, subsequent visits should resume on the original visit schedule.  Missed 
assessments at prior visits should not be duplicated at subsequent visits.  If possible, all 
study procedures for a visit should be completed on the same day. 
It is the responsibility of the investigator to ensure that all procedures are performed 
according to the protocol.  Written informed consent must be obtained and will be 
implemented before protocol-specific procedures are performed.  The risks and benefits 
of participating in the study will be verbally explained to each potential subject before 
entering into the study.  The procedures to be performed at each study visit are 
described below and the timing of the procedures is provided in the schedule of 
assessments (Table 1).  If performed at the site, evolocumab administration must be 
after completion of blood draw and vital sign procedures. 
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The investigator should instruct the subject to report to the site (eg, telephone call) any 
adverse events, device-related adverse effects, serious adverse events, or 
disease-related events at any time (ie, between scheduled visits). 
Laboratory Assessments 
Subjects must be fasting for ≥ 9 hours before each study visit where fasting lipid 
samples are obtained.  To preserve the integrity of FOURIER blinding and database 
locking, no local lipid assessments may be performed until either FOURIER is unblinded 
or at least 12 weeks after the subject’s last administration of FOURIER investigational 
product (evolocumab or placebo), whichever is earlier.  On-study laboratory samples will 
be analyzed using a central laboratory.  Additional laboratory assessments that may be 
deemed necessary to evaluate (serious) adverse events will be processed locally. 
The following laboratory assessments will be performed at the time points listed in the 
schedule of assessments (Table 1): 
• 
fasting lipid panel: 
− 
total cholesterol 
− 
triglycerides 
− 
LDL-C 
− 
HDL-C 
− 
VLDL-C 
− 
non-HDL-C 
• 
ApoA1 
• 
ApoB 
• 
Lp(a) 
• 
serum or urine pregnancy test (women of childbearing potential only) 
• 
FSH (if needed [see Exclusion Criterion 207]) 
Vital Signs 
Use of an automated oscillometric device for blood pressure measurement is preferred 
and recommended.  Blood pressure should be recorded using the same arm as in 
FOURIER.  The appropriate size cuff should be used.  Blood pressure and heart rate 
measurements will be determined after the subject has been seated for at least 
5 minutes.  The subject’s pulse should be measured for 30 seconds and the number 
multiplied by 2 to obtain heart rate. 
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Coronary Revascularization Procedure and Death Information 
Coronary revascularization procedure and death information for cardiovascular 
events of interests must be collected in the eCRF that occur after signing the ICF 
through the EOS/Safety Follow-Up visit for this study, or 30 days (+ 3 days) after 
the last administration of evolocumab, whichever is later.  Sites will be prompted 
for this information when necessary. 
7.2.1 
Enrollment and Baseline Procedures (Day 1) 
Subjects who sign the ICF and meet eligibility criteria will be enrolled.  Day 1, defined as 
the day of the first administration of evolocumab in this study, should occur on the same 
day as the FOURIER EOS visit.  If this is not possible, subjects will return to the study 
site for day 1 procedures while continuing their background LLT. 
Enrollment will be managed at a site level to allow the following subjects to enroll if 
eligibility criteria are met: 
a) subjects who have at least 2 years of study exposure in FOURIER 
b) subjects from EBBINGHAUS, regardless of study exposure 
c) subjects who have less than 2 years of study exposure in FOURIER and did not 
participate in EBBINGHAUS 
Enrollment of eligible subjects may be limited at the site level, to maintain a 1:1 ratio 
between subject groups “a” and “c” (ie, subjects who have ≥ 2 years of study exposure in 
FOURIER and subjects who have less than 2 years of study exposure in FOURIER and 
did not participate in EBBINGHAUS) or to manage overall recruitment into the OLE. 
Ongoing adverse events from the end of the parent study (FOURIER), whether they 
have resolved or not at the time of signing the informed consent for the OLE (now 
classified as medical history), will be collected in the relevant medical history eCRF 
page.  Medical history from prior to the date of enrollment into the parent study will not 
be collected in the OLE with the exception of heterozygous familial hypercholesterolemia 
(HeFH) diagnostic evidence.  Any medical history on local diagnoses of HeFH 
(ie, criteria outlined by the Simon Broome Register Group [Scientific Steering 
Committee, 1991], the Dutch Lipid Clinic Network [World Health Organization, 1999], 
MEDPED [Williams et al, 1993]) or confirmed by genotyping, will be collected.  
Demographic data (except age) will be carried over from the parent study.  Demographic 
data, including sex, age, race, and ethnicity, may be used to study their possible 
association with subject safety and treatment effectiveness. 
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The following procedures are to be completed during day 1; however, assessments 
performed at the FOURIER/EBBINGHAUS (as applicable) EOS visit should not be 
repeated unless day 1 is > 90 days after the FOURIER EOS visit.  If administered at the 
site, evolocumab is to be administered after completion of the blood draws and vital 
signs. 
• 
confirmation that the ICF has been signed 
• 
review of targeted concomitant therapy 
• 
review of adverse events, serious adverse events, device-related adverse effects, 
and disease-related events.  Any events that occurred between FOURIER EOS and 
day 1, if applicable, will be recorded on the Event eCRF. 
• 
physical examination 
• 
vital signs (sitting blood pressure and heart rate) 
• 
body weight 
• 
coronary revascularization procedure and death information (sites will be 
prompted for this information when necessary) 
• 
CANTAB SWM, PAL, and RTI tests (subjects who participated in the EBBINGHAUS 
study only) 
• 
blood draws for fasting lipids (≥ 9-hour fasting sample), ApoA1, ApoB, Lp(a), and 
FSH (only if required to ensure menopause [see Exclusion Criterion 207]) 
• 
blood draw or urine sample for a serum or urine pregnancy test (women of 
childbearing potential only) 
• 
administration of evolocumab at study site (see Section 6.2.1 for instruction and 
supervision of subjects), if applicable 
• 
dispensing evolocumab (prefilled AI/Pens or PIs), if applicable 
7.2.2 
Treatment 
The following procedures will be completed during the 5-year (260-week) treatment 
period at the times designated in the schedule of assessments (Table 1).  If 
administered at the site, evolocumab is to be administered after completion of the blood 
draws and vital signs. 
• 
review of targeted concomitant therapy 
• 
review of adverse events, serious adverse events, device-related adverse effects, 
and disease-related events 
• 
vital signs (sitting blood pressure and heart rate) 
• 
body weight 
• 
coronary revascularization procedure and death information (sites will be 
prompted for this information when necessary) 
• 
CANTAB SWM, PAL, and RTI tests (subjects who participated in the EBBINGHAUS 
study only) 
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• 
blood draws for fasting lipids (≥ 9-hour fasting sample), ApoA1, ApoB, and Lp(a) 
• 
blood draw or urine sample for a serum or urine pregnancy test (women of 
childbearing potential only) 
• 
administration of evolocumab at study site (see Section 6.2.1 for instruction and 
supervision of subjects), if applicable 
• 
reconciliation of used evolocumab, and dispensing evolocumab (prefilled AI/Pens or 
PIs), if applicable 
The investigator should instruct the subject to report to the site (eg, by telephone call) 
any adverse events, device-related adverse effects, serious adverse events, or 
disease-related events at any time (ie, between scheduled visits).  In addition, subjects 
will be contacted by telephone as designated in the schedule of assessments (Table 1) 
for collection of adverse events, device-related adverse effects, serious adverse events, 
or disease-related events. 
In addition to the time points listed in the schedule of assessments (Table 1), all 
CANTAB assessments should be performed if a subject from the EBBINGHAUS study 
reports a neurocognitive adverse event. 
If, in the opinion of the investigator, a subject is unable to tolerate evolocumab, that 
subject will discontinue evolocumab but will continue to return for all other study 
procedures and measurements until the EOS. 
If a subject withdraws from the study early, investigators should make every effort to 
complete and report the observations as thoroughly as possible up to the date of 
withdrawal.  If possible, the end of investigational product administration procedures 
should be completed at the time of withdrawal. 
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 
of death should be obtained and reported. 
7.2.3 
Safety Follow-up/End of Study Visit 
The safety follow-up/EOS visit is to be scheduled at least 30 days (+ 3 days) after the 
last dose of evolocumab, unless they are continuing their participation in the study after 
ending evolocumab prior to study completion.  This safety follow-up will be done by 
phone.  The following procedures are to be completed during the EOS visit: 
• 
review of targeted concomitant therapy 
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• 
review of adverse events, serious adverse events, device-related adverse effects, 
and disease-related effects 
• 
coronary revascularization procedure and death information (sites will be 
prompted for this information when necessary) 
7.3 
Cambridge Neuropsychological Test Automated Battery Tests 
The CANTAB is a computer-based cognitive assessment system consisting of a battery 
of neuropsychological tests, administered to subjects who participated in EBBINGHAUS 
(Study 20130385) using a touch screen computer.  The following 3 tests will be 
completed: 
• 
SWM 
• 
PAL 
• 
RTI 
These 3 tests assess the key cognitive domains of working memory/executive function, 
episodic memory, and psychomotor speed/attention.  Completion of this test battery will 
take approximately 25 minutes at each time point. 
The CANTAB platform has been used in interventional clinical studies to test (and 
demonstrate) both cognitive impairment and enhancement (Attwood et al, 2007; 
Elliott et al, 1997; Greig et al, 2005; Harmer et al, 2001; Jäkälä et al, 1999; Rusted and 
Warburton, 1988; Ryan et al, 2006) and was used in the EBBINGHAUS study.  The 
subtests of the CANTAB selected for this study have established sensitivity to cognitive 
dysfunction in amnestic clinical syndromes such as mild cognitive impairment and 
Alzheimer’s disease (Egerhazi et al, 2007) and have also been used to demonstrate 
cognitive safety for drug therapy (eg, Kollins et al, 2011). 
The results of the cognitive tests will not be communicated to the investigator. 
Additional information about the CANTAB SWM, PAL, and RTI tests administered in this 
study is provided in Appendix F. 
7.3.1 
Spatial Working Memory 
