Clinical trial NCT03080935
Conditions: Dyslipidemia
Sponsor: Amgen
Start date: 2017-03-13; Completion date: 2022-03-04
Enrollment: 1600 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a multicenter, open-label extension (OLE) study designed to assess the extended long-term safety of evolocumab in subjects who have completed the FOURIER trial (Study 20110118). Approximately 1600 subjects will be enrolled in this study. This study will continue for 260 weeks (approximately 5 years).

Detailed description:
This is a multicenter, open-label extension (OLE) study designed to assess the extended long-term safety of evolocumab in subjects who have completed the FOURIER trial (Study 20110118). FOURIER is a randomized placebo-controlled study of evolocumab, in patients with clinically evident atherosclerotic CVD on stable effective statin therapy. Subjects at sites participating in FOURIER OLE (Study 20160250) who are eligible and have signed the FOURIER OLE informed consent will be enrolled after completion of FOURIER.

The FOURIER OLE study requires laboratory assessments at day 1, week 12, and thereafter approximately every 6 months from day 1; the corresponding blood samples will be processed using a central laboratory.

Upon enrollment in FOURIER OLE study, 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 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. 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and complete procedures/assessments from enrollment through the date of study termination unless the subject has withdrawn consent, irrespective of whether the subject is continuing to receive treatment.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.

Arms: arm 1: Single arm study administering Evolocumab.
Interventions: intervention 1: Evolocumab
Intervention descriptions: intervention 1: Subjects will receive Evolocumab 140 mg every 2 weeks (Q2W) or 420 mg monthly (QM), according to the subject's preference.

Protocol documents:
Prot_000.pdf: 
Product:  Evolocumab 
Protocol Number:  20160250 
Date:  19 February 2020 
Page 1 of 70 
CONFIDENTIAL 
 
 
Title:  A Multicenter, Open-label, Single-arm, Extension Study to Assess 
Long-term Safety of Evolocumab Therapy in Subjects With Clinically Evident 
Cardiovascular Disease in Selected European Countries 
Amgen Protocol Number (evolocumab) 20160250 
EudraCT number 2016-004066-26 
NCT number:  NCT03080935 
Clinical Study Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Phone:  +1-805-447-1000 
Key Sponsor Contact(s): 
, MD  
Clinical Research Medical Director 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Telephone:  
 
Email:  
 
Original Protocol Date: 
10 November 2016 
Amendment 01 Date: 
14 December 2018 
Amendment 02 Date: 
19 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; Amgen’s general number in the US (1-805-447-1000).  
This protocol was developed, reviewed, and approved in accordance with 
Amgen’s standard operating procedures. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160250 
Date:  19 February 2020 
Page 2 of 70 
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 Subjects With 
Clinically Evident Cardiovascular Disease in Selected European Countries”, 
dated19 February 2020, and agree to abide by all provisions set forth therein.   
I agree to comply with the International Conference on Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines.  
I agree to ensure that 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:  20160250 
Date:  19 February 2020 
Page 3 of 70 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Multicenter, Open-label, Single-arm, Extension Study to Assess Long-term Safety of 
Evolocumab Therapy in Subjects With Clinically Evident Cardiovascular Disease in Selected 
European Countries 
Study Phase:  3b 
Indication:  Dyslipidemia 
Primary Objective:  To describe the safety and tolerability of long-term administration of 
evolocumab.  
Secondary Objective(s):  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. 
Hypothesis:  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 
extended long-term safety of evolocumab in subjects who have completed the FOURIER trial 
(Study 20110118).  FOURIER is a randomized placebo-controlled study of evolocumab, in 
patients with clinically evident atherosclerotic CVD on stable effective statin therapy.  Subjects at 
sites participating in FOURIER OLE (Study 20160250) who are eligible and have signed the 
FOURIER OLE informed consent will be enrolled after completion of FOURIER. 
The FOURIER OLE study requires laboratory assessments at day 1, week 12, and thereafter 
approximately every 6 months from day 1; the corresponding blood samples will be processed 
using a central laboratory.   
Upon enrollment in FOURIER OLE study, 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 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.   
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 1600 subjects will be enrolled in this study. 
Summary of Subject Eligibility Criteria:  Subjects must have completed FOURIER 
(Study 20110118) while still receiving assigned investigational product and provided informed 
consent for this FOURIER OLE (20160250) 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 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160250 
Date:  19 February 2020 
Page 4 of 70 
CONFIDENTIAL 
 
 
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.   
Investigational Product 
Amgen Investigational Product Dosage and Administration:  Evolocumab will be 
administered using a handheld mechanical (spring-based) prefilled 1.0 mL auto-injector/pen 
(AI/pen) or an on-body electromechanical 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. 
Procedures:  Mandatory study visits will occur at day 1, week 12 and thereafter approximately 
every 6 months from day 1.  Evolocumab resupply visits will be scheduled quarterly (every 
12 weeks).  The last resupply of evolocumab will occur 12 weeks after the week 240 visit.  
Evolocumab will be supplied directly to 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 concomitant therapy, 
adverse events, adverse device effects, serious adverse events, and disease-related events; 
laboratory assessments, including fasting lipid panel, apolipoprotein A1, apolipoprotein B, and 
lipoprotein(a); serum 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 3).   
Statistical Considerations:  The primary and secondary endpoints will use the OLE safety 
subset (OLE study only) which includes all subjects who received at least 1 dose of open-label 
evolocumab in the OLE study. 
Statistical analyses in this open-label study are descriptive in nature.  No statistical inference or 
missing value imputation is planned.  No formal hypothesis 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 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.  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 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160250 
Date:  19 February 2020 
Page 5 of 70 
CONFIDENTIAL 
 
 
treatment-emergent events reported on the Event electronic case report form (eCRF), 
including CEC reviewed events and disease related events.  All CEC reviewed events will be 
reported. 
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. 
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(s)/Date(s):  
Version 5, 20 March 2015 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160250 
Date:  19 February 2020 
Page 6 of 70 
CONFIDENTIAL 
 
 
Figure 1.  Study Design and Treatment Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EOS = end of study; Q2W = every 2 weeks; QM = monthly 
W240:  Subjects may be contacted by phone at week 240. 
EOS:  safety follow-up phone call.  A follow-up phone call is scheduled to occur at least 30 days (+ 3 days) after the last administration of evolocumab. 
Evolocumab resupply visits will be scheduled quarterly (every 12 weeks). 
 
Evolocumab 140 mg 
Q2W or 420 mg QM   
Informed 
consent for 
20160250 
 
EOS 
Placebo 140 mg  
Q2W or 420 mg QM 
Evolocumab 140 mg Q2W or 420 mg QM 
per subject preference  
approx. 1600 subjects 
Laboratory Assessments 
Visits 
D1 
W48 
W96 
W144 
W192 
W24 
W12 
W72 
W120 
W168 
W216 W240 
Completing FOURIER while 
on assigned treatment 
W260 
 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160250 
Date:  19 February 2020 
Page 7 of 70 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
AI/pen 
auto-injector/pen 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANA 
anti-nuclear antibody 
ApoA1 
apolipoprotein A1 
ApoB 
apolipoprotein B 
AST 
aspartate aminotransferase 
CBC 
complete blood count 
CEC 
Clinical Events Committee 
CPK 
creatine phosphokinase 
CTCAE 
Common Terminology Criteria for Adverse Events 
CRF 
case report form 
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  
eCRF 
electronic case report form 
EDC 
electronic data capture 
eSAE 
electronic serious adverse event 
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 the purposes of final collection of data for the primary 
endpoint(s), for the purpose of conducting the primary analysis, 
whether the study concluded as planned in the protocol or was 
terminated early  
end of study (primary 
completion) 
defined as when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary 
endpoint 
end of treatment 
defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject 
EOI 
event of interest 
EoIP 
end of investigational product administration 
EOS 
end of study for individual subject; defined as the last day that 
protocol-specified procedures are conducted for an individual subject 
EU 
European Union 
FOURIER 
Study 20110118; the parent study for this open-label extension study 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160250 
Date:  19 February 2020 
Page 8 of 70 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
FOURIER OLE 
open-label extension study of the FOURIER study 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HCV 
hepatitis C virus 
HDL-C 
high-density lipoprotein cholesterol 
HeFH 
heterozygous familial hypercholesterolemia 
HIV 
human immunodeficiency virus 
HRT 
hormonal replacement therapy 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IFU 
instructions for use 
INR 
international normalized ratio 
IPIM 
Investigational Product Instruction Manual 
IRB/IEC 
institutional review board/independent ethics committee 
IUD 
intrauterine device 
IUS 
intrauterine hormonal-releasing system 
IVR 
Interactive Voice Response 
IWR 
Interactive Web Response 
LDH 
lactate dehydrogenase 
LDL-C 
low-density lipoprotein cholesterol 
LDLR 
low-density lipoprotein receptor 
LKM1 
liver kidney microsomal antibody 1 
LLT 
lipid-lowering therapy 
Lp(a) 
lipoprotein(a) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
myocardial infarction 
NASH 
nonalcoholic fatty liver disease including steatohepatitis 
non-HDL-C 
non-high-density lipoprotein cholesterol 
OLE 
open-label extension 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
PI 
personal injector 
POR 
proof of receipts 
Q2W 
every 2 weeks 
QM 
monthly 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160250 
Date:  19 February 2020 
Page 9 of 70 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
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. 
STEMI 
ST segment elevation myocardial infarction 
TBL 
total bilirubin 
TIA 
transient ischemic attack 
UA 
unstable angina 
ULN 
upper limit of normal 
VLDL-C 
very low-density lipoprotein cholesterol 
WHO 
World Health Organization 
 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160250 
Date:  19 February 2020 
Page 10 of 70 
CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................. 3 
Study Glossary .................................................................................................................. 7 
1. 
OBJECTIVES ......................................................................................................... 14 
1.1 
Primary ....................................................................................................... 14 
1.2 
Secondary .................................................................................................. 14 
1.3 
Exploratory ................................................................................................. 14 
2. 
BACKGROUND AND RATIONALE ........................................................................ 14 
2.1 
Cardiovascular Disease .............................................................................. 14 
2.2 
Amgen Investigational Product Background ............................................... 17 
2.3 
Rationale .................................................................................................... 17 
2.4 
Clinical Hypothesis ..................................................................................... 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 Criteria ......................................................................................... 19 
4.2 
Exclusion Criteria ........................................................................................ 20 
5. 
SUBJECT ENROLLMENT ..................................................................................... 20 
5.1 
Treatment Assignment ............................................................................... 21 
6. 
TREATMENT PROCEDURES ............................................................................... 21 
6.1 
Classification of Product(s), Medical Device(s) and/or 
Combination Product(s) .............................................................................. 21 
6.2 
Investigational Product ............................................................................... 21 
6.2.1 
Amgen Investigational Product - Evolocumab ............................ 21 
6.2.1.1 
Dosage, Administration, and Schedule .................... 22 
6.2.1.2 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 23 
6.2.2 
Non-Amgen Non-investigational Product ................................... 24 
6.2.2.1 
Non-Amgen Non-investigational 
Product - Background Lipid-lowering 
Therapy .................................................................... 24 
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Product:  Evolocumab 
Protocol Number:  20160250 
Date:  19 February 2020 
Page 11 of 70 
CONFIDENTIAL 
 
 
6.2.2.2 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 24 
6.3 
Hepatotoxicity Stopping and Rechallenge Rules ........................................ 25 
6.3.1 
Criteria for Withholding and/or Permanent 
Discontinuation of Amgen Investigational Product and 
Other Protocol-required Therapies Due to Potential 
Hepatotoxicity ............................................................................. 25 
6.3.2 
Criteria for Rechallenge of Amgen Investigational 
Product and Other Protocol-required Therapies After 
Potential Hepatotoxicity .............................................................. 27 
6.4 
Concomitant Therapy ................................................................................. 27 
6.5 
Medical Devices ......................................................................................... 28 
6.6 
Product Complaints .................................................................................... 28 
6.7 
Excluded Treatments, Medical Devices, and/or Procedures 
During Study Period ................................................................................... 28 
6.8 
Contraceptive Requirements ...................................................................... 29 
6.8.1 
Female Subjects ......................................................................... 30 
6.8.2 
Male Subjects ............................................................................. 31 
6.8.3 
Unacceptable Methods of Birth Control for Female 
Subjects ..................................................................................... 31 
7. 
STUDY PROCEDURES ......................................................................................... 31 
7.1 
Schedule of Assessments .......................................................................... 31 
7.2 
General Study Procedures ......................................................................... 34 
7.2.1 
Screening, Enrollment, and Study Day 1 .................................... 35 
7.2.2 
Treatment ................................................................................... 35 
7.2.3 
Safety Follow-up Visit/End of Study Visit .................................... 36 
7.2.4 
Description of Study Procedures ................................................ 37 
7.2.4.1 
Medical History ........................................................ 37 
7.2.4.2 
Vital Signs ................................................................ 37 
7.2.4.3 
Review of Safety Events .......................................... 37 
7.2.4.4 
Physical Examination ............................................... 38 
7.2.4.5 
Physical Measurements:  Weight ............................. 38 
7.2.4.6 
Laboratory Assessments ......................................... 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 ........................................................................................ 41 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 41 
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Product:  Evolocumab 
Protocol Number:  20160250 
Date:  19 February 2020 
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9.1 
Definition of Safety Events ......................................................................... 41 
9.1.1 
Disease-related Events .............................................................. 41 
9.1.2 
Adverse Events .......................................................................... 42 
9.1.3 
Serious Adverse Events ............................................................. 43 
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 
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 ................... 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 .............................................. 49 
10.1.2 
Analysis Sets .............................................................................. 49 
10.1.3 
Covariates and Subgroups ......................................................... 49 
10.1.4 
Handling of Missing and Incomplete Data .................................. 49 
10.2 
Sample Size Considerations ...................................................................... 50 
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 Efficacy Endpoints .................................................... 52 
10.4.4 
Exploratory Efficacy Endpoints ................................................... 52 
10.4.5 
Additional Safety Analyses ......................................................... 52 
11. 
REGULATORY OBLIGATIONS ............................................................................. 52 
11.1 
Informed Consent ....................................................................................... 52 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 53 
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 ............................................................. 55 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160250 
Date:  19 February 2020 
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CONFIDENTIAL 
 