The SWM test assesses the subject’s ability to retain spatial information and manipulate 
it in working memory.  This test of working memory and executive function is particularly 
sensitive to dorsolateral prefrontal cortical functioning.  It is a self-ordered task that also 
measures strategy and is sensitive to frontal lobe and executive dysfunction 
(Manes et al, 2002; Owen et al, 1996; Owen et al, 1990).  A number of colored boxes 
are presented on the screen, and the computer hides a token in these boxes one at a 
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time.  The subject is instructed to touch the boxes in turn to search for the token that has 
been hidden.  When a token is found it should be placed in a home area on the right side 
of the screen.  The subject then searches for more tokens until the same number of 
tokens as the number of colored boxes has been found.  The key task instruction is that 
the computer will never hide a token in the same box twice in the same problem.  As the 
test progresses, the task becomes more difficult, up to a maximum of 8 boxes. 
Exploratory endpoints of the study are the SWM strategy index of executive function and 
SWM between-errors score.  An efficient strategy for completing the task is to follow a 
planned search sequence, beginning with a specific box and then returning to start each 
new search sequence with that same box as soon as a token has been found.  The 
strategy score represents the number of times a subject begins a search with a different 
box, with a high score representing an inefficient use of strategy and planning and a low 
score representing an efficient use of strategy (Owen et al, 1990).  The between-errors 
score is the number of times that the subject revisited a box in which a token had 
previously been found.  A lower score indicates better performance. 
7.3.2 
Paired Associates Learning 
The PAL test assesses visuospatial episodic memory.  This test is particularly sensitive 
to changes in medial temporal lobe functioning.  Boxes are displayed on the screen and 
open in turn to reveal a number of patterns.  Subjects are instructed to try to remember 
the location in which each pattern was shown.  After all the boxes have been opened, 
each pattern is then shown in the center of the screen in a randomized order, and the 
subject touches the box in which the pattern was located.  If an error is made, the 
patterns are presented again to remind the subject of their locations.  As the test 
progresses, the stages become more difficult as the number of patterns to be 
remembered increases, up to a maximum of 8 patterns.  For subjects who fail to 
complete all levels, an adjusted score is calculated that allows for errors predicted in the 
stages that were not attempted. 
The exploratory endpoint of PAL total errors adjusted is comprised of the number of 
errors committed by the subject plus an adjustment for the estimated number of errors 
he/she would have made on any stages that were not reached.  A lower score indicates 
better performance. 
7.3.3 
Reaction Time 
The RTI test assesses psychomotor speed and attention.  The RTI test is a direct 
analogue of the rodent 5-choice serial reaction time test, one of the best studied 
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behavioral paradigms.  In humans, the CANTAB RTI test has been extensively studied 
and shows differential sensitivity to pharmacological manipulation and to clinical 
impairment associated with a range of conditions, including mild cognitive impairment 
and Alzheimer’s disease.  The subject holds down a button until a spot appears in 1 of 
5 circles on the screen.  As soon as possible after the spot flashes, the subject lifts 
his/her finger from the button and touches the circle in which the spot appeared. 
The exploratory endpoint of RTI median 5-choice reaction time is the median duration 
between the onset of the stimulus and the release of the button.  A lower score indicates 
better performance. 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects can decline to continue receiving evolocumab 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 evolocumab or other protocol-required therapies and 
must discuss with the subject the possibilities for continuation of the schedule of 
assessments (Table 1) and collection of data, including endpoints and adverse events 
and must document this decision in the subject’s medical records.  The investigator must 
discuss the different options of follow-up (eg, in person, by telephone/mail, through 
family/friends, in correspondence/communication with other treating physicians, from 
review of the medical records or public records as permitted by applicable law).  Such 
public record searches may be conducted by the site or vendors approved by the site.  
Subjects who have discontinued evolocumab 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. 
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publically available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study. 
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8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from evolocumab 
and/or other protocol-required therapies, protocol procedures, or the study as a whole at 
any time prior to study completion. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 12.1. 
8.3 
Reasons for Removal From Treatment or Study 
8.3.1 
Reasons for Removal From Treatment 
Reasons for removal from protocol-required investigational product (evolocumab) or 
procedural assessments include any of the following: 
• 
subject request 
• 
safety concern (eg, due to an adverse event, protocol deviation, non-compliance, 
requirement for alternative therapy, protocol-specified criteria [see Section 6.2.2], 
pregnancy) 
• 
decision by sponsor (other than subject request, safety concern, lost to follow-up) 
• 
death 
• 
lost to follow-up 
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
• 
decision by sponsor 
• 
withdrawal of consent from study 
• 
death 
• 
lost to follow-up 
8.4 
Lost to Follow-up 
A subject will be considered lost to follow-up at the end of the study if he or she 
repeatedly fails to return for scheduled visits and is unable to be contacted by the study 
site. 
The site must attempt to contact the subject at each scheduled visit 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 
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to and/or is able to continue in the study.  These contact attempts are to be documented 
in the subject’s medical record. 
For subjects who are lost to follow-up, the investigator (or vendors approved by the site) 
can search publicly available records as permitted by applicable law to ascertain survival 
status.  This ensures that the data set(s) produced as an outcome of the study is/are as 
comprehensive as possible. 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
Disease-related Events 
Disease-related events are events (serious or nonserious) anticipated to occur in the 
study population due to the underlying disease.  All serious disease-related events 
will be recorded and reported to the sponsor or designee within 24 hours.  In this 
study, subjects have hyperlipidemia and clinically evident atherosclerotic CVD.  
Therefore, disease-related events include the following:  manifestations and 
complications of atherosclerotic vascular disease such as coronary artery disease, 
angina, myocardial infarction, ischemic stroke, TIA, carotid artery disease, peripheral 
vascular disease (including complications such as claudication), and testing suggesting 
progression of atherosclerotic vascular disease.  Such events do not meet the definition 
of an adverse event unless assessed to be more severe than expected for the subject’s 
condition. 
Disease-related events and/or disease-related outcomes that do not qualify as serious 
adverse events include: 
• 
An event which is part of the normal course of disease under study (eg, disease 
progression in oncology or hospitalization due to disease progression) is to be 
reported as a disease-related event. 
• 
Death due to the disease under study is to be recorded on the Event eCRF. 
If the outcome of the underlying disease is worse than that which would normally be 
expected for the subject, or if the investigator believes there is a causal relationship 
between the investigational product (evolocumab)/protocol required-therapies and 
disease worsening, this must be reported as an adverse event or serious adverse event. 
9.1.2 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
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The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record. 
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease 
(eg, diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected, and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study or involves 
an intervention such as elective cosmetic surgery or a medical procedure while on study, 
is not considered an adverse event. 
A device-related adverse effect is any adverse event related to the use of a medical 
device.  Device-related adverse 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. 
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative, requests to withdraw from protocol-required therapies 
due to an adverse event, refer to Section 8.1 for additional instructions on the 
procedures recommended for safe withdrawal from protocol-required therapies or the 
study. 
9.1.3 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria (unless it meets the definition of a disease-related event as 
defined in Section 9.1.1): 
• 
fatal 
• 
life threatening (places the subject at immediate risk of death) 
• 
requires in-patient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
congenital anomaly/birth defect 
• 
other medically important serious event 
A disease-related event (eg, angina) is to be reported as a serious adverse event if: 
• 
the subject’s pre-existing condition becomes worse than what the investigator would 
consider typical for a patient with the same underlying condition, or 
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• 
the investigator believes a causal relationship exists between the investigational 
medicinal product/protocol-required therapies and the event, 
• 
and the event meets at least 1 of the serious criteria above. 
An adverse event would meet the criterion of “requires hospitalization,” if the event 
necessitated an admission to a health care facility (eg, overnight stay). 
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event.”  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, DILI (see Appendix A for 
DILI reporting criteria), or events that necessitate an emergency room visit, outpatient 
surgery, or urgent intervention. 
The criteria for grade 4 in the National Cancer Institute Common Terminology Criteria for 
Adverse Events (CTCAE) grading differ from the regulatory criteria for serious adverse 
events.  It will be left to the investigator’s judgment to also report these grade 4 
abnormalities as serious adverse events.  For any adverse event that applies to this 
situation, comprehensive documentation of the event’s severity status must be recorded 
in the subject’s medical record. 
9.2 
Safety Event Reporting Procedures 
9.2.1 
Reporting Procedures for Disease-related Events 
The investigator is responsible for ensuring that all disease-related events observed by 
the investigator or reported by the subject that occur after the FOURIER EOS visit 
through the EOS visit for this study (FOURIER OLE) or 30 days (+ 3 days) after the last 
administration of evolocumab, whichever is later, are recorded using the Event eCRF.  
Additionally, the investigator is required to report a fatal disease-related event on the 
Event eCRF. 
All serious disease-related events will be recorded and reported to the sponsor or 
designee within 24 hours. The investigator will submit any updated serious 
disease-related event data to the sponsor within 24 hours of it being available. 
Events assessed by the investigator to be related to the investigational product 
(evolocumab)/protocol-required therapies, and determined to be serious, require 
reporting of the event on the Event eCRF. 
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9.2.2 
Adverse Events 
9.2.2.1 
Reporting Procedures for Adverse Events That Do Not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after the FOURIER EOS visit through 
the EOS visit for this OLE study, or 30 days (+ 3 days) after the last administration of 
evolocumab, whichever is later, are reported using the Event eCRF.  The investigator is 
responsible for ensuring that all device-related adverse effects observed by the 
investigator or reported by the subject that occur after the FOURIER EOS visit through 
the EOS visit for this OLE study or 30 days (+ 3 days) after the last administration of 
evolocumab, whichever is later, are reported using the Event eCRF. 
The investigator must assign all of the following adverse event attributes: 
• 
adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms) 
• 
dates of onset and resolution (if resolved) 
• 
severity 
• 
assessment of relatedness to investigational product (evolocumab and/or the 
medical devices [prefilled AI/Pen or PI]), any study-mandated activity or procedure, 
or other protocol-required/study-mandated therapies 
• 
action taken 
The adverse event grading scale used will be the CTCAE.  The grading scale used in 
this study is described in Appendix A.  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 eCRF. 
The investigator must assess whether the adverse event is possibly related to 
investigational medicinal product (evolocumab).  This relationship is indicated by a “yes” 
or “no” response to the question:  Is there a reasonable possibility that the event may 
have been caused by the investigational medicinal product? 
The investigator must assess whether the adverse event is possibly related to the 
prefilled AI/Pen or PI investigational device used to administer investigational medicinal 
product (evolocumab).  The relationship is indicated by a “yes” or “no” response to the 
question:  Is there a reasonable possibility that the event may have been caused by the 
investigational device? 
The investigator must assess whether the adverse event is possibly related to 
study-mandated statin background therapy.  This relationship is indicated by a “yes” or 
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“no” response to the question:  Is there a reasonable possibility that the event may have 
been caused by study-mandated statin background therapy? 
The investigator must assess whether the adverse event is possibly related to any other 
study-mandated activity or procedure.  This relationship is indicated by a “yes” or “no” 
response to the question:  Is there a reasonable possibility that the event may have been 
caused by a study activity/procedure? 
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the investigator's judgment) are not to be 
recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. 
The investigator is expected to follow reported adverse events until stabilization or 
reversibility. 
9.2.2.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after the FOURIER EOS visit 
through the EOS visit for this OLE study, or 30 days (+ 3 days) after the last 
administration of evolocumab, whichever is later, are recorded in the subject’s medical 
record and are submitted to Amgen.  All serious adverse events must be submitted to 
Amgen within 24 hours following the investigator’s knowledge of the event via the Event 
eCRF. 
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event Contingency Report Form within 24 hours of the investigator’s 
knowledge of the event.  See Appendix B for a sample of the Serious Adverse Event 
Worksheet/electronic Serious Adverse Event Contingency Report Form.  If the first 
notification of a serious adverse event is reported to Amgen via the electronic Serious 
Adverse Event Contingency Report Form, the data must be entered into the EDC 
system when the system is again available. 
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The investigator must assess whether the serious adverse event is possibly related to 
any study-mandated activity or procedure.  This relationship is indicated by a “yes” or 
“no” response to the question:  Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure? 
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility. 
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours after knowledge of the new information.  The investigator may be 
asked to provide additional follow-up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the Event eCRF. 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and 
Good Clinical Practice (GCP). 
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local procedures and statutes. 
9.2.2.3 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events after the 
protocol-required reporting period or after the EOS.  However, these serious adverse 
events can be reported to Amgen.  In some countries (eg, European Union member 
states), investigators are required to report serious adverse events that they become 
aware of after the EOS.  If serious adverse events are reported, the investigator is to 
report them to Amgen within 24 hours following the investigator’s knowledge of the 
event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases for the purpose of expedited 
reporting. 
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9.2.2.4 
Reporting a Safety Endpoint as a Study Endpoint 
Not applicable. 
9.2.2.5 
Serious Adverse Events That Are Not To Be Reported in an 
Expedited Manner 
Not applicable. 
9.3 
Pregnancy and Lactation Reporting 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking protocol-required therapies, the pregnancy should be reported to 
Amgen as specified below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur after the last dose of protocol-required therapies and 
for an additional 15 weeks after the end of treatment with evolocumab. 
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  The pregnancy should be 
reported on the Pregnancy Notification Worksheet (Appendix C).  Amgen Global Patient 
Safety will follow up with the investigator regarding additional information that may be 
requested. 
If a lactation case occurs while the female subject is taking protocol-required therapies, 
the lactation case should be reported to Amgen as specified below. 
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur after the last dose of protocol-required therapies and for an 
additional 15 weeks after the end of treatment with evolocumab. 
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of event.  A lactation case should be reported on the 
Lactation Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow 
up with the investigator regarding additional information that may be requested. 
Amgen is sponsoring 2 prospective, observational studies of pregnant women who have 
been exposed to Repatha® (evolocumab) at any point during pregnancy and/or 
breastfeeding.  One study registry is conducted in the US and Canada, and the other 
one in Europe, South Africa, and Australia.  Participants are not asked to make any 
changes to their healthcare routine.  While subjects who are pregnant are not eligible for 
the 20130295 study, if a site investigator/health care practitioner has a subject who 
becomes pregnant while receiving evolocumab, they will be advised to refer the subject 
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to Amgen’s evolocumab pregnancy registry according to the place of residency.  To 
learn more about the study in the US and Canada, you can go to MotherToBaby.org or 
call at 877.311.8972.  More information on the pregnancy registry study in Europe, 
South Africa, and Australia is available in the respective study protocol 
(Protocol ID:  20150162 and the following websites; ClinicalTrials.gov and 
AmgenTrials.com). 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoint 
The primary endpoint is the subject incidence of adverse events. 
10.1.1.2 
Secondary Endpoints 
The secondary endpoints are the following: 
• 
percent change of LDL-C from baseline at each scheduled visit 
• 
achievement of an LDL-C < 40 mg/dL (1.03 mmol/L) at each scheduled visit 
10.1.1.3 
Exploratory Endpoints 
The exploratory endpoints in subjects who completed the EBBINGHAUS study are the 
following: 
• 
SWM strategy index of executive function 
• 
SWM between-errors score 
• 
PAL total errors adjusted 
• 
RTI median 5-choice reaction time 
The exploratory endpoints in all subjects are the following: 
• 
change and percent change from baseline at each scheduled visit in each of the 
following lipid parameters: 
− 
total cholesterol 
− 
triglycerides 
− 
LDL-C 
− 
HDL-C 
− 
VLDL-C 
− 
non-HDL-C 
− 
ApoA1 
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− 
ApoB 
− 
Lp(a) 
• 
subject incidence of events positively reviewed by the CEC: 
− 
all deaths 
− 
cardiovascular events of interest: 
o MI 
o stroke 
o coronary revascularization 
o hospitalization for unstable angina 
o hospitalization for heart failure 
o TIA 
10.1.2 
Analysis Sets 
The long-term safety analysis set (FOURIER and OLE studies) includes all subjects who 
were randomized to and received evolocumab or placebo in the FOURIER study 
regardless of whether the subjects enrolled in the OLE study. 
The OLE safety analysis set (OLE study only) includes all subjects who received at least 
1 dose of open-label evolocumab in the OLE study. 
The OLE CANTAB analysis set (OLE study only) includes all subjects who enrolled in 
the EBBINGHAUS study and received at least 1 dose of open-label evolocumab in the 
OLE study. 
10.1.3 
Covariates and Subgroups 
The planned covariates and subgroups include the following: 
• 
age (< 65 years, ≥ 65 years) 
• 
sex (male, female) 
• 
race (white, non-white) 
10.2 
Sample Size Considerations 
It is estimated approximately 5000 subjects who completed the FOURIER study will be 
enrolled.  Based on a sample size of 5000 subjects, Table 2 lists the width of 
95% confidence intervals for a range of various underlying adverse event rates. 
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Table 2.  Confidence Interval Width for Adverse Event Rates 
Percent Underlying Adverse Event 
Width of 95% Confidence Interval 
0.01% 
0.056% 
0.05% 
0.124% 
0.10% 
0.176% 
1.00% 
0.552% 
2.00% 
0.776% 
3.00% 
0.946% 
4.00% 
1.086% 
5.00% 
1.208% 
10.3 
Planned Analyses 
10.3.1 
Interim Analyses 