 
12.3 
Study Monitoring and Data Collection ........................................................ 56 
12.4 
Investigator Responsibilities for Data Collection ........................................ 57 
12.5 
Language.................................................................................................... 57 
12.6 
Publication Policy ....................................................................................... 57 
12.7 
Compensation ............................................................................................ 58 
13. 
REFERENCES ....................................................................................................... 59 
14. 
APPENDICES ........................................................................................................ 61 
List of Tables 
Table 1.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................... 26 
Table 2.  Acceptable Methods of Effective Contraception for Female Subjects .............. 30 
Table 3.  Schedule of Assessments ................................................................................ 32 
Table 4.  Laboratory Analyte Listing ................................................................................ 39 
Table 5.  Confidence Interval Width for Adverse Event Rates ........................................ 50 
List of Figures 
Figure 1.  Study Design and Treatment Schema .............................................................. 6 
List of Appendices 
Appendix A.  Additional Safety Assessment Information ................................................ 62 
Appendix B.  Sample Serious Adverse Event Report Form ............................................ 64 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................... 67 
Appendix D.  Recommended Lipid-lowering Background Therapy ................................. 69 
Appendix E.  Drugs With Known Major Interactions With Statin Background 
Therapy .................................................................................................... 70 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160250 
Date:  19 February 2020 
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1. 
OBJECTIVES 
1.1 
Primary 
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 of < 40 mg/dL (1.03 mmol/L) 
1.3 
Exploratory 
The exploratory objectives are the following:   
• 
To describe the effects of long-term administration on non-high-density lipoprotein 
cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol, lipoprotein(a) 
(Lp[a]), triglycerides, high-density lipoprotein cholesterol (HDL-C), LDL-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 world-wide epidemic; and 
though over the last 2 decades CVD mortality has declined (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 
(WHO) estimated 57 million deaths world-wide, of which 36 million were due to 
non-communicable causes.  CVD accounted for over 17 million of these deaths, nearly 
80% of which were due to heart attacks and strokes alone (responsible for 7.3 million 
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 arena is immense 
(World Health Organization, 2011). 
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Dyslipidemia is a major modifiable risk factor for the development of CVD.  It is 
estimated that approximately 100 and 34 million Americans have a 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, Europe, and Japan are currently treated with dyslipidemia therapies.  
The rationale for treatment of dyslipidemia, particularly elevated LDL-C, extends from 
extensive clinical trial 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 trials 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, 
non-fatal myocardial infarction [MI], coronary revascularization, or stroke).  Importantly, 
this meta-analysis, which also evaluated 5 trials that compared more versus less 
intensive statin therapy, did not find a 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 primary and 
secondary prevention studies where subjects are 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 these patients on lipid 
reduction therapy still have cardiovascular events (Libby and Theroux, 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 (Grundy et al, 2004; 
National Cholesterol Education Program, 2002), Cholesterol Treatment Trialists’ 
Collaboration (2010) data suggest that novel agents that are capable of providing 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160250 
Date:  19 February 2020 
Page 16 of 70 
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additional LDL-C lowering 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).  
Non-statin 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%. 
Recently, the IMPROVE-IT study evaluated cardiovascular outcomes (cardiovascular 
death, MI, hospital admission for unstable angina [UA], 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 myocardial 
infarction (STEMI), or non-STEMI or UA, less than 10 days before enrollment 
(Cannon et al, 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 non-statin therapy, ezetimibe.  
Considering the remaining cardiovascular risk despite the availability of statin therapy 
and given that non-statin 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 non-statin agent that will get a significant proportion of patients to 
LDL-C goal and further reduce cardiovascular risk.  This need is especially evident 
among individuals at high risk for future cardiovascular events; namely, those who have 
already suffered from a MI, non-hemorrhagic stroke, or 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 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160250 
Date:  19 February 2020 
Page 17 of 70 
CONFIDENTIAL 
 
 
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 suggests 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 specific section of the Evolocumab (AMG 145) Investigator’s Brochure for 
additional information related to the physical, chemical, and pharmaceutical properties 
and formulation(s). 
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 1600 subjects will be enrolled. 
2.4 
Clinical Hypothesis 
The 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, OLE study designed to assess the extended long-term safety of 
evolocumab in subjects who have completed the FOURIER (Study 20110118) trial.  
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160250 
Date:  19 February 2020 
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FOURIER is a randomized, placebo-controlled study of evolocumab, in patients with 
clinically evident atherosclerotic CVD on stable effective statin therapy.  After signing the 
informed consent, subjects should be enrolled within 7 days.  Subjects at sites 
participating in FOURIER OLE who are eligible and have signed the FOURIER OLE 
informed consent will be enrolled after completion of FOURIER.   
The FOURIER OLE study requires laboratory assessments at day 1, week 12, and 
thereafter approximately every 6 months from day 1 (see Section 7.2); the 
corresponding blood samples will be processed using a central laboratory.  Upon 
enrollment in FOURIER OLE study, 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 (Figure 1) at the end of the 
protocol synopsis section. 
The study endpoints are defined in Section 10.1.1. 
3.2 
Number of Sites 
Approximately 100 centers will participate in this study in selected European countries 
(Belgium, Denmark, Germany, France, Italy, Portugal, and Sweden).  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 
1600 subjects will be enrolled in this study. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160250 
Date:  19 February 2020 
Page 19 of 70 
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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 purposes of 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, long-term follow-up), as applicable. 
4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).  This log may be completed and updated via an Interactive Voice Response 
(IVR)/Interactive Web Response (IWR) system.   
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1). 
4.1 
Inclusion Criteria 
101 
Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures. 
102 
Subject had completed FOURIER (Study 20110118) while still receiving 
assigned Investigational Product. 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160250 
Date:  19 February 2020 
Page 20 of 70 
CONFIDENTIAL 
 
 
4.2 
Exclusion Criteria 
201 
Permanent discontinuation of Investigational Product during FOURIER for any 
reason including an adverse event or serious adverse event. 
202 
Currently receiving treatment in another investigational device or drug study, or 
less than 4 weeks since ending treatment on another investigational device or 
drug study(ies).  Other investigational procedures while participating in this study 
are excluded. 
203 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject and investigator’s knowledge. 
204 
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 known sensitivity to any of the active substances or excipients 
(eg, sodium acetate) to be administered during dosing.   
206 
Females who are pregnant or breastfeeding or planning to become pregnant or 
breastfeed during treatment with evolocumab and for an additional 15 weeks 
after treatment with evolocumab discontinues. 
207 
Female subjects of childbearing potential unwilling to use an acceptable method 
of effective contraception during treatment and for an additional 15 weeks after 
the last dose of protocol-required therapies.  Refer to Section 6.8 for additional 
contraceptive information. 
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).  Subject 
or the subject's legally acceptable representative 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, documents and dates this decision in the subject's medical record, 
and contacts the IVR/IWR system to enroll the subject.   
Each subject who enter into the screening period for the study (after signing the 
IRB/IEC-approved ICF) are to be assigned the same subject identification number as the 
parent study (FOURIER Study 20110118) 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.   
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160250 
Date:  19 February 2020 
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The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment. 
5.1 
Treatment Assignment 
All subjects will receive open-label evolocumab. 
The treatment assignment date is to be documented in the subject’s medical record and 
on the enrollment case report form (CRF).  
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Product(s), Medical Device(s) and/or Combination 
Product(s) 
The Amgen investigational product used in this study includes:  evolocumab.   
The non-Amgen non-investigational products used in this study includes:  background 
LLTs, including a statin.   
The investigational medical devices used in this study includes:  prefilled 
auto-injector/pen (AI/pen) or personal injector (PI). 
Note:  Non-investigational medical devices (ie, medical device[s] not under study) or 
medicinal products will be described in Section 6.5. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of evolocumab and the investigational medical devices used in this 
study.  
6.2 
Investigational Product 
6.2.1 
Amgen Investigational Product - Evolocumab 
Evolocumab will be manufactured and packaged by Amgen Inc., and distributed using 
Amgen clinical study drug distribution procedures.  Evolocumab will be presented 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 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160250 
Date:  19 February 2020 
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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 directly to 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 electronic case report form (eCRF).  Subjects 
should return used evolocumab for reconciliation by the site. 
6.2.1.1 
Dosage, Administration, and Schedule 
Evolocumab will be administered SC Q2W or QM for approximately 260 weeks in 
accordance with the instructions in the IPIM and IFU.  The last resupply of 
evolocumab will occur 12 weeks after the week 240 visit.  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 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. 
When evolocumab is scheduled to be 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 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160250 
Date:  19 February 2020 
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CONFIDENTIAL 
 
 
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. 
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. 
The effects of overdose of this product are not known. 
6.2.1.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
No dose adjustments of evolocumab will be allowed in this study. 
Evolocumab is administered on a Q2W or QM schedule.  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.  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.  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.  Additionally, subjects taking 420 mg evolocumab QM will have the opportunity to 
switch drug administration (3 administrations by prefilled AI/pen or 1 administration by 
PI) at any scheduled time point.  The reason for dose change of evolocumab is to be 
recorded on each subject’s eCRF(s). 
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. 
If a subject dose of evolocumab is missed or late, administration should occur as soon 
as possible if there are 7 days or more 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. 
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 
Approved 
 
 


Product:  Evolocumab 
Protocol Number:  20160250 
Date:  19 February 2020 
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recur with rechallenge of evolocumab, then evolocumab should be permanently 
discontinued. 
Information on when to stop Amgen investigational product due to hepatotoxicity is 
provided in Section 6.3. 
6.2.2 
Non-Amgen Non-investigational Product 
Non-Amgen non-investigational products including background LLT (including statin), 
will also be used in this study.  These therapies will not be provided or reimbursed by 
Amgen. 
6.2.2.1 
Non-Amgen Non-investigational Product – Background 
Lipid-lowering Therapy 
6.2.2.1.1 
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, frequency, and 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.   
Subjects should consult the investigator if they miss a dose of background statin. 
6.2.2.2 
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.  The reason for dose change of non-Amgen non-investigational 
product is to be recorded on each subject’s eCRF(s). 
If a subject has elevated ad hoc laboratory values (Section 6.3) 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 
Approved 
 
 


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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. 
6.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Routine hepatic laboratory assessments are not required for this study.  However, the 
guidelines (Section 6.3.1) apply for elevated liver enzymes noted during ad hoc tests.   
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio [INR] and/or signs/symptoms of hepatitis [as 
described below]) may meet the criteria for withholding or permanent discontinuation of 
Amgen investigational product or other protocol-required therapies as specified in the 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation 
(July 2009).   
6.3.1 
Criteria for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due 
to Potential Hepatotoxicity 
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver biomarkers (TBL, INR and transaminases) has not been 
identified. 
Important alternative causes for elevated AST/ ALT and/or TBL values include, but are 
not limited to: 
• 
Hepatobiliary tract disease 
• 
Viral hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, Herpes 
Simplex Virus, Varicella, toxoplasmosis, and Parvovirus) 
• 
Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia. 
• 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants and mushrooms 
Approved 
 
 


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• 
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 (NASH) 
• 
Non-hepatic causes (eg, rhabdomyolysis, hemolysis) 
If investigational product(s) is/are withheld, the subject is to be followed according to 
recommendations in Appendix A for possible drug-induced liver injury (DILI). 
Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL, is discovered and the laboratory abnormalities resolve 
to normal or baseline (Section 6.3.2). 
Table 1.  Conditions for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity 
Analyte 
Temporary Withholding 
Permanent Discontinuation 
TBL 
> 3x upper limit of normal (ULN) at 
any time 
> 2x ULN 
 