Interim analyses will be performed to support safety data reporting and assessments of 
other listed endpoints.  The study is not anticipated to stop early unless an unexpected 
safety signal is detected that is assessed by Amgen Safety to warrant study stop. 
10.3.2 
Primary Analysis 
The primary analysis activities are commenced based on achieving the end of study 
milestone described in Section 3.5.2. 
10.4 
Planned Methods of Analysis 
10.4.1 
General Considerations 
Statistical analyses in this open-label study will be descriptive in nature.  No statistical 
inference or missing value imputation is planned.  No formal hypotheses will be tested in 
this study.  Subject disposition, demographics, and baseline characteristics will be 
summarized.  Summary statistics for continuous variables will include the number of 
subjects, mean, median, standard deviation or standard error, minimum, and maximum.  
For categorical variables, the frequency and percentage will be given.  Unless specified 
otherwise, the baseline value is defined as the subject’s baseline value from the parent 
study (FOURIER/EBBINGHAUS). 
For all endpoints, results will be summarized by the randomized treatment group from 
the FOURIER study and overall, unless specified otherwise. 
The primary analysis of all primary, secondary, and exploratory endpoints will use data 
from the OLE study only.  Additional analyses combining the data from the OLE study 
and FOURIER/EBBINGHAUS study will be performed as applicable. 
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All deaths and cardiovascular events of interest (MI, stroke, coronary revascularization, 
hospitalization for unstable angina, hospitalization for heart failure, and TIA) will be 
reviewed by an independent external CEC, using standardized definitions.  The CEC is 
external to Amgen and primarily comprises both academic clinical physicians (to include 
cardiologists) and medical reviewers trained on the clinical trial protocol, the CEC 
charter, and CEC processes.  The chairman of the CEC is responsible for overseeing 
the operations in conformance with the CEC charter and for supervising the flow of data 
between the sponsor/data management and the CEC.  Committee members are 
qualified in the appropriate subspecialty and free of conflict of interest.  The CEC 
reviews events according to pre-specified criteria defined in the CEC charter.  The CEC 
will be blinded to the original randomized treatment group from the FOURIER study. 
10.4.2 
Primary Endpoint 
The current Medical Dictionary for Regulatory Activities version at the time of data lock 
will be used to code all adverse events and disease related events to a system organ 
class and preferred term.  Exposure-adjusted subject incidence rates of all 
treatment-emergent adverse events, serious adverse events, fatal adverse events, 
adverse events leading to withdrawal from evolocumab, device-related adverse events, 
and disease related events will be tabulated for the overall OLE study period using the 
OLE safety analysis set.  These events will also be presented by yearly subject 
exposure time intervals.  All adverse event summaries for the primary analysis of 
the primary endpoint will include all treatment-emergent events reported on the 
Event eCRF, including CEC reviewed events and disease related events. 
Adverse event data from the OLE study will also be combined with FOURIER study data 
as an additional analysis, and positively reviewed events will not be included in the 
adverse event analysis to remain consistent with FOURIER adverse event reporting.  
The analysis will be performed using the long-term safety analysis set. 
10.4.3 
Secondary Endpoints 
Summary statistics of the secondary endpoints (percent change of LDL-C from baseline 
and achieving an LDL-C < 40 mg/dL) will be provided. 
10.4.4 
Exploratory Endpoints 
Summary statistics for CANTAB assessments, including SWM strategy index of 
executive function, SWM between-errors score, PAL total errors adjusted, and RTI 
median 5-choice reaction time, will be provided based on the OLE CANTAB analysis set. 
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Summary statistics for percent change from baseline at each scheduled visit for each 
exploratory lipid parameter will be summarized. 
Subject incidence of positively reviewed events (by an independent external CEC) will 
be summarized. 
10.4.5 
Additional Safety Analyses 
Vital signs will be summarized using descriptive statistics at each scheduled visit.  
Concomitant medications of interest and exposure to evolocumab will be summarized. 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample ICF is provided for the investigator to prepare the informed consent 
document to be used at his or her site.  Updates to the template are to be communicated 
formally in writing from the Amgen clinical study manager to the investigator.  The written 
informed consent document is to be prepared in the language(s) of the potential patient 
population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol-specific screening procedures or any investigational product (evolocumab) is 
administered. 
The acquisition of informed consent is to be documented in the subject’s medical 
records, and the ICF is to be signed and personally dated by the subject and by the 
person who conducted the informed consent discussion.  The original signed ICF is to 
be retained in accordance with institutional policy, and a copy of the signed consent form 
is to be provided to the subject. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
ICF to the subject and must allow for questions.  Thereafter, both the subject and the 
witness must sign the ICF to attest that informed consent was freely given and 
understood. 
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed ICF, other written subject information, and any 
proposed advertising material must be submitted to the IRB/IEC for written approval.  A 
copy of the written approval of the protocol and ICF must be received by Amgen before 
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recruitment of subjects into the study and shipment of Amgen investigational product 
(evolocumab). 
The investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator is to notify the IRB/IEC of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures. 
The investigator is responsible for obtaining annual IRB/IEC approval/renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IRB/IEC continuance of approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
• 
Subjects are to be identified by a unique subject identification number. 
• 
Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations. 
• 
On the eCRF demographics page, in addition to the unique subject identification 
number, the age at time of enrollment must be included. 
• 
For serious adverse events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with 
local laws and regulations), and date of birth (in accordance with local laws and 
regulations). 
• 
Documents that are not submitted to Amgen (eg, signed ICFs) are to be kept in 
confidence by the investigator, except as described below. 
In compliance with federal regulations/International Conference on Harmonisation (ICH) 
GCP guidelines, it is required that the investigator and institution permit authorized 
representatives of the company, 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. 
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11.4 
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 who contributed a high number of eligible subjects 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
If Amgen amends the protocol, agreement from the investigator must be obtained.  The 
IRB/IEC must be informed of all amendments and give approval.  The investigator must 
send a copy of the approval letter from the IRB/IEC to Amgen. 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
investigator reserve the right to terminate the investigator’s participation in the study 
according to the study contract.  The investigator is to notify the IRB/IEC in writing of the 
study’s completion or early termination and send a copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
12.2 
Study Documentation and Archive 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on eCRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
eCRF 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. 
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
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inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.  Elements should include: 
• 
subject files containing completed study-related worksheets, ICFs, and subject 
identification list 
• 
study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
• 
if kept, proof of receipt/delivery sheet, Investigational Product Accountability Record, 
Return of Investigational Product for Destruction Form, Final Investigational Product 
Reconciliation Statement (if applicable), and all drug-related correspondence 
In addition, all original source documents supporting entries in the eCRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, eCRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Amgen clinical monitor is responsible for verifying the eCRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical 
research.  The clinical monitor is to have access to subject medical records and other 
study-related records needed to verify the entries on the eCRFs. 
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 eCRFs, are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function (or 
designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy storage 
areas, laboratories) and review of study-related records will occur to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 
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Data capture for this study is planned to be electronic: 
• 
All source documentation supporting entries into the eCRFs must be maintained and 
readily available. 
• 
Updates to eCRFs will be automatically documented through the software’s “audit 
trail.” 
• 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During this 
review, subject data are checked for consistency, omissions, and any apparent 
discrepancies.  In addition, the data are reviewed for adherence to the protocol and 
GCP.  To resolve any questions arising from the clinical data management review 
process, data queries are created in the EDC system database for site resolution 
and subsequently closed by the EDC system or by an Amgen reviewer. 
• 
The investigator signs only the Investigator Verification Form for this EDC study or 
the investigator applies an electronic signature in the EDC system if the study is set 
up to accept an electronic signature.  This signature indicates that investigator 
inspected or reviewed the data on the eCRF, the data queries, and agrees with the 
content. 
12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw 
before the completion of all protocol-required visits and are unable or unwilling to 
continue the schedule of assessments (Table 1), the investigator can search publically 
available records (where permitted) to ascertain survival status.  This ensures that the 
data set(s) produced as an outcome of the study is/are as comprehensive as possible. 
12.5 
Language 