 
OR 
INR 
-- 
> 1.5 (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 8x ULN at any time 
 
> 5x ULN but < 8x ULN for ≥ 2 weeks 
 
> 5x ULN but < 8x ULN and unable to 
adhere to enhanced monitoring 
schedule 
 
> 3x ULN with clinical signs or 
symptoms that are consistent with 
hepatitis (such as right upper 
quadrant pain/tenderness, fever, 
nausea, vomiting, jaundice). 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values 
 
> 3x ULN (when baseline was 
< ULN) 
 
OR 
 
ALP 
> 8x ULN at any time 
-- 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal 
Approved 
 
 


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6.3.2 
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 Table 1) 
should never be rechallenged. 
6.4 
Concomitant Therapy 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.7.  Concomitant therapies are to be collected from informed consent 
through the end of safety follow-up period. 
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 (HRT) 
• 
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 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 3).  
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 
required to refrain from unaccustomed intensive exercise (eg, heavy lifting or long runs) 
48 hours prior to each visit. 
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6.5 
Medical Devices 
The following investigational medical devices, prefilled AI/pen or PI, will be used in this 
study and provided by Amgen (Section 6.2).  Additional details for each medical device 
is to be provided in the IPIM.   
The evolocumab AI/pen is a single use disposable, handheld mechanical "spring-based" 
device for fixed dose SC injection of 140 mg/mL evolocumab in 1.0 mL deliverable 
volume. 
The evolocumab PI is a single use, disposable, on-body electromechanical injection 
device that is copackaged with a prefilled Crystal Zenith cartridge containing 120 mg/mL 
evolocumab in a 3.5 mL deliverable volume. 
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard of 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.   
6.6 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug 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 drugs, devices or combination products provisioned and/or 
repackaged/modified by Amgen.  Drugs or devices includes investigational product 
(evolocumab), AI/pen, and PI.   
Any product complaints associated with an investigational product (evolocumab) or 
devices supplied by Amgen are to be reported according to the instructions provided in 
the IPIM. 
6.7 
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 
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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 
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. 
6.8 
Contraceptive Requirements 
Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Female in the following categories are not considered of child bearing potential: 
1. Premenopausal female with 1 of the following: 
a.  Documented hysterectomy 
b.  Documented bilateral salpingectomy 
c.  Documented bilateral oophorectomy 
Note:  Site personnel documentation from the following sources is acceptable:  
1) review of subject medical records, 2) subject medical examination, or 3) subject 
medical history interview. 
2. Premenarchal female 
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3. Postmenopausal female 
a.  A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle-stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or HRT.  However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient. 
b.  Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they 
wish to continue their HRT during the study.  Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
6.8.1 
Female Subjects 
Female subjects of childbearing potential must agree to use an acceptable method of 
effective contraception (as described in Table 2 below) during treatment and for an 
additional 15 weeks after the last dose of protocol-required therapies. 
Table 2.  Acceptable Methods of Effective Contraception for Female Subjects 
• 
combined (estrogen and progestogen) or progestogen-only hormonal methods given via 
oral, intravaginal, transdermal, injectable, or implantable route 
• 
intrauterine device (IUD) 
• 
intrauterine hormonal-releasing system (IUS) 
• 
bilateral tubal ligation/occlusion 
• 
vasectomized partner (provided that partner is the sole sexual partner of the female subject 
of childbearing potential and that the vasectomized partner has received medical 
assessment of the surgical success) 
• 
sexual abstinence (defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments.  The reliability of sexual abstinence 
must be evaluated in relation to the duration of the trial and the preferred and usual lifestyle 
of the subject.) 
• 
male or female condom with or without spermicide 
• 
cap, diaphragm or sponge with spermicide 
• 
double barrier method:  the male uses a condom and the female may choose either a cap, 
diaphragm, or sponge with spermicide.  A female condom is not an option due to the risk of 
tearing when both partners use a condom. 
If a female subject is suspected of being pregnant, the protocol-required therapies must 
be stopped immediately and may not be resumed until absence of pregnancy has been 
medically confirmed.   
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6.8.2 
Male Subjects 
Male subjects are not required to use contraception while taking evolocumab. 
6.8.3 
Unacceptable Methods of Birth Control for Female Subjects 
Birth control methods that are considered unacceptable in clinical trials include:  periodic 
abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method. 
Female subjects of childbearing potential must receive pregnancy prevention counseling 
and be advised of the risk to fetus if they become pregnant during treatment and for 
15 weeks after the last dose of protocol-required therapies.   
Additional medications given during the study may alter the contraceptive requirements.  
These additional medications may require female subjects to use highly effective 
methods of contraception and for an increased length of time.  The investigator must 
discuss these contraceptive changes with the subject. 
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments 
 
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Table 3.  Schedule of Assessments 
Time point/Frequency 
Screening D1 W12 W24 W48 W72 W96 W120 W144 W168 W192 W216 W240a 
W260b 
EOSc 
General Procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Review for 
AEs/ADEs/SAEs/DREs 
 
Continually throughout entire study 
Concomitant therapy 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Body weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Coronary revascularization 
procedure and death 
informationh 
 
Continually throughout entire study 
Laboratoryd 
Fasting lipid panel and 
ApoA1, ApoB, Lp(a) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Serum pregnancy  
(FSH) 
Xe 
X 
(X) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Evolocumabf 
Administration at study siteg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Evolocumab 
dispense/reconcile 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xb 
 
Footnotes defined on next page 
 
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ADE = adverse device effect; AE = adverse event; AI/pen = auto-injector/pen; ApoA1 = apolipoprotein A1; ApoB = apolipoprotein B; BP = blood pressure; D1 = day 1 
(first administration of evolocumab in FOURIER OLE study); DRE = disease-related events; eCRF = electronic case report form;EOS = end of study; 
FSH = follicle-stimulating hormone; HR = heart rate; Lp(a) = lipoprotein(a); PI = personal injector; SAE = serious adverse event; Q2W = every 2 weeks; 
QM = monthly; W = week. 
Mandatory study visits will occur at day 1, week 12, and thereafter approximately every 6 months from day 1 (each site visit has a window of ± 2 weeks).  Resupply 
visits will be scheduled quarterly (every 12 weeks).  Evolocumab will be supplied directly to sites.  The last resupply of evolocumab will occur 12 weeks after the 
week 240 visit. 
a Subjects may be contacted by phone at week 240. 
b No evolocumab to be dispensed; reconciliation only. 
c 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.   
d On-study blood samples for these assessments will be processed at central laboratory.  Additional laboratory assessments that may be deemed necessary to 
evaluate (serious) AEs will be processed locally.  Serum pregnancy in females of childbearing potential.  FSH only if needed to establish postmenopausal status. 
e Screening pregnancy test to be completed within 7 days prior to enrollment by local institutional standard practice. 
f Subjects administer evolocumab at a Q2W or QM schedule and 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.  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. 
g Recommended if study visit is within dosing schedule for the patient.  
h 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. 
 
 
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7.2 
General Study Procedures 
Mandatory study visits will occur at day 1, week 12 and thereafter approximately every 
6 months from day 1 (each site visit has a window of ± 2 weeks).  Resupply visits will be 
scheduled quarterly (every 12 weeks).  The last resupply of evolocumab will occur 
12 weeks after the week 240 visit.  Evolocumab will be supplied directly to the site.  
Method of resupply will be determined based on local regulations as well as available 
infrastructure.  Assessments and procedures are per Schedule of Assessments  
(Table 3) and include vital signs, physical exam, body weight, concomitant therapy, 
adverse events/adverse device effects/serious adverse events/disease-related events 
assessments, fasting lipid panel, serum pregnancy testing (females of childbearing 
potential), and evolocumab administration.  If evolocumab is administered at the site, the 
administration by SC injection will be done after all other procedures have been 
completed.   
All on-study visits and dosing should be scheduled from FOURIER OLE study day 1 
(day of first administration of evolocumab in FOURIER OLE 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 3).  If a study 
visit is missed or late, all attempts should be made to bring the subject in to complete 
required assessments.  If the visit occurs outside the visit window, subsequent visits 
should resume on the original visit schedule.  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 carried out.  The risks and benefits 
of participating in the study will be verbally explained to each potential subject prior to 
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 3).  If performed at the site, evolocumab administration must be 
after completion of blood draw procedures, as applicable. 
The investigator should instruct the subject to report to the site (eg, telephone call) any 
adverse events, adverse device effects, serious adverse events, or disease-related 
events at any time (ie, between scheduled visits). 
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7.2.1 
Screening, Enrollment, and Study Day 1 
Subjects who meet eligibility criteria will be enrolled and within 3 days of enrollment will 
complete study day 1 procedures (as listed in Table 3), while continuing their 
background LLT.  Day 1 is defined as the day of first administration of evolocumab in the 
FOURIER OLE study. 
Subjects of childbearing potential are required to have a pregnancy test within 7 days 
prior to enrollment.  This test is to be performed locally per institutional standard 
practice.  Results are to be reviewed and documented before the subject can be 
enrolled. 
For prior therapies,  refer to Section 6.4. 
The following procedures are to be completed during the screening period or study day 1 
at time points designated in the Schedule of Assessments (Table 3):   
• 
confirmation that the ICF has been signed 
• 
age and other demographic data (including sex, race, and ethnicity, that will be 
carried over from the parent study) may be used to study their possible association 
with subject safety and treatment effectiveness 
• 
medical/surgical history 
• 
vital signs (eg, sitting blood pressure and heart rate) 
• 
adverse event/serious adverse event/adverse device effect/disease-related event 
reporting 
• 
concomitant therapy 
• 
physical examination as per standard of care (including medical/surgical history).  
Physical examination findings should be recorded on the appropriate eCRF 
(eg, medical history, event).  
• 
body weight 
• 
coronary revascularization procedure and death information (sites will be 
prompted for this information when necessary) 
• 
laboratory assessments including local and central laboratories, as applicable 
• 
blood draw for a serum pregnancy test (women of childbearing potential only by 
central laboratory per local institutional standard practice) 
• 
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) 
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 3).  
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Administration of evolocumab is to be administered after completion of the blood draws 
and vital signs during each visit that it is required. 
• 
vital signs (eg, sitting blood pressure and heart rate) 
• 
review of adverse events/serious adverse events/adverse device 
effects/disease-related events 
• 
review of concomitant therapy 
• 
body weight 
• 
coronary revascularization procedure and death information (sites will be 
prompted for this information when necessary) 
• 
blood draws for fasting lipids (≥ 9-hour fasting sample), ApoA1, ApoB, and Lp(a) 
• 
blood draw for a serum pregnancy test (women of childbearing potential only by 
central laboratory per local institutional standard practice) 
• 
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, serious adverse events, adverse device effects, 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 3) for collection of 
adverse events, serious adverse events, adverse device effects, disease-related events. 
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 through 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 week 260 procedures should be completed at the time of 
withdrawal (see Section 7.2.3). 
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 Visit/End of Study Visit 
A safety follow-up is scheduled to occur at least 30 days (+ 3 days) after last 
administration of evolocumab.  This safety follow-up will be done by phone (Table 3).   
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The study required procedures during the EOS visit are outlined below:   
• 
review of adverse events/serious adverse events/adverse device 
effects/disease-related events 
• 
review of concomitant therapy 
• 
coronary revascularization procedure and death information (sites will be 
prompted for this information when necessary) 
7.2.4 
Description of Study Procedures 
7.2.4.1 
Medical History 
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. 
7.2.4.2 
Vital Signs 
The following measurements must be performed:  systolic/diastolic blood pressure and 
heart rate. 
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. 
Record all measurements on the vital signs eCRF. 
7.2.4.3 
Review of Safety Events 
All adverse events, serious adverse events, adverse device effects, and disease-related 
events must be recorded on the subject’s 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.  All reported adverse events are 
followed until resolution or stabilization. 
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During the independent review of deaths and cardiovascular events of interest, 
investigators may be prompted to provide additional information. 
7.2.4.3.1 
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. 
7.2.4.4 
Physical Examination 
A complete physical examination is to include examination of cardiovascular and 
respiratory systems, abdominal examination, and general neurologic examination. 
7.2.4.5 
Physical Measurements:  Weight 
Weight in kilograms should be measured without shoes. 
7.2.4.6 
Laboratory Assessments 
Subjects must be fasting for ≥ 9 hours before each study visit where fasting lipid 
samples are obtained.  On-study laboratory samples will be analyzed centrally as noted 
in the Schedule of Assessments (Table 3).  Additional laboratory assessments that may 
be deemed necessary to evaluate (serious) adverse events will be processed locally. 
Table 4 outlines the specific analytes that will be assessed during the study. 
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Table 4.  Laboratory Analyte Listing 
Laboratory 
Chemistry 
Laboratory 
Coagulation 
Laboratory 
Urinalysis 
Laboratory 
Hematology 
Other Labs 
None 
None 
None 
None 
Fasting lipid panel: 
• Total cholesterol 
• Triglycerides  
• LDL-C 
• HDL-C  
• VLDL-C  
• non-HDL-C 
ApoA1 
ApoB  
Lp(a) 
Pregnancy test (females of 
childbearing potential) 
FSH (if applicable) 
ApoA1 = apolipoprotein A1; ApoB = apolipoprotein B; FSH = follicle-stimulating hormone; 
HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; 
Lp(a) = lipoprotein(a); non-HDL-C = non-high-density lipoprotein cholesterol; VLDL-C = very low-density 
lipoprotein cholesterol 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution.   
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product, device or other protocol-required therapies and must 
discuss with the subject the possibilities for continuation of the Schedule of Assessments 
(Table 3) 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 investigational product, device, and/or protocol required 
therapies as well as study assessments or procedures should not be automatically 
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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, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study. 
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 from investigational 
product, device, and/or other protocol-required therapies, protocol procedures, or the 
study as a whole at any time prior to study completion. 
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(s) or procedural 
assessments include any of the following: 
• 
subject request 
• 
safety concern (eg, due to an adverse event, ineligibility determined, protocol 
deviation, non-compliance, requirement for alternative therapy, protocol-specified 
criteria [see Section 6.2.1.2], pregnancy) 
• 
death 
• 
lost to follow-up 
• 
decision by Sponsor (other than subject request, safety concern, lost to follow-up) 
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
• 
decision by sponsor 
• 
withdrawal of consent from study 
• 
death 
• 
lost to follow-up 
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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 
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 non-serious) anticipated to occur in the 
study population due to the underlying disease.  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, MI, 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 that do not qualify as adverse events or serious adverse events:  
• 
An event which is part of the normal course of disease under study (eg, disease 
progression in oncology or hospitalization due to disease progression) is to be 
reported as a disease-related event.  
• 
Death due to the disease under study is to be recorded on the Event eCRF. 
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Disease-related events that would qualify as an adverse event or serious adverse event: 
• 
An event based on the underlying disease that is worse than expected as assessed 
by the investigator for the subject’s condition or if the investigator believes there is a 
causal relationship between the investigational product (evolocumab)/study 
treatment/protocol-required therapies and disease worsening, this must be reported 
as an adverse event or serious adverse event. 
Disease-related events will be collected through OLE duration including the safety 
follow-up visit, and will be recorded using the Event eCRF per Section 9.2.1.  
9.1.2 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease 
(eg, diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected, and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study or involves 
an intervention such as elective cosmetic surgery or a medical procedure while on study, 
is not considered an adverse event.   
An adverse device effect is any adverse event related to the use of a medical device.  
Adverse device effects include adverse events resulting from insufficient or inadequate 
instructions for use, adverse events resulting from any malfunction of the device, or 
adverse events resulting from use error or from intentional misuse of the device. 
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study.   
Approved 
 
 


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9.1.3 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria (unless it meets the definition of a disease-related event as 
defined in Section 9.1.1): 
• 
fatal 
• 
life threatening (places the subject at immediate risk of death) 
• 
requires in-patient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
congenital anomaly/birth defect 
• 
other medically important serious event 
A disease-related event (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 
• 
if the investigator believes a causal relationship exists between the investigational 
medicinal product(s)/protocol-required therapies and the event,  
• 
and the event meets at least 1 of the serious criteria. 
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.   
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 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, are recorded on the Event eCRF as a 
disease-related event.   
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.   
Approved 
 
 


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Disease-related events assessed by the investigator to be more severe than expected 
and/or related to the investigational medicinal product (evolocumab)/study 
treatment/protocol-required therapies, and determined to be serious, must be recorded 
on the Event eCRF as serious adverse events.   
Additionally, the investigator is required to report a fatal disease-related event on the 
Event eCRF as a disease-related event.   
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 and adverse device 
effects observed by the investigator or reported by the subject that occur after signing 
the ICF through the EOS/Safety Follow-Up 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 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 
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 adverse event grading scale used will be the Common Terminology Criteria for 
Adverse Events (CTCAE).  The grading scale used in this study is described in 
Appendix A.   
The investigator must assess whether the adverse event is possibly related to 
investigational medicinal product (evolocumab) and/or other protocol-required therapies.  
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 and/or other protocol-required therapies? 
The investigator must assess whether the adverse event is possibly related to the 
prefilled AI/Pen or PI investigational devices used to administer investigational medicinal 
Approved 
 
 


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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 any 
study-mandated activity (eg, administration of investigational product, protocol-required 
therapies, use of medical devices and/or procedure including any screening 
procedures).  This relationship is indicated by a “yes” or “no” response to the question:  
Is there a reasonable possibility that the event may have been caused by a study activity 
(eg, administration of investigational product, protocol-required therapies, use of medical 
devices), and/or 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 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 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 (eSAE) Contingency Report Form within 24 hours of the 
investigator’s knowledge of the event.  See Appendix B for a sample of the Serious 
Adverse Event Worksheet/eSAE Contingency Report Form.  For EDC studies where the 
Approved 
 
 


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first notification of a Serious Adverse Event is reported to Amgen via the eSAE 
Contingency Report Form, the data must be entered into the EDC system when the 
system is again available. 
The investigator must assess whether the serious adverse event is possibly related to 
investigational medicinal product (evolocumab) and/or other protocol-required therapies.  
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 and/or other protocol-required therapies? 
The investigator must assess whether the serious adverse event is possibly related to 
the prefilled AI/Pen or PI investigational devices 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 serious adverse event is possibly related to 
any study-mandated activity (eg, administration of investigational product, 
protocol-required therapies, use of medical devices and/or procedure including any 
screening procedures).  This relationship is indicated by a “yes” or “no” response to the 
question:  Is there a reasonable possibility that the event may have been caused by a 
study activity (eg, administration of investigational product, protocol-required therapies, 
use of medical devices), and/or procedure? 
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility.  
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Event 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 
Approved 
 
 


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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 regulatory requirements and procedures. 
9.2.2.3 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after EOS.  However, these serious adverse 
events can be reported to Amgen.  In some countries (eg, European Union [EU] member 
states), investigators are required to report serious adverse events that they become 
aware of after end of study.  If serious adverse events are reported, the investigator is to 
report them to Amgen within 24 hours following the investigator’s knowledge of the 
event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases for the purposes of expedited 
reporting. 
9.3 
Pregnancy and Lactation Reporting 
If a female subject becomes pregnant while the subject is taking evolocumab report the 
pregnancy to Amgen Global Patient Safety as specified below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
report pregnancies that occur for an additional 15 weeks after the last dose of 
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.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C).  Amgen Global Patient Safety will 
follow-up with the investigator regarding additional information that may be requested.  
If a female subject becomes pregnant during the study, the investigator should attempt 
to obtain information regarding the birth outcome and health of the infant. 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, stillbirth, 
or neonatal death or there is a fetal or neonatal congenital anomaly) the investigator will 
report the event as a serious adverse event.  
Approved 
 
 


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If a female breastfeeds while taking protocol-required therapies report the lactation case 
to Amgen as specified below.  
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up with 
the investigator regarding additional information that may be requested. 
If a male subject's female partner becomes pregnant, the investigator should discuss 
obtaining information regarding the birth outcome and health of the infant from the 
pregnant partner. 
Amgen is sponsoring a prospective, observational study of pregnant women who have 
been exposed to Repatha® (evolocumab) at any point during pregnancy and/or 
breastfeeding.  The registry is conducted 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 20160250 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 to Amgen’s evolocumab pregnancy 
registry according to the place of residency.  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 for this study 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 
Approved 
 
 


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10.1.1.3 
Exploratory Endpoints 
The exploratory endpoints for this study are the following:  
• 
Change and percent change from baseline at each scheduled visit in each of the 
following lipid parameters:   
o total cholesterol 
o triglycerides 
o HDL-C 
o VLDL-C 
o LDL-C 
o non-HDL-C 
o ApoA1 
o ApoB 
o Lp(a) 
• 
Subject incidence of events positively reviewed by the CEC: 
o All deaths 
o Cardiovascular events of interest: 
 MI 
 Stroke 
 Coronary revascularization 
 Hospitalization for unstable angina 
 Hospitalization for heart failure 
 TIA 
10.1.2 
Analysis Sets 
The OLE safety analysis set includes all subjects who received at least 1 dose of 
open-label evolocumab in the OLE study.  This analysis set will be used for all analyses. 
10.1.3 
Covariates and Subgroups 
The planned covariates and subgroups include the following: 
• 
age (< 65 years, ≥ 65 years) 
• 
sex (male, female) 
• 
race 
10.1.4 
Handling of Missing and Incomplete Data 
No missing value imputation is planned for primary, secondary, or exploratory endpoints. 
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10.2 
Sample Size Considerations 
It is estimated approximately 1600 subjects who completed the FOURIER trial will be 
enrolled.  Based on sample size of 1600 subjects, Table 5 lists the width of 
95% confidence interval (CI) for a range of various underlying adverse event rates. 
Table 5.  Confidence Interval Width for Adverse Event Rates 
Underlying Adverse Event Rate (%) 
Width of 95% Confidence Interval 
0.01 
0.098 
0.05 
0.219 
0.10 
0.310 
1.00 
0.975 
2.00 
1.372 
3.00 
1.672 
4.00 
1.920 
5.00 
2.136 
10.3 
Planned Analyses 
10.3.1 
Interim Analyses 
There will be interim analyses to support safety data reporting and assessments of other 
listed endpoints.  The study is not anticipated to stop early unless a major unexpected 
safety signal is detected.  
10.3.2 
Primary Analysis 
Primary analysis activities are commenced based on achieving the EOS 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 are descriptive in nature.  No statistical 
inference or missing value imputation is planned.  No formal hypothesis 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) and all analyses (primary, secondary, exploratory, and safety) will be 
performed on the OLE safety analysis set.  For all endpoints, results will be summarized 
Approved 
 
 


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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 study will be performed as applicable. 
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 (MedDRA) version at the time of 
the 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 investigational product, device-related 
adverse events, and disease related events will be tabulated for overall OLE study 
period.  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.  All CEC reviewed events will be 
reported. 
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. 
Approved 
 
 


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10.4.3 
Secondary Efficacy 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 Efficacy Endpoints 
Summary statistics of exploratory endpoints will be provided at each scheduled visit for 
each exploratory lipid parameter.  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 also 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 Manager to the investigator.  The written ICF 
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 or legally acceptable representative 
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.  A legally acceptable 
representative is an individual or other body authorized under applicable law to consent, 
on behalf of a prospective subject, to the subject’s participation in the clinical study.   
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record.   
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
Approved 
 
 


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records, and the ICF is to be signed and personally dated by the subject or a legally 
acceptable representative 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 or legally 
acceptable representative. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
ICF to the subject and must allow for questions.  Thereafter, both the subject and the 
witness must sign the ICF to attest that informed consent was freely given and 
understood.   
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed ICF, other written subject information, and any 
proposed advertising material must be submitted to the IRB/IEC for written approval.  A 
copy of the written approval of the protocol and ICF must be received by Amgen before 
recruitment of subjects into the study and shipment of Amgen investigational product. 
The investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent 
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, include the age at time of enrollment.   
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• 
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 governmental/International Conference on Harmonisation (ICH) GCP 
guidelines, it is required that the investigator and institution permit authorized 
representatives of the company, of the regulatory agency(s), and the IRB/IEC direct 
access to review the subject’s original medical records for verification of study-related 
procedures and data.  Direct access includes examining, analyzing, verifying, and 
reproducing any records and reports that are important to the evaluation of the study.  
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
11.4 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of 
multi-center studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
• 
a recognized expert in the therapeutic area 
• 
an investigator who provided significant contributions to either the design or 
interpretation of the study 
• 
an investigator contributing a high number of eligible subjects 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
Amgen may amend the protocol at any time.  After Amgen amends the protocol, the 
investigator is to return the signed Investigator’s Signature page confirming agreement 
to continue participation in the study according to the amendment.  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 and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
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 Clinical Trial Agreement.  The investigator is to notify the IRB/IEC in 
Approved 
 
 


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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 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.   
Elements to include: 
• 
subject files containing completed eCRFs, 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 
• 
investigational product-related correspondence including Proof of Receipts (POR), 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable. 
• 
non-investigational product(s), and/or medical device(s) or combination product(s) 
documentation, as applicable. 
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. 
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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 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 Research & Development Compliance 
and Audit function (or designees).  Inspection of site facilities (eg, pharmacy, 
protocol-required therapy storage areas, laboratories) and review of study-related 
records will occur to evaluate the study conduct and compliance with the protocol, ICH 
GCP, and applicable regulatory requirements. 
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. 
Approved 
 
 


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12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 3), the investigator can search publicly 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.  Consult the country-specific 
language requirements. 
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 may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff as appropriate as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the International Committee of Medical Journal Editors (ICMJE) Recommendations for 
the Conduct of Reporting, Editing, and Publications of Scholarly Work in Medical 
Journals (ICMJE, 2013), 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; and (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. 
Approved 
 