The eCRFs must be completed in English.  TRADENAMES® (if used) for concomitant 
medications may be entered in the local language. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
12.6 
Publication Policy 
To coordinate dissemination of data from this study, Amgen encourages the formation of 
a publication committee consisting of several investigators and appropriate Amgen staff, 
the governance and responsibilities of which are set forth in a Publication Charter.  The 
committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
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not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Recommendations for the Conduct, Reporting, Editing, and Publication of 
Scholarly Work in Medical Journals (International Committee of Medical Journal Editors, 
2013, updated 2014), which states: 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published; (4) agreement to be accountable for all aspects of the work 
in ensuring that questions related to the accuracy or integrity of any part of the work 
are appropriately investigated and resolved.  Authors should meet conditions 1, 2, 3, 
and 4. 
• 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 
• 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
• 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
• 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
12.7 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the informed consent that 
is available as a separate document.  Subjects may be compensated for other 
inconveniences not associated with study-related injuries (eg, travel costs), if permitted 
under applicable regional laws or regulatory guidelines. 
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13. 
REFERENCES 
Abifadel M, Varret M, Rabes J-P, et al.  Mutations in PCSK9 cause autosomal dominant 
hypercholesterolemia.  Nat Genet.  2003;34:154-156. 
Attwood AS, Higgs S, Terry P.  Differential responsiveness to caffeine and perceived 
effects of caffeine in moderate and high regular caffeine consumers.  
Psychopharmacology (Berl).  2007;190:469–477. 
Bruckert E, Hayem G, Dejager S, Yau C, Bégaud B.  Mild to moderate muscular 
symptoms with high-dosage statin therapy in hyperlipidemic patients-the PRIMO study.  
Cardiovasc Drugs Ther.  2005;19:403-414. 
Cannon CP; the IMPROVE IT Investigators.  Ezetimibe added to statin therapy after 
acute coronary syndromes.  N Engl J Med.  2015;372:2387-2397. 
Cholesterol Treatment Trialists' (CTT) Collaborators.  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. 
Egerházi A, Berecz R, Bartók E, Degrell I.  Automated neuropsychological test battery 
(CANTAB) in mild cognitive impairment and in Alzheimer’s disease.  Prog 
Neuropsychopharmacol Biol Psychiatry.  2007;31:746–751. 
Elliott R, Sahakian BJ, Matthews K, Bannerjea A, Rimmer J, Robbins TW.  Effects of 
methylphenidate on spatial working memory and planning in healthy young adults.  
Psychopharmacology (Berl).  1997;131:196–206. 
Amgen.  Evolocumab Investigator’s Brochure, version 9.0. 
Franc S, Dejager S, Bruckert E, Chauvenet M, Giral P, Turpin G.  A comprehensive 
description of muscle symptoms associated with lipid-lowering drugs.  Cardiovasc Drugs 
Ther.  2003;17:459-465. 
Greig NH, Sambamurti K, Yu Q, Brossi A, Bruinsma GB, Lahiri DK.  An overview of 
phenserine tartrate, a novel acetylcholinesterase inhibitor for the treatment of 
Alzheimer’s disease.  Curr Alzheimer Res.  2005;2:281–290. 
Grundy SM, Cleeman JI, Merz CN, et al.  Implications of recent clinical trials for the 
National Cholesterol Education Program Adult Treatment Panel III guidelines.  
Circulation.  2004;110:227-239. 
Harmer CJ, McTavish SFB, Clark L, Goodwin GM, Cowen PJ.  Tyrosine depletion 
attenuates dopamine function in healthy volunteers.  Psychopharmacology (Berl).  
2001;154:105–111. 
International Committee of Medical Journal Editors.  Recommendations for the conduct, 
reporting, editing, and publication of scholarly work in medical journals 2013:  
http://www.icmje.org/ 
Jäkälä P, Riekkinen M, Sirviö J, Koivisto E, Riekkinen P.  Clonidine, but not guanfacine, 
impairs choice reaction time performance in young healthy volunteers.  
Neuropsychopharmacology.  1999;21:495–502. 
Kannel WB.  Range of serum cholesterol values in the population developing coronary 
artery disease.  Am J Cardiol.  1995;76:69C-77C. 
Kannel WB, Castelli WP, Gordon T.  Lipoprotein cholesterol in the prediction of 
atherosclerotic disease:  New perspectives based on the Framingham Study.  Ann Int 
Med.  1979;90:85-91. 
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Kannel WB, et al.  The Framingham Study:  An epidemiological investigation of 
cardiovascular disease, Section 30.  Some characteristics related to the incidence of 
cardiovascular disease and death:  The Framingham Study.  18-year follow-up.  
Washington, DC, Dept of Health, Education, and Welfare, Publication No. (NIH) 
74-599, 1974. 
Kollins SH, López F, Vince BD, et al.  Psychomotor functioning and alertness with 
guanfacine extended release in subjects with attention-deficit/hyperactivity disorder.  
J Child Adolesc Psychopharmacol.  2011;21:111–120. 
Libby P.  The forgotten majority:  unfinished business in cardiovascular risk reduction.  
J Am Coll Cardiol.  2005;46:1225-1228. 
Manes F, Sahakian BJ, Clark L, et al.  Decision making processes following damage to 
the prefrontal cortex.  Brain.  2002;125:624–639. 
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, 
and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).  
Third report of the National Cholesterol Education Program (NCEP) Expert Panel on 
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult 
Treatment Panel III) final report.  Circulation.  2002;106:3143-3421. 
Owen AM, Evans AC, Petrides M.  Planning and spatial working memory:  a positron 
emission tomography study in humans.  Eur J Neurosci.  1996;8:353–364. 
Owen AM, Downes JJ, Sahakian BJ, Polkey CE, Robbins TW.  Planning and spatial 
working memory following frontal lobe lesions in man.  Neuropsychologia.  
1990;28:1021–1034. 
Rusted JM, Warburton DM.  Original investigations The effects of scopolamine on 
working memory in healthy young volunteers.  Psychopharmacology (Berl).  
1988;96:145–152. 
Ryan CM, Freed MI, Rood JA, Cobitz AR, Waterhouse BR, Strachan MWJ.  Improving 
metabolic control leads to better working memory in adults with type 2 diabetes.  
Diabetes Care.  2006;29:345–351. 
Sabatine MS, Guigliano RP, Wiviott SD, et al.  Efficacy and safety of evolocumab in 
reducing lipids and cardiovascular events.  N Engl J Med.  2015;372:1500-1509. 
Scientific Steering Committee of the Simon Broome Register Group.  Risk of fatal 
coronary heart disease in familial hypercholesterolaemia.  BMJ.  
1991;303(6807):893-896. 
Tolonen H, Keil U, Ferrario M, Evans A, WHO MONICA Project.  Prevalence, awareness 
and treatment of hypercholesterolaemia in 32 populations:  results from the WHO 
MONICA Project.  Int J Epidemiol.  2005;34:181-192. 
Williams RR, Schumacher MC, Barlow GK, et al.  Documented need for more effective 
diagnosis and treatment of familial hypercholesterolemia according to data from 
502 heterozygotes in Utah.  Am J Cardiol.  1993;72:18D-24D. 
World Health Organization.  Familial Hypercholesterolaemia (FH):  Report of a second 
WHO consultation.  Geneva 1999. 
World Health Organization.  Global atlas on cardiovascular disease prevention and 
control.  Mendis S, Puska P, Norrving B editors.  Geneva 2011; 
http://www.who.int/cardiovascular_diseases/publications/atlas_cvd/en/ 
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14. 
APPENDICES 
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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
Refer to CTCAE version 4.0 for adverse event grading and information.  The CTCAE is 
available at the following link:  
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: 
1 
MILD:  aware of sign or symptom, but easily tolerated 
2 
MODERATE:  discomfort enough to cause interference with usual activity 
3 
SEVERE:  incapacitating with inability to work or do usual activity 
4 
LIFE-THREATENING:  refers to an event in which the subject was, in the view of 
the investigator, at risk of death at the time of the event (This category is not to 
be used for an event that hypothetically might have caused death if it was more 
severe.) 
5 
FATAL 
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 according to the criteria specified in Section 6.4 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 eCRF (eg, Event eCRF) 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 Section 9.1.3. 
Additional Clinical Assessments and Observation 
All subjects in whom evolocumab or protocol-required therapies are withheld (either 
permanently or conditionally) due to potential DILI as specified in Section 6.4.1 and 
Section 6.4.2 or who have AST or ALT elevations > 3 x ULN are to undergo a period of 
close observation until abnormalities return to normal or to the subject’s baseline levels.  
Assessments that are to be performed during this period include: 
• 
AST, ALT, ALP, and bilirubin (total and direct) are to be repeated within 24 hours. 
• 
In cases of TBL > 2 x ULN, retesting of liver tests and bilirubin (total and direct) is to 
be performed every 24 hours until laboratory abnormalities improve. 
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Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the evolocumab and/or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
• 
Investigation of alternative causes for elevated AST or ALT and/or elevated TBL is to 
be initiated: 
− 
Complete blood count with differential is to be obtained to assess for 
eosinophilia. 
− 
Serum total immunoglobulin immunoglobulin G, anti-nuclear antibody, 
anti-smooth muscle antibody, and liver kidney microsomal antibody 1 are to be 
obtained to assess for autoimmune hepatitis. 
− 
Serum acetaminophen (paracetamol) levels are to be obtained. 
− 
A more detailed history of the following is to be obtained: 
• 
prior and/or concurrent diseases or illness 
• 
exposure to environmental and/or industrial chemical agents 
• 
symptoms (if applicable), including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting, and fever 
• 
prior and/or concurrent use of alcohol, recreational drugs, and special diets 
• 
concomitant use of medications (including nonprescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
− 
Viral serologies are to be obtained. 
− 
Creatine phosphokinase, haptoglobin, lactate dehydrogenase, and peripheral 
blood smear are to be obtained. 
− 
Appropriate liver imaging is to be performed, if clinically indicated. 
• 
Appropriate blood sampling is to be obtained for pharmacokinetic analysis. 
• 
Hepatology consult is to be obtained (liver biopsy may be considered in consultation 
with an hepatologist). 
• 
The subject and the laboratory tests (ALT, AST, and TBL) are to be followed until all 
laboratory abnormalities return to baseline or normal.  The close observation period 
is to continue for a minimum of 4 weeks after discontinuation of all evolocumab and 
protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications, and laboratory results must be captured in corresponding eCRFs. 
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Appendix B.  Sample Serious Adverse Event Report Form 
 