 


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• 
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. 
Approved 
 
 


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13. 
REFERENCES 
Abifadel M, Varret M, Rabes JP, et al.  Mutations in PCSK9 cause autosomal dominant 
hypercholesterolemia.  Nat Genet.  2003;34:154-156. 
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, Blazing MA, Giugliano RP, et al.  Ezetimibe Added to Statin Therapy after 
Acute Coronary Syndromes.  N Engl J Med.  2015;372:2387-2397. 
Cholesterol Treatment Trialists' (CTT) Collaboration, Baigent C, Blackwell L, et al.  
Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of 
data from 170,000 participants in 26 randomised trials.  Lancet.  2010;376:1670-1681. 
Evolocumab (AMG 145) Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc. 
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. 
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. 
International Committee of Medical Journal Editors, Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals:  Writing and Editing for Biomedical 
Publication.  2013.  http://www.icmje.org/ 
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, D.C., Dept. of Health, Education, and Welfare, Publication No. (NIH) 
1974:74-599. 
Kannel WB, Castelli WP, Gordon T.  Lipoprotein cholesterol in the prediction of 
atherosclerotic disease: New perspectives based on the Framingham Study.  Ann Intern 
Med.  1979;90:85-91. 
Kannel WB.  Range of serum cholesterol values in the population developing coronary 
artery disease.  Am J Cardiol.  1995;76:69C-77C. 
Libby, P and Theroux P.  Pathophysiology of coronary artery disease.  Circulation.  
2005;111:3481-3488. 
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. 
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. 
Approved 
 
 


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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/ 
Approved 
 
 


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14. 
APPENDICES 
Approved 
 
 


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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
Refer to National Cancer Institute Common Terminology Criteria for Adverse Events 
(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 
Drug-induced Liver Injury Reporting & Additional Assessments  
Reporting 
To facilitate appropriate monitoring for signals of drug-induced liver injury (DILI), cases 
of concurrent aspartate aminotransferase (AST) or alanine aminotransferase (ALT) and 
total bilirubin (TBL) and/or international normalized ratio (INR) elevation according to the 
criteria specified in Section 6.3 require the following: 
• 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded). 
• 
The appropriate case report form (CRF) (eg, Event CRF) that captures information 
necessary to facilitate the evaluation of treatment-emergent liver abnormalities is to 
be completed and sent to Amgen.  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.2.2.2. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Table 1 or who experience AST or ALT elevations > 3x upper limit of normal (ULN) or 
2-fold increases above baseline values for subjects with elevated values before drug are 
to undergo a period of “close observation” until abnormalities return to normal or to the 
subject’s baseline levels.   
Assessments that are to be performed during this period include:  
• 
Repeat AST, ALT, alkaline phosphatase (ALP), bilirubin (total and direct), and INR 
within 24 hours  
• 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, bilirubin (total and 
direct), and INR is to be performed every 24 hours until laboratory abnormalities 
improve 
Approved 
 
 


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Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
• 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL.  The following are to be considered depending on the clinical situation: 
− 
complete blood count (CBC) with differential to assess for eosinophilia 
− 
serum total immunoglobulin G, anti-nuclear antibody (ANA), anti-smooth muscle 
antibody, and liver kidney microsomal antibody 1 (LKM1) to assess for 
autoimmune hepatitis 
− 
serum acetaminophen (paracetamol) levels 
− 
a more detailed history of:  
o prior and/or concurrent diseases or illness  
o exposure to environmental and/or industrial chemical agents  
o symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
o prior and/or concurrent use of alcohol, recreational drugs and special diets 
o concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
− 
viral serologies 
− 
creatine phosphokinase (CPK), haptoglobin, lactate dehydrogenase (LDH), and 
peripheral blood smear 
− 
appropriate liver imaging if clinically indicated 
• 
appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected  
• 
hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist) 
• 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  
The “close observation period” is to continue for a minimum of 4 weeks after 
discontinuation of all investigational product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications, and laboratory results must be captured in corresponding electronic case 
report forms (eCRFs). 
Approved 
 
 


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Appendix B.  Sample Serious Adverse Event Report Form 
 
Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 
Approved 
 
 


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Approved 
 
 


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Appendix D.  Recommended Lipid-lowering Background Therapy 
It is recommended that subjects continue the same background lipid-lowering therapy 
(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 6.7.  
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. 
Approved 
 
 


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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, human immunodeficiency virus 
(HIV) or hepatitis C virus (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 
Approved 
 
 


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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 Subjects With Clinically Evident 
Cardiovascular Disease in Selected European Countries 
 
Amgen Protocol Number (evolocumab) 20160250 
EudraCT number 2016-004066-26 
NCT number:  NCT03080935 
 
Amendment Date: 
19 February 2020 
 
Rationale: 
This 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. 
− 
The identified Events of Interest (EOIs) were removed from the protocol and are 
no longer pre-specified. 
• 
Update the Schedule of Assessments: 
− 
Added week 260 (replacing End of Investigational Product Administration [EoIP]) 
back into the schedule of assessments to realign with the 20130295 sister study 
and to clarify that the week 260 visit still applies. 
− 
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. 
• 
Clarify dosing details: 
− 
details regarding the switch frequency between auto-injector/pen (AI/pen) and 
personal injected (PI) were added, and  
− 
the last resupply of evolocumab will occur 12 weeks after the week 240 visit. 
• 
Update the exploratory objectives in Section 1.3 to be consistent with exploratory 
endpoints in Section 10.1.1.3 
• 
Remove language in the definition of Primary Completion to align with current 
protocol template.  
• 
Administrative, typographical, and formatting changes were made throughout the 
protocol 
Approved 
 
 


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Date:  14 December 2018 
Page 1 of 32 
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Amendment 1 
Protocol Title:  A Multicenter, Open-label, Single-arm, Extension Study to Assess 
Long term Safety of Evolocumab Therapy in Subjects With Clinically Evident 
Cardiovascular Disease in Selected European Countries 
 
Amgen Protocol Number (evolocumab) 20160250 
 
Amendment Date: 
14 December 2018 
Rationale: 
The following changes are being made to the study for the reasons indicated: 
• 
Financial disclosure statement text removed as this is not applicable to this study 
(only European sites will be participating) 
• 
An independent external Clinical Events Committee was established and will 
review deaths and cardiovascular events of interest; cardiovascular events of 
interest to be reviewed were defined 
• 
The term “targeted” concomitant therapy was removed throughout; all 
concomitant therapy will be assessed. 
• 
Clarification of statistical considerations:  primary analysis of all endpoints in the 
OLE study will only use OLE study data and how CEC events will be analyzed. 
• 
Exposure time intervals were modified 
• 
Clarifications of text or update with current template and Amgen standards: 
o Clarification of text to indicate that the lipid profiles are conducted at 
scheduled visits and not on a yearly basis 
o Self-evident correction text was removed as it is no longer an Amgen 
standard 
o Week 260 was removed as part of end of study definition for clarity 
o Concomitant therapy for disease under study, antibiotics, and then all 
other therapies:  information collected was clarified  
o Male contraception language removed as not applicable. 
o Clarification of how data will be collected and defined when a subject 
transitions from parent to OLE study, including medical history and what 
data will be transferred to OLE was provided. 
o Definition of subject withdrawal updated throughout and aligned with 
current template. 
o Redundant text for subject withdrawal and concomitant therapy removed. 
o Resupply period was clarified  
o Lot number was changed to box number for accuracy 
Approved 
 
 


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Date:  14 December 2018 
Page 2 of 32 
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o Lost to follow up section added for clarity 
o Figure 1 text modified for clarity 
o Table 3: Schedule of Assessments text modified for clarity 
Administration, typographical and formatting changes were made throughout the 
protocol.  Updates have been implemented to align with the current template. 
Approved 
 
 

SAP_001.pdf: 
Product:  Evolocumab 
Protocol Number:  20160250 
 
Date:  24 March 2022 
Page 1 of 38 
CONFIDENTIAL 
 
 
Statistical Analysis Plan 
 
Protocol Title: 
A Multicenter, Open-label, Single-arm, Extension 
Study to Assess Long-term Safety of Evolocumab 
Therapy in Subjects With Clinically Evident 
Cardiovascular Disease in Selected European 
Countries 
Short Protocol Title: 
FOURIER-OLE 
Protocol Number: 
20160250 
NCT Number: 
NCT03080935 
Authors: 
 
 (PAREXEL) 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Phone: +1-805-447-1000 
SAP Date: 
Document Version 
Date 
Original 
Amendment 1 (v2.0) 
Amendment 2 (v3.0) 
29 March 2019 
27 May 2020 
24 March 2022 
 
 


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Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
29MAR2019 
 
Amendment 1 (v2.0) 
27MAY2020 
Changes 
1. Change one of the authors from 
 to 
 
Rationale: Study statistician role had 
been transitioned from 
 
 to 
. 
2. Update statistical analysis plan (SAP) 
version and date throughout this SAP 
Rationale: Statistical analysis plan 
was amended 
3. Replace one of the cardiovascular 
events of interest :revascularization 
with coronary revascularization 
throughout this SAP 
Rationale: To identify the specific 
vascular territory of interest, which is 
the coronary circulation 
4. Change the definition of age in 
section 5.2 
Rationale: To clarify age at enrollment 
is the subject’s age in years as 
recorded on Demographics eCRF of 
the parent study 
5. Remove adverse event events of 
interest (EOIs) throughout this SAP 
Rationale: Events of interest (EOIs) 
are no longer pre-specified in the 
protocol 
6. Update the wording of the primary 
endpoint in Table 9-1 
Rationale: This change is to make it 
clear that all events listed are 
treatment emergent 
7. Update the language in Section 9.5.1 
Analyses of Primary Endpoint 
Rationale: To clarify that all adverse 
event summaries will include not only 
Clinical Events Committee (CEC) 
reviewed events but also disease 
related events; to clarify that subject 
incidence and exposure-adjusted 
subject incidence rate will be 
tabulated by system organ class, high 
level term and preferred term which is 
similar to how they were summarized 
for the parent study;  to clarify that 
disease related events will be coded 
with Medical Dictionary for Regulatory 
Activities (MedDRA) 
8. Remove the fifth and the seventh 
paragraphs in section 9.5.1 
Rationale: The third paragraph has 
captured the information  


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9. Remove efficacy from the title in 
section 9.5.2 and 9.5.3 
Rationale: To align with the title in 
section 9.5.1 
10. Replace “serious AE” with “serious 
TEAE” in section 9.6.1 
Rationale: To clarify only serious AEs 
which are treatment emergent 
11. Specify the analysis set in section 
9.6.2 and 9.6.3 
Rationale: To clarify that laboratory 
test results and vital signs will only be 
summarized based on the OLE safety 
analysis set 
12. Remove the change of exploratory 
objective in section 10 
Rationale: The exploratory objective 
not included in Protocol Amendment 1 
are now included in Protocol 
Amendment 2 
13. Remove End of Investigational 
Product Administration (EOIP) in 
Appendix. A 
Rationale: To realign with the 
20130295 sister study and to clarify 
that week 260 visit applies 
14. Add one analysis in section 9.7 
Rationale: The team agree on adding 
a listing for events which occurred in 
the time between the subject’s EOS 
date in parent study and the 
enrolment date of the OLE 
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Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Amendment 2 (v3.0) 
24March2022 
Changes: 
1. Change in one of the author of Study 
Statistician from 
 to 
 
2. Update statistical analysis plan (SAP) 
version and date throughout this SAP 
Rationale: Statistical analysis plan 
was amended 
3. Removed long-term safety analysis 
set (including parent [FOURIER] 
subjects who did not rollover into this 
OLE study) and related analysis from 
SAP and clarified the rationale in 
section 10. 
Rationale: The pre-specified planned  
analyses in the SAP focus on the long 
term safety data in the subjects who 
enrolled into this OLE study (i.e., OLE 
safety analysis set) rather than the long-
term safety analysis set which also 
includes parent study subjects who did 
not rollover into this OLE study. We will 
include parent studydata and OLE data 
from those that enrolled in the OLE for 
the analysis. More details will be 
provided in SAP section 9. 
4. Add the explanations for “ABI” and 
“PAD” in the list of abbreviations 
Rationale: To explain the abbreviation 
of a new definition added in section 
5.2 
5. Added explanation for “K-M” in the list 
of abbreviations as included for 
efficacy tables. 
6. Added a new subgroup analysis in 
the list per request from Clinical team 
to analyze the long term exposure 
effect in subjects with evolocumab. 
7. Update the definition of planned 
covariates in section 4.1 
Rationale: Since this study is for 
estimation and summarizes 
descriptive statistics.  Covariate 
analysis involves modelling; 
therefore, covariate analysis is not 
applicable for this study. 
8. Update section 5 to include definition 
of censoring date and time to event 
Rationale: We need those to be able to 
compare the results of OLE vs parent 
study. 
9. Provided more details on the 
definition of last dose date in section 
5.1 and apparently updated language 