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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 
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Appendix D.  Recommended Lipid-lowering Background Therapy 
It is recommended that subjects continue the same background LLT, including statin, as 
taken during FOURIER.  Background LLT should be optimized for the individual subject 
consistent with local professional society guidelines.  All subjects should receive at least 
an effective statin dose, ie, at least atorvastatin 20 mg daily or equivalent.  Where locally 
approved, highly effective statin therapy, defined as at least atorvastatin 40 mg daily or 
equivalent, is recommended. 
No other lipid therapy is required for the FOURIER OLE study.  Ezetimibe and other 
commercially available lipid therapy at dosages approved by local regulatory authorities 
may be added to any of these regimens except excluded medication as per Section 6.8.  
These therapies, including statins, are not provided or reimbursed by Amgen (except if 
required by local regulation).  Background LLT received at enrollment should remain 
unchanged throughout the entire duration of the study. 
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Appendix E.  Drugs With Known Major Interactions With Statin Background 
Therapy 
Atorvastatin: 
• 
strong CYP3A4 inhibitors (eg, itraconazole, ketoconazole, and other antifungal 
azoles, erythromycin, clarithromycin, telithromycin, HIV or HCV protease inhibitors, 
systemic cyclosporine nefazodone and grapefruit juice in large quantities [> 1 quart 
or approximately 1 L daily]) 
Simvastatin: 
• 
strong CYP3A4 inhibitors (eg, itraconazole, ketoconazole, and other antifungal 
azoles, erythromycin, clarithromycin, telithromycin, HIV or HCV protease inhibitors, 
systemic cyclosporine nefazodone and grapefruit juice in large quantities [> 1 quart 
or approximately 1 L daily]) 
• 
verapamil 
• 
diltiazem 
• 
danazol 
• 
if simvastatin > 20 mg 
− 
amlodipine 
− 
amiodarone 
− 
ranolazine 
Rosuvastatin: 
• 
systemic cyclosporine 
• 
and if rosuvastatin > 10 mg, HIV or HCV protease inhibitors 
Pitavastatin: 
• 
systemic cyclosporine 
• 
erythromycin 
• 
rifampin 
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Appendix F.  Cambridge Neuropsychological Test Automated Battery Tests 
The CANTAB SWM, PAL, and RTI will be completed by subjects who completed the 
EBBINGHAUS study (Study 20130385). 
Brief descriptions with screenshots for these 3 tests are provided on the pages below.  
Interactive test demos can be accessed at the following website: 
http://www.cambridgecognition.com/clinicaltrials/cantabsolutions/tests 
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Spatial Working Memory 
A number of colored boxes are presented on the screen, and the computer hides a 
token in these boxes one at a time.  The subject is instructed to touch the boxes in turn 
to search for the token that has been hidden.  When a token is found, it should be placed 
in a home area on the right side of the screen.  The subject then searches for more 
tokens until the same number of tokens as the number of colored boxes has been found.  
The key task instruction is that the computer will never hide a token in the same box 
twice.  As the test progresses, the task becomes more difficult, with up to a maximum of 
8 boxes.  The color and position of the boxes used are changed from trial to trial to 
discourage the use of stereotyped search strategies. 
Step-by-step Example 
Colored boxes are shown on the screen.  One of the boxes contains a token.  The 
subject chooses 1 box and opens it by touching the box on the screen.  If the box is 
empty, the box closes after a few seconds and another box needs to be touched. 
 
If a box contains a token, the box stays open until the token is transferred to the column 
on the right side of the screen. 
 
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The token is transferred to the column on the right side of the screen by touching the 
column.  The open box closes. 
 
The next token needs to be found by touching another box. 
 
No box contains more than 1 token, so the subject needs to remember where she/he 
has found a token previously and try not to return to those boxes. 
 
Upon completion a “complete” message is briefly displayed. 
 
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The test starts with practice problems with 3 boxes and becomes gradually more difficult 
with problems having 4 boxes, 6 boxes, and then 8 boxes at the most difficult stage. 
 
The SWM test ends after it has been completed with a total of 8 boxes on the screen. 
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Paired Associates Learning 
Boxes are displayed on the screen and open in turn to reveal a number of patterns.  
Subjects are instructed to try to remember the location in which each pattern was shown.  
After all the boxes have been opened, each pattern is then shown in the center of the 
screen in a randomized order, and the subject touches the box in which the pattern was 
located.  If an error is made, the patterns are presented again to remind the subject of 
their locations.  As the test progresses, the stages become more difficult as the number 
of patterns to be remembered increases, up to a maximum of 8 patterns. 
Step-by-step Example 
Six boxes are displayed on the screen. 
 
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Two of the boxes contain a pattern.  The boxes are opened in a random order to reveal 
the locations of the patterns. 
 