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in definition for Enrollment date and 
Study day 1. 
10. Added Categories of Time to first-
event Endpoints with definitions and 
derivations in section 5.1 
11.  Rationale – To incorporate the last 
known survival status information 
when censoring for mortality 
endpoints especially for those lost 
to follow up patients or patients 
that withdrew consent. 
12. Updated derivation for patient years 
of follow up for TEAE. 
             Rationale – To count parent study 
and OLE period as two distinct periods which 
are added together, rather than 1 period from 
parent study’s first dose to end of OLE 
 
13. Update IP and Study Exposure 
Derivation for the combined parent 
and OLE study period. 
Rationale – To only sum of the two 
separate study exposure from the 
parent study and OLE studies (i.e., 
excluding the gap time between end 
of parent study and start of OLE) 
instead of the continuous study 
exposure from start of parent study till 
end of OLE (i.e., including the gap 
time between end of parent study and 
start of OLE. 
14. Update section 8.3.2 to include 
imputation methods for handling 
partial dates of the CEC reviewed 
events and death events. 
     Rationale: To be consistent with            
Fourier reporting. 
15. Update the wording of the primary 
endpoint in Table 9-1 
Rationale: This change is to clarify 
that all events listed are treatment 
emergent 
16. Updated section 9.3 to include 
COVID-19 related protocol deviations 
and important protocol deviations 
Rationale: Per GDE-409220, the 
COVID-19 related PD and IPD will also 
be summarized and listed as per Amgen 
standard 
17. Update the language in section 9.5.1 
Analyses of Primary Endpoint 
Rationale: To clarify that all adverse 
event summaries will include not only 
Clinical Events Committee (CEC) 
reviewed events but also disease 
related events; to clarify that disease 
related events will be coded with 


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Medical Dictionary for Regulatory 
Activities (MedDRA) 
18. Updated section 9.5.2 and section 
9.5.3 
Rationale – To specify that those 
would be analyzed. 
19. Update the LDL-C subgroup to LDL-
C40 mg/dl in section 9.6.1 
     Rationale: LDL-C  40 mg/dl is used 
to be consistent with other low LDL-C 
achievement analysis 
20. Updated section 9.5.3 for sensitivity 
analysis 
Rationale – To perform analysis for 
cardiovascular events that occurred 
during the gap (i.e.between subjects 
EOS date in parent study and OLE 
study enrolment date). 
21. Specified the analysis set in section 
9.6.1, 9.6.2, 9.6.3, 9.6.4 and 9.6.5. 
22. Updated the analysis window for 
week 260 
Rationale: to make sure the lipid 
assessments are properly included 
for the analysis 
23. Updated term from “FOURIER” to 
“parent” study. 
24. Added Appendix D. 
Rationale – To understand the 
ACC/AHA guidelines for lipid 
modifying background therapy. 
Page 2 of 2 
 
 


Product:  Evolocumab 
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Table of Contents 
1. 
Introduction ........................................................................................................... 11 
2. 
Objectives, Endpoints and Hypotheses ................................................................. 11 
2.1 
Objectives and Endpoints .......................................................................... 11 
2.2 
Hypotheses and/or Estimations ................................................................. 12 
3. 
Study Overview .................................................................................................... 12 
3.1 
Study Design ............................................................................................. 12 
3.2 
Sample Size .............................................................................................. 12 
4. 
Covariates and Subgroups ................................................................................... 13 
4.1 
Planned Covariates ................................................................................... 13 
4.2 
Subgroups ................................................................................................. 13 
5. 
Definitions ............................................................................................................. 14 
5.1 
Study Time Points ..................................................................................... 14 
5.2 
Demographic and Baseline-related Definitions .......................................... 18 
5.3 
Other Study Related Definitions ................................................................ 19 
6. 
Analysis Sets ........................................................................................................ 22 
6.1 
OLE Safety Analysis Set ........................................................................... 22 
7. 
Planned Analyses ................................................................................................. 23 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 23 
7.2 
Primary Analysis ....................................................................................... 23 
8. 
Data Screening and Acceptance ........................................................................... 23 
8.1 
General Principles ..................................................................................... 23 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 23 
8.3 
Handling of Missing and Incomplete Data ................................................. 23 
8.3.1               Patterns of Missing Data ................................................................ 23 
8.3.2              Handling of Missing Data ................................................................ 23 
8.4 
Detection of Bias ....................................................................................... 25 
8.5 
Outliers ..................................................................................................... 25 
8.6 
Distributional Characteristics ..................................................................... 26 
8.7 
Validation of Statistical Analyses ............................................................... 26 
9. 
Statistical Methods of Analysis.............................................................................. 26 
9.1 
General Considerations ............................................................................. 26 
9.2 
Subject Accountability ............................................................................... 27 
9.3 
Important Protocol Deviations ................................................................... 27 
9.4 
Demographic and Baseline Characteristics ............................................... 28 
9.5 
Efficacy Analyses ...................................................................................... 28 
9.5.1 
Analyses of Primary Endpoint .................................................... 29 
9.5.2 
Analyses of Secondary Endpoints ............................................. 30 


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9.5.3 
Analyses of Exploratory Endpoints ............................................ 30 
9.6 
Safety Analyses ........................................................................................ 31 
9.6.1 
Safety Analysis of Low LDL-C ................................................... 31 
9.6.2 
Vital Signs ................................................................................. 31 
9.6.3 
Exposure to Investigational Product .......................................... 31 
9.6.4 
Exposure to Other Protocol-specified Treatment ....................... 31 
9.6.5 
Exposure to Concomitant Medication ........................................ 31 
9.7 
Other Analyses ......................................................................................... 32 
10. 
Changes From Protocol-specified Analyses.......................................................... 32 
11. 
Literature Citations / References ........................................................................... 32 
12. 
Appendices ........................................................................................................... 33 
Appendix D.  Lipid Modifying Background Therapy .. Error! Bookmark not defined. 
 
List of Tables 
Table 3-1.  Confidence Interval Width for Adverse Event Rates..................................... 13 
Table 8-1. Imputation Rules for Incomplete Dates ......................................................... 24 
Table 9-1.  Endpoint Summary Table ............................................................................ 28 
List of Appendices 
Appendix A.  Analytical Study Week Assignments ......................................................... 34 
Appendix B.  Common Terminology Criteria for AEs (CTCAE) ...................................... 36 
Appendix C.  Mortality Endpoints Censoring ..................... Error! Bookmark not defined. 
Appendix D.  Lipid Modifying Background Therapy .......... Error! Bookmark not defined. 
 


Product:  Evolocumab 
Protocol Number:  20160250 
 
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List of Abbreviations and Definition of Terms 
 
Abbreviation or Term 
Definition/Explanation 
ABI 
Ankle-brachial index 
AE 
Adverse event 
ALP 
Alkaline phosphatase  
ALT (SGPT) 
Alanine aminotransferase (serum glutamic-pyruvic transaminase) 
ApoA1 
Apolipoprotein A1 
ApoB 
Apolipoprotein B 
AST (SGOT) 
Aspartate aminotransferase (serum glutamic-oxaloacetic 
transaminase) 
CEC 
Clinical events committee 
CI 
Confidence Interval 
CSR 
Clinical study report 
CTCAE 
Common terminology criteria for adverse events 
CVD 
Cardiovascular disease 
DRE 
Disease-related event 
eCRF 
Electronic case report form 
EOI 
Event of interest 
EOIP 
End of investigational product 
EOS 
End of study 
FOURIER 
Study 20110118; the parent study for this open-label extension study 
FOURIER OLE 
Open-label extension study of the FOURIER study (Study) 
GSO-DM 
Amgen global study operations - data management 
HDL-C 
High-density lipoprotein cholesterol 
HeFH 
Heterozygous familial hypercholesterolemia 
hsCRP 
High sensitivity C-reactive protein 
IP 
Investigational product 
IPD 
Important protocol deviation 
K-M 
Kaplan-Meier 
LDL-C 
Low-density lipoprotein cholesterol 
LLT 
Lipid-lowering therapy 
Lp(a) 
Lipoprotein(a) 
MI 
Myocardial infarction 
MedDRA 
Medical Dictionary for Regulatory Activities 
non-HDL-C 
Non-high-density lipoprotein cholesterol 
OLE 
Open-label extension 
PAD 
Peripheral arterial disease 


Product:  Evolocumab 
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Abbreviation or Term 
Definition/Explanation 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
Q1 
The first quartile 
Q2W 
Every 2 weeks 
Q3 
The third quartile 
QM 
Monthly; defined as every 4 weeks 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
TEAE 
Treatment emergent adverse event 
TIA 
Transient ischemic attack 
UC 
Ultracentrifugation 
VLDL-C 
Very low-density lipoprotein cholesterol 
WHO DRUG 
World Health Organization Drug 
 


Product:  Evolocumab 
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1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol amendment 2 for study 20160250, 
AMG 145 evolocumab dated 19 February 2020. The scope of this plan includes the pre-
specified analyses and will be executed by the Amgen Global Biostatistical Science 
department unless otherwise specified. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
To describe the safety and 
tolerability of long-term 
administration of evolocumab 
 
Subject incidence of adverse events 
Secondary 
 
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 of 
< 40 mg/dL (1.03 mmol/L) 
 
Percent change of LDL-C from baseline at 
each scheduled visit 
 
 
Achievement of an LDL-C level < 40 mg/dL 
(1.03 mmol/L) at each scheduled visit 
Exploratory 
 
To describe the effects of long-term 
administration on non-high-density 
lipoprotein cholesterol (non-HDL-C), 
apolipoprotein B (ApoB), total 
cholesterol, lipoprotein(a) (Lp[a]), 
triglycerides, high-density lipoprotein 
cholesterol (HDL-C), LDL-C, very 
low-density lipoprotein (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 
 
Change and percent change from baseline at 
each scheduled visit in each of the following 
lipid parameters: 
 
non-HDL-C 
 
ApoB 
 
Total cholesterol 
 
Lp(a) 
 
Triglycerides 
 
HDL-C 
 
LDL-C  
 
VLDL-C 
 
ApoA1 
 
Subject incidence of events positively reviewed 
by the CEC: 
 
All deaths 
 
Cardiovascular events of interest: 
o 
Myocardial Infarction (MI) 
o 
Stroke 
o 
Coronary revascularization 
o 
Hospitalization for unstable 
angina 
o 
Hospitalization for heart failure 
o 
Transient Ischemic Attack 
(TIA) 


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2.2 
Hypotheses and/or Estimations 
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). 
3. 
Study Overview 
3.1 
Study Design 
This is a multicenter, open-label extension (OLE) study designed to assess the extended 
long-term safety of evolocumab in subjects who have completed the FOURIER trial 
(Study 20110118). FOURIER is a randomized placebo-controlled study of evolocumab, 
in patients with clinically evident atherosclerotic CVD on stable effective statin therapy. 
Subjects at sites participating in FOURIER OLE (Study 20160250) who are eligible and 
have signed the FOURIER OLE informed consent will be enrolled after completion of 
FOURIER.  
The FOURIER OLE study requires laboratory assessments at day 1, week 12, and 
thereafter approximately every 6 months from day 1; the corresponding blood samples 
will be processed using a central laboratory.  
Upon enrollment in FOURIER OLE study, 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 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. 
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. 
3.2 
Sample Size 
It is estimated approximately 1600 subjects who completed the FOURIER trial will be 
enrolled. Based on sample size of 1600 subjects, Table 3-1 lists the width of 
95% confidence interval (CI) for a range of various underlying adverse event rates. 


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Table 3-1.  Confidence Interval Width for Adverse Event Rates 
Underlying Adverse Event Rate (%) 
Width of 95% Confidence Interval 
0.01 
0.098 
0.05 
0.219 
0.10 
0.310 
1.00 
0.975 
2.00 
1.372 
3.00 
1.672 
4.00 
1.920 
5.00 
2.136 
 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates  
Not applicable 
4.2 
 
Subgroups 
The planned subgroups include the following: 
 
Baseline age (< 65 years, ≥ 65 years; < 75 years, ≥ 75 years) 
 
Sex (male, female) 
 
Race (white, non-white) 
 
Prior non-hemorrhagic stroke (yes, no) 
 
Symptomatic PAD (yes, no) 
 
Prior MI (No, < 1 year, 1 - < 2 years, ≥ 2 years) 
 
Baseline PCSK9 level (< median, ≥ median) 
 
Baseline LDL-C by quartiles (Q1, median, Q3) 
 
Baseline HDL-C by quartiles (Q1, median, Q3) 
 
Baseline triglycerides by quartiles (Q1, median, Q3) 
 
Baseline hsCRP (< 2 mg/L, ≥ 2 mg/L) 
 
Ezetimibe use at baseline (yes, no) 
 
ACC/AHA high statin background therapy intensity at baseline (yes, no) 
 
History of type 2 diabetes (yes, no) 
 
Heterozygous Familial Hypercholesterolemia (HeFH) at OLE enrollment (definite, 
probable, neither definite nor probable) 
 
Subjects who were randomized to and received evolocumab group in the 
parent (i.e., FOURIER) study with ≥ 7 years of the combined exposure for 
evolocumab across the parent and OLE studies. 
 


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5. 
Definitions 
5.1 
Study Time Points 
Baseline 
The baseline value is defined as the subject’s baseline value from the parent study 
(FOURIER), unless otherwise specified.  
First Dose Date of Investigational Product (IP) 
For each subject, the first dose date of IP is the date of the first administration of 
evolocumab in this OLE study. 
End of Investigational Product (EOIP) Date 
For each subject, end of investigational product is the date reported on End of 
Investigational Product Administration eCRF. 
Last Dose Date of Investigational Product 
For each subject, the last dose date of investigational product is defined as the 
date of the last administration of investigational product (evolocumab or placebo). 
If the last dose was administered in-clinic, then the Last IP Dose Date is the last 
start date captured on the IP Administration (In-Clinic) eCRF page.  
If the last dose was administered at a non-investigator site location, then the Last 
IP Dose Date is defined as the final dose date reported by the subject on the Non-
Clinic Final Investigational Product Dose Date eCRF page. 
End of Study (EOS) Date 
For each subject, the end of study date is defined as the last day that protocol-specified 
procedures are conducted for an individual subject, including safety follow-up and 
survival assessment. The EOS date is recorded on the End of Study eCRF. 
Enrollment Date 
The enrollment date for each subject is recorded on the Subject Enrollment eCRF in the 
OLE study. 
Study Day 1  
Study day 1 is defined as the day of the first administration of evolocumab in the study or 
the day of enrollment for subjects who are not administered any dose of evolocumab. 
 


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Study Day  
For each subject, and for a given date of interest, study day is defined as the number of 
days since study day 1:  
Study day  (date of interest – study day 1 date)  1 
If the date of interest is prior to the study day 1: 
Study day  (date of interest – study day 1 date) 
Study End Date 
The study end date is the last EOS date of all enrolled subjects. 
Categories of Time-to-first-event Endpoints 
All time-to-first-event endpoints in this study are categorized below. 
 
Composite 
o time to cardiovascular death, myocardial infarction, hospitalization 
for unstable angina, stroke, or coronary revascularization, 
whichever occurs first  
o time to cardiovascular death, myocardial infarction, or stroke, 
whichever occurs first 
o time to cardiovascular death or hospitalization for worsening heart 
failure, whichever occurs first 
o time to ischemic fatal or non-fatal stroke or transient ischemic 
attack, whichever occurs first 
o time to the first fatal and non-fatal myocardial infarction 
o time to the first fatal and non-fatal stroke 
 
Non-mortality 
o time to the first coronary revascularization 
 
Mortality 
o time to cardiovascular death 
o time to coronary death 
o time to death by any cause 


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Censoring date   
Endpoints are censored differently according to the endpoint categories.  The 
censoring schema are described in below: 
 
censoring date for the composite and non-mortality endpoints is the EOS 
date in the OLE study. 
 
censoring (or time-to-event) for mortality endpoints are detained in 
appendix C. 
 
Time-to-first-event Definition 
 
For the time-to-first-event analysis based on combined the parent and OLE 
data, the events adjudicated as positive in the parent study and occurred prior to 
or on subject last confirmed survival status date in the parent study (i.e., primary 
analysis in the parent study; please see the definition in the parent study SAP 
version 3.1 dated Aug 09, 2016) are included in addition to the events reviewed 
as positive in the OLE study (defined as below). 
 
For the time-to-first-event analysis based on the OLE data only, mortality 
events reviewed as positive and occurred prior to or on later of (the EOS 
date or last known survival status date from eCRF page(s) in this OLE 
study) and non-mortality events reviewed as positive and occurred prior to 
or on the EOS date are included.  For those subjects who already 
experience such event in the parent study, their time to event and censor 
flag are same as those in the parent study. 
 
For those subjects who didn’t experience such event in the parent study, 
the derivation of the time-to-event and censoring date is presented below 
For analyses combined both the parent and OLE studies 
Endpoint 
Time-to-event for 
subjects with events 
Censoring date for 
subjects without events 
Composite or Non-
mortality 
First event onset date 
reviewed by CEC in OLE 
study – randomization 
date in the parent study 
1 
EOS date in OLE study 
 


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Mortality 
Death endpoint date 
reviewed by CEC in OLE 
study – randomization 
date in the parent study 
1 
For subjects who died not 
due to death endpoint, the 
censoring date is the 
death date (reviewed by 
CEC) in OLE study 
For remaining subjects, 
the censoring date is max 
(EOS date, last known 
survival status date from 
eCRF page(s)) in the OLE 
study 
 
For analyses based on OLE data only 
Composite or Non-
mortality 
First event onset date 
reviewed by CEC in OLE 
– enrolment date in OLE 
study 1 
EOS date in OLE study 
 
Mortality 
Death endpoint date 
reviewed by CEC in OLE 
study – enrolment date 
in OLE study 1 
For subjects who died not 
due to death endpoint, the 
censoring date is the 
death date (reviewed by 
CEC) in OLE study 
For remaining subjects, 
the censoring date is max 
(EOS date, last known 
survival status date from 
eCRF page(s)) in the OLE 
study 
 
Patient-years of follow-up for treatment emergent adverse events  
For analyses based on combined both the parent and OLE studies: 
1) Subjects had first event in parent study: date (first event) – date (first dose 
date in FOURIER)  1 
2) Subjects had first event in OLE: study exposure in parent study  (date 
(first event) – first dose date in OLE  1) 
3) Subjects didn’t have events: study exposure in parent study  (min [date 
(EOS in OLE), date (last dose date in OLE)30] – first dose date in OLE  1) 
For analyses based on OLE study: 
1) Subjects had events: date (first event in OLE) – date (first dose date in 
OLE)  1 


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2) Subjects didn’t have events: min [date (EOS in OLE), date (last dose date in 
OLE)30] – date (first dose date in OLE)  1 
5.2 
Demographic and Baseline-related Definitions 
Age 
Age at baseline is the subject’s baseline age at the parent study. Age at enrollment is 
the subject’s age in years as recorded on Demographics eCRF of the parent study. 
Baseline Lipid and Lipid-related Parameters 
Baseline values for lipids (total cholesterol, HDL-C, non-HDL-C, LDL-C, VLDL-C, and 
triglycerides), ApoA1, ApoB, hsCRP, Lp(a) and their derived parameters (eg, ratio 
between them) are defined as the two most recent non-missing concentrations 
measured through central lab prior to or on the parent study randomization date. If for 
only reason only 1 value is available, then that value will be used as baseline. 
Change (absolute change) From Baseline 
The arithmetic difference from baseline at a given time point: 
Change from baseline  (value at given time point – baseline value) 
Percent Change From Baseline 
The percent change from baseline for a given variable at a given time point is defined 
as: 100 x (change from baseline / baseline value) 
Baseline Metabolic Syndrome 
Baseline metabolic syndrome is defined as the eCRF data of history history of metabolic 
syndrome at parent study baseline. 
Baseline Major Risk Factors 
Baseline major risk factors are defined at FOURIER study baseline: 
 
Diabetes (type 1 or type 2) 
 
Age  65 years at randomization in parent study (and  85 years at time of 
informed consent in parent study) 
 
MI or non-hemorrhagic stroke within 6 months of screening in parent study 
 
Additional diagnosis of myocardial infarction or non-hemorrhagic stroke excluding 
qualifying MI or non-hemorrhagic stroke 
 
Current daily cigarette smoking 


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 
History of symptomatic PAD (intermittent claudication with ABI  0.85, or 
peripheral arterial revascularization procedure, or amputation due to 
atherosclerotic disease) if eligible by MI or stroke history 
Baseline Minor Risk Factors 
Baseline minor risk factors are defined at parent study baseline: 
 
History of non-MI related coronary revascularization 
 
Residual coronary artery disease with  40 stenosis in  2 large vessels 
 
Most recent HDL-C  40 mg/dL (1.0 mmol/L) for men and  50 mg/dL (1.3 
mmol/L) for women by central laboratory before randomization 
 
Most recent hsCRP  2.0 mg/L by central laboratory before randomization 
 
Most recent LDL-C  130 mg/dL (3.4 mmol/L) or non-HDL-C  160 mg/dL (4.1 
mmol/L) by central laboratory before randomization 
 
Metabolic syndrome 
Other Baseline Values 
Other baseline values are defined at FOURIER study baseline. 
For targeted concomitant medications data, the medication taken at baseline is defined 
as the medication collected at day 1 visit (ie, currently medications taken at time of day 1 
visit) in parent study.  
For all other variables, the baseline value is defined as the last non-missing value 
collected prior to or on randomization date in parent study. 
5.3 
Other Study Related Definitions 
Treatment-emergent adverse event 
Events are categorized as Adverse Events (AEs) or Disease-related Events (DREs)   
starting on or after first dose of investigational product as determined by the flag 
indicating if the event started prior to the first dose on the Events eCRF and up to the 
EOS/Safety Follow-up visit or 30 days after the last administration of evolocumab, 
whichever is earlier. 
Treatment-Emergent Disease-Related Events 
Events categorized as Disease-related Events (DREs) defined in Protocol Section 9.1.1 
starting on or after first dose of investigational product as determined by the flag 
indicating if the disease-related event started prior to the first dose on the Events eCRF 
and up to the EOS/Safety Follow-up visit or 30 days after the last administration of 
evolocumab, whichever is earlier. 
Analytical Study Week Assignments 


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Analytical windows will be used to assign parameters to study weeks. The algorithm is 
provided in Appendix A.  
 


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Investigational Product (IP) 
Investigational product includes evolocumab 140 mg every two weeks (Q2W) and 420 
mg monthly (QM). 
IP Exposure Period in Months (Parent study) 
For subjects whose last IP dose is Q2W: 
IP exposure period  [min(last IP dose date in parent study  14 days, EOS date) – 
first IP dose date in parent study  1] / 365.25 x12 
For subjects whose last IP dose is QM: 
IP exposure period  [min(last IP dose date in parent study  28 days, EOS date) – 
first IP dose date in parent study  1] / 365.25 x12 
IP Exposure Period in Months (For OLE period) 
For subjects whose last IP dose is Q2W: 
IP exposure period in OLE period [min(last IP dose date in OLE period  14 days, 
EOS date) – first IP dose date in OLE period  1] / 365.25 x12 
For subjects whose last IP dose is QM: 
IP exposure period in OLE period [min(last IP dose date in OLE period  28 days, 
EOS date) – first IP dose date in OLE period  1] / 365.25 x12 
IP Exposure Period in Months (For the combined parent and OLE periods) 
For each subject, IP exposure in combined periods is the sum of the IP exposure 
in the parent study (defined above) plus the IP exposure in the OLE period 
(defined above). 
Study Exposure Period in Months (Parent study) 
For each randomized subject, study exposure period  [(EOS date in parent study 
– Randomization date)  1] / 365.25 x12 
Study Exposure Period in Months (For OLE period) 
For each subject, study exposure period in OLE period  [(EOS date – enrollment date) 
 1] / 365.25 x12 
 


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Study Exposure Period in Months (For the combined parent and OLE periods) 
For each subject, study exposure in combined periods is the sum of the study 
exposure in the parent study (defined above) plus the study exposure in the OLE 
period (defined above). 
Reflexive Approach for LDL-C and VLDL-C 
For all analyses related to LDL-C and VLDL-C, unless specified otherwise, an LDL-C 
reflexive approach will be used. When calculated LDL-C is less than 40 mg/dL or 
triglycerides are  400 mg/dL, the ultracentrifugation (UC) LDL-C value and UC VLDL-C 
value from the same blood sample will be used instead, if available. 
Two Consecutive LDL-C Values  cutoff (25 mg/dL and 40 mg/dl)The algorithm for 
defining the 2 consecutive LDL-C values  25 mg/dL / 40 mg/dL separated by at least 
21 days within OLE study period is summarized below: 
1) For each blood sample draw date that has at least one LDL-C value within OLE 
study period, identify the lowest LDL-C value 
a. If UC values exist regardless of the presence of calculated LDL-C values, 
the lowest UC LDL-C value will be used 
b. If only calculated LDL-C values exist, the lowest calculated LDL-C value 
will be used 
2) If a subject has 2 consecutive (separated by at least 21 days) LDL-C values that 
are  25 mg/dL / 40 mg/dL within OLE study period, then the subject will be 
considered as a subject with two consecutive LDL-C values  25 mg/dL / 40 
mg/dL within OLE study period. 
Two consecutive LDL-C in the parent study has been defined and derived in the same 
way as above. 
6. 
Analysis Sets 
6.1 
OLE Safety Analysis Set 
The OLE safety analysis set includes all subjects who received at least 1 dose of open-
label evolocumab in the OLE study. 
 