 
 
 
 
 
After all the boxes have opened, 1 pattern is shown in the center of the screen.  The 
subject touches the box in which he/she thinks the pattern was located. 
 
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The other pattern is shown in the center of the screen.  The subject touches the box in 
which he/she thinks that pattern was located. 
 
If the subject responds correctly, the test progresses to more difficult stages with 
4 patterns, 6 patterns, then 8 patterns at the most difficult level.  For the 8-pattern stage, 
2 additional white boxes are included on the screen.  If at any stage the subject does not 
respond correctly, the boxes re-open to remind the subject where the patterns are 
located.  The subject can try again until the maximum number of attempts has been 
reached. 
The PAL test ends when the 8-pattern stage has been completed or at an earlier stage if 
the maximum number of attempts has been reached and the subject has not responded 
correctly. 
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Reaction Time 
The subject holds down a button until a spot appears in 1 of 5 circles on the screen.  As 
soon as possible after the spot flashes, the subject lifts their finger from the button and 
touches the circle in which the spot appeared. 
Step-by-step Example 
A button and 5 circles are displayed on the screen. 
 
The subject holds down the button with the index finger of their dominant hand to initiate 
the trial. 
 
A spot flashes in one of the circles.  The subject releases the button and uses the same 
finger to touch inside the circle in which the spot appeared as quickly as possible. 
 
The RTI test begins with 10 practice trials and is completed when 30 assessed trials 
have been performed. 
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Amendment 3 
Protocol Title:  A Multicenter, Open-label, Single-arm, Extension Study to Assess 
Long-term Safety of Evolocumab Therapy in Patients With Clinically Evident 
Cardiovascular Disease 
 
Amgen Protocol Number Evolocumab 20130295 
NCT Number:  02867813 
EudraCT Number:  2015-004780-36 
Amendment Date: 
26 February 2020 
Rationale: 
The protocol is being amended to: 
• 
Update safety language: 
− 
Safety Section updated to reflect that all serious drug-related events must be 
recorded and reported to the sponsor or designee within 24 hours 
− 
Included “coronary revascularization” throughout the protocol to identify the 
specific vascular territory of interest, which is the coronary circulation. 
• 
Update the Schedule of Assessments: 
− 
Coronary revascularization procedure and death information added throughout to 
support the independent safety review of cardiovascular events of interest and 
deaths by the Clinical Events Committee (CEC). 
• 
Clarify that all adverse event summaries for the primary analysis of the primary 
endpoint will include all treatment-emergent events reported on the Event electronic 
Case Report Form (eCRF), including CEC reviewed events and disease related 
events 
• 
Replaced “automated mini-doser (AMD)” with “personal injector (PI)” to align with 
program-level naming convention: 
• 
Administrative, typographical, and formatting changes were made throughout the 
protocol 
 
 
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Amendment 2 
Protocol Title:  A Multicenter, Open-label, Single-arm, Extension Study to Assess 
Long-term Safety of Evolocumab Therapy in Patients With Clinically Evident 
Cardiovascular Disease 
 
Amgen Protocol Number Evolocumab 20130295 
NCT Number:  02867813 
EudraCT Number:  2015-004780-36 
Amendment Date: 
08 April 2019 
Rationale: 
The protocol is being amended to: 
• 
align the protocol with the evolocumab 20160250 study 
• 
incorporate an independent external clinical events committee (CEC) to review all 
deaths and cardiovascular events of interest 
• 
modify statistical considerations to clarify that the primary analysis will use data from 
the open-label extension (OLE) study only 
• 
add exploratory endpoint “to describe the effects of long-term administration of 
evolocumab on subject incidence of death and cardiovascular events of interest” 
• 
incorporate language about Amgen sponsoring of 2 prospective observational 
studies of pregnant women who have been exposed to evolocumab 
• 
update the study glossary 
• 
clarify and update text to align with the current template (FORM-001520) and Amgen 
standards 
• 
clarify text to indicate that the secondary endpoints will be conducted at scheduled 
visits and not on a yearly basis 
• 
remove self-evident corrections (SEC) text, as it is no longer an Amgen standard 
• 
remove “week 260” from end of study (primary completion date) definition for clarity 
• 
clarify language related to the collection of concomitant therapy 
• 
clarify the evolocumab resupply period 
• 
change “lot number” to “box number” for accuracy 
• 
modify Table 1 footnote text to clarify that subjects will be contacted by phone at 
least 30 days (+ 3 days) after last evolocumab administration, unless they are 
continuing their participation in the study after ending evolocumab prior to study 
completion 
• 
make editorial changes (including typographical, grammatical, and formatting) 
throughout the document. 
 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20130295 
Date:  20 November 2017 
Page 1 of 17 
CONFIDENTIAL 
 
 
Amendment 1 
Protocol Title:  A Multicenter, Open-label, Single-arm, Extension Study to Assess 
Long term Safety of Evolocumab Therapy in Patients With Clinically Evident 
Cardiovascular Disease 
 
Amgen Protocol Number 20130295 
EudraCT number 2015-004780-36 
 
Amendment Date: 
20 November 2017 
 
Rationale: 
This protocol is being amended to: 
• 
Clarify that subjects will only be allowed to obtain investigational product at the study 
site (per supply chain, delivery methods are not a feasible option for this study).  
Sites are responsible for distributing investigational product to subjects and they may 
not have the adequate process to guarantee that investigational product will not be 
compromised during transportation. 
• 
Primary completion and end of study language (Section 3.5.2) has been updated to 
align with current protocol template in order to clearly define these terms and when 
they occur 
• 
Update the scheduled visit window from ±7 days to ±14 days for all visits in order to 
allow for subject flexibility as site visits are every 6 months 
• 
Add an on-site administration and dispensation/reconciliation of investigational 
product at week 240 in order to ensure subjects have enough investigational product 
to last through week 260 
• 
Separate the week 260 visit and end of study visit into 2 separate columns in the 
Schedule of Assessments, as the end of study visit is a phone call 30 days after the 
last dose of evolocumab that serves as a safety follow-up visit collecting targeted 
concomitant medications and adverse events (aligns with Section 9.2).  This has also 
been clarified in Section 7.2.3. 
• 
Clarify that subjects should be allowed to eat and drink between fasting bloodwork 
and CANTAB assessments 
• 
Remove collection of temperature and respiratory rate from vital signs assessment 
as they were not collected during the parent study and thus do not need to be 
collected in this open-label extension study 
• 
Clarify how demographic data and medical history will be defined and obtained at 
enrollment (rolled over from parent study) 
• 
Provide clearer guidelines for obtaining a subject’s vital status after discontinuation 
from the study 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20130295 
Date:  20 November 2017 
Page 2 of 17 
CONFIDENTIAL 
 
 
• 
Clarify the procedures that should be followed if a patient discontinues from 
treatment and/or the study 
• 
Add instructions for handling subjects who are lost to follow-up to clarify when a 
subject would be considered a “lost to follow-up” in the study and define the site 
expectation to keep trying to contact with the “lost to follow-up” subjects until the end 
of the study 
• 
Remove tabulation of disease-relate events from primary endpoint as the parent 
study did not collect the disease-related event data, thus it is not possible to do the 
tabulation involving parent data 
• 
Make administrative and editorial corrections throughout the protocol 
Approved