Product:  Evolocumab 
Protocol Number:  20160250 
 
Date:  24 March 2022 
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7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
Interim analysis will be performed to support safety data reporting and assessments of 
other listed endpoints. 
7.2 
Primary Analysis 
Primary analysis activities are commenced based on achieving the EOS milestone 
described in Protocol Section 3.5.2. 
8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses.  This study will use the RAVE 
database. 
All data collected in the eCRF will be extracted from RAVE. Protocol deviations will be 
transferred from eClinical. Details on data transfer will be provided in the Data Transfer 
Plan. 
8.3 
Handling of Missing and Incomplete Data 
8.3.1               Patterns of Missing Data  
Subjects may be missing specific data points for various reasons. In general, data may 
be missing due to a subject’s early withdrawal from study, a missed visit, or 
non-evaluability of a data point or an endpoint at a particular point in time. All attempts 
will be made to capture missing or partial data for this trial prior to the data cutoff date. 
The frequency and pattern of missing data for selected endpoints will be assessed 
through descriptive summaries of the measurements over time. 
There will be no imputation for missing data other than date imputation described in the 
next section. 
8.3.2              Handling of Missing Data 
Missing and partially missing dates will be queried. Partial/missing EOS dates will 
be imputed as the maximum of (last dose date of IP, vital signs assessments, lab 
assessments, AE start dates, concomitant medication start dates and imputed 
EOS date if partially missing). Partial/missing onset dates (reviewed by CEC) of 


Product:  Evolocumab 
Protocol Number:  20160250 
 
Date:  24 March 2022 
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time-to- first-event endpoints will be imputed using the following algorithm, with 
the reference date being the enrollment date.  
• Impute the missing year as the year of the reference date  
• Impute the missing month as January  
• Impute the missing day as 1st  
Partial/missing start dates of adverse events and disease-related adverse events 
will be imputed using the following algorithm, with the reference date being the 
first dose date. 
• Impute the missing year as the year of the reference date  
• Impute the missing month as January  
• Impute the missing day as 1st  
If any of the resulting dates are prior to the reference date, the imputed date will 
be reset to the reference date. Please note for completely missing start dates of 
adverse-events and disease-related adverse where ‘Did event start before first 
dose of investigational product?’ on eCRF is recorded as ‘Yes’ will not be 
imputed. In addition, any imputed death dates will be the maximum of (the all 
adverse event start dates [use imputed event dates if missing], subject EOS dates 
[use imputed EOS dates if missing], and subject last confirmed survival status 
date recorded on the survival status eCRF page). For CEC death events and AE 
death event start dates, missing or partial missing dates will use the imputed 
death dates. 
Adverse events with a valid answer to the question ‘Did event start before first dose of 
investigational product?’ on eCRF can be well defined based on the answer regardless 
of dates being completely or partially missing. Adverse events that cannot be determined 
as prior to IP or not either by the question above or by the onset date will be counted as 
treatment-emergent adverse events. 
Concomitant medication with completely or partially missing start dates will be queried. 
After the query is resolved and the date is still incomplete with year only or year and 
month only, the start date will be imputed as described in Table 8-1 below. 
Table 8-1. Imputation Rules for Incomplete Dates 
 
Missing 
Imputation 
Exception 


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Protocol Number:  20160250 
 
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Start date  
Day 
1 
Default to Study Day 1 if an 
event starts the same year and 
month as Study Day 1 
Day-Month 
1-Jan 
Default to Study Day 1 if an 
event started the same year as 
Day 1 
There are two cases for start date is missing: 
 
End date is after first dose date or missing (i.e. medication is ongoing), the 
medication will be considered as being taken at OLE study baseline and post 
baseline. 
 
End date is prior to first dose date, the medication will not be considered as 
being taken at OLE study baseline or post baseline. 
Partial/missing start dates of cardiovascular medical history events which 
occurred during the gap between subjects' EOS date in the parent study and OLE 
study enrolment date will be imputed as follows for the sensitivity analysis: 
 
If day is missing, impute to 1st of the month. If the partial start date is the 
same month as EOS date in parent study, impute to EOS date in parent study 
+1 
 
If day and month are missing, impute to 1st Jan of that year. If the partial start 
date is the same year as parent study EOS date, impute to EOS date in parent 
study +1 
 
If start date is completely unknown, no imputation and event will not be 
considered in the gap 
 
8.4 
Detection of Bias 
Important protocol deviations likely to impact the analysis and interpretation of the 
endpoints will be tabulated in the Clinical Study Report (CSR). 
If any sensitivity analyses are required to evaluate potential biases in the study’s 
conclusions, the sources of the potential biases and results of the sensitivity analyses 
will be documented in the CSR.  
8.5 
Outliers 
Various methods, including univariate summaries, histograms, scatter plots, box plots, 
and line graphs, will be used to identify outliers in key variables. Extreme data points will 


Product:  Evolocumab 
Protocol Number:  20160250 
 
Date:  24 March 2022 
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be identified during the review of the data prior to database snapshot. Such data points 
will be reviewed with clinical data management to ensure accuracy. Unless specified 
otherwise, all analyses will include outliers in the data. Sensitivity analyses may be 
undertaken if extreme outliers for a variable are observed. 
8.6 
Distributional Characteristics 
There are no distributional requirements for the planned analyses. Therefore, no 
assessment will be made. 
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.   
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Statistical analyses in this open-label study are descriptive in nature. No formal 
hypothesis will be tested in this study. No statistical inference is planned.  
Subject disposition, demographics, and baseline characteristics and exposure to IP will 
be summarized.   
Summary statistics for continuous variables will include the number of subjects (n), 
mean, standard deviation (SD) or standard error (SE), median, the first (Q1) and third 
(Q3) quartiles, minimum, and maximum. For categorical variables, the frequency and 
percentage will be given. The baseline value is defined as the subject’s baseline value 
from the parent study as defined in Section 5.2, unless specified otherwise. All analyses 
will be performed on the OLE safety analysis set. 
Interim and final analyses will be based on data collected from this study combined with 
the data from the FOURIER study as applicable. For all endpoints, results will be 
summarized by the randomized treatment group from the parent study and overall, 
unless specified otherwise. 


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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 parent study. 
There will be no imputation for missing data other than date imputation described in 
Section 8.3.2 
9.2 
Subject Accountability 
The number and percent of subjects who were enrolled into the OLE study, received IP, 
completed IP, discontinued IP and reasons for discontinuing during the OLE study, 
completed the OLE study, and discontinued the OLE study and reasons for 
discontinuing will be summarized by the randomized treatment group in parent study and 
overall. 
OLE enrollment by region, country and investigator and, key study dates for the first 
subject enrolled, last subject enrolled and last subject’s end of study will be presented. 
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s visit and updated during the IPD reviews throughout the study prior to 
database lock. These definitions of IPD categories, subcategory codes, and descriptions 
will be used during the course of the study. Eligibility deviations are defined in the 
protocol. 
The number of subjects reporting Protocol Deviations and Important Protocol 
Deviations due to COVID-19 impact will be summarized in a table. A Protocol 
Deviation listing of subjects impacted due to COVID-19 impact will also be 
provided. 


Product:  Evolocumab 
Protocol Number:  20160250 
 
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9.4 
Demographic and Baseline Characteristics 
All baseline tables will be summarized by the randomized treatment groups in parent 
study. Baseline tables will summarize the following: baseline characteristics, 
demographics, cardiovascular medical history, laboratory parameters, physical 
measurements and lipid regulating medication. 
9.5 
Efficacy Analyses 
Table 9-1.  Endpoint Summary Table 
Endpoint 
Primary Summary (Long-Term Safety Analysis 
Set and OLE Safety Analysis Set) 
Primary Endpoint 
Treatment emergent adverse events 
• 
Adverse events 
• 
Serious adverse events 
• 
Fatal adverse events 
• 
AEs leading to withdrawal from IP 
• 
Device-related adverse events 
• 
Disease related events 
Subject incidence and exposure adjusted 
subject incidence rate  
Secondary Endpoints 
Percent change of LDL-C from baseline 
Summary statistics at each scheduled visit 
Achieving an LDL-C level < 40 mg/dL 
Summary statistics at each scheduled visit 
Exploratory Endpoints 
Change and percent change from baseline 
 non-HDL-C 
 ApoB 
 Total cholesterol 
 Lp(a) 
 Triglycerides 
 HDL-C 
 LDL-C  
 VLDL-C 
 ApoA1 
Summary statistics at each scheduled visit 


Product:  Evolocumab 
Protocol Number:  20160250 
 
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Endpoint 
Primary Summary (Long-Term Safety Analysis 
Set and OLE Safety Analysis Set) 
Subject incidence of events positively 
reviewed by the CEC: 
o All deaths 
▪ 
Cardiovascular death 
▪ 
Non-cardiovascular death 
▪ 
Undetermined Cause of 
death 
o Cardiovascular events of 
interest: 
▪ 
Myocardial Infarction (MI) 
▪ 
Coronary 
revascularization 
▪ 
Hospitalization for 
unstable angina 
▪ 
Heart failure 
▪ 
Cerebrovascular Events 
▪ 
Coronary heart disease 
death 
Subject incidence of events positively reviewed 
by the CEC 
 
9.5.1 
Analyses of Primary Endpoint 
The current Medical Dictionary for Regulatory Activities version at the time of data lock 
will be used to code all adverse events (AEs) and disease related events to a system 
organ class and a preferred term. 
Treatment-emergent adverse events are events with an onset after the administration of 
the first dose of investigational product as defined in Section 5.3. 
The subject incidence and exposure-adjusted subject incidence rate of all 
treatment-emergent adverse events, serious adverse events, fatal adverse events, 
adverse events leading to withdrawal of evolocumab, device-related adverse events, 
and disease-related events will be tabulated by system organ class (SOC), high level 
term (HLT), and preferred term (PT) in alphabetical order 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. 
The analyses described above (subject incidence, exposure-adjusted subject incidence 
rate) will also be performed combining data from the OLE study and the parent study 


Product:  Evolocumab 
Protocol Number:  20160250 
 
Date:  24 March 2022 
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using the OLE safety analysis set and also be analyzed separately for the 
subgroup of subjects who were randomized to and received evolocumab group in 
the parent study with ≥ 7 years of the combined exposure for evolocumab across 
the parent and OLE study. Events from parent study classified as Target IP TEAEs will 
be included (adverse events occurring from the first dose of IP date to 30 days after the 
last dose of IP date or EOS, whichever occurs first). Disease-related events from the 
OLE study will be reclassified as adverse events and positively reviewed events from the 
OLE study will not be included to remain consistent with parent study adverse event 
reporting. This analysis will be presented by the randomized treatment in the parent 
study. 
Subject incidence of treatment emergent and serious adverse events occurring in at 
least 1% of the subjects by preferred term will be provided in descending order of 
frequency for the overall OLE study period only and combined parent and OLE study 
periods.   
 
9.5.2 
Analyses of Secondary Endpoints 
Summary statistics of the secondary endpoints (percent change of LDL-C from baseline 
and achieving an LDL-C level < 40 mg/dL) will be analyzed based on the OLE Safety 
Analysis Set at each scheduled visit for the overall parent and OLE study periods. 
9.5.3 
Analyses of Exploratory Endpoints 
The change and percent change from baseline in lipid parameters at each scheduled 
visit will be summarized based on the OLE Safety Analysis Set for the overall parent 
and OLE study periods. For continuous exploratory endpoints, summary statistics 
(number of subjects, mean, median, standard deviation or standard error, first and third 
quartiles, minimum, and maximum) at all scheduled visits will be calculated. Subject 
incidence, exposure-adjusted subject incidence rate, and yearly Kaplan Meier (K-
M) estimates of positively reviewed events (by an independent external CEC) will be 
summarized for both the OLE study period and combined parent and OLE study 
periods. All deaths will be summarized by cardiovascular death (including 
coronary heart disease death), non-cardiovascular death and undetermined cause 
of death. A sensitivity analysis will be performed for the following composite 
endpoints: 


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 
time to cardiovascular death, myocardial infarction, hospitalization for 
unstable angina, stroke, or coronary revascularization, whichever occurs 
first  
 
time to cardiovascular death, myocardial infarction, or stroke, whichever 
occurs first 
In this analysis, cardiovascular events which occurred during the gap between 
subjects End of Study date in the parent study and OLE study enrolment date will 
be included in the time to event analysis. 
9.6 
Safety Analyses 
9.6.1 
Safety Analysis of Low LDL-C 
The safety analyses (TEAE and serious TEAE) will be summarized for subjects with any 
postbaseline LDL-C and all postbaseline LDL-C with the cutoffs of < 25 mg/dL, < 40 
mg/dL and ≥ 40 mg/dL for the OLE study period using the OLE safety analysis set. 
In addition, the safety analyses will be summarized in subjects with 2 consecutive 
postbaseline LDL-C < 25 mg/dL and LDL-C < 40 mg/dL separated by at least 21 days. 
9.6.2 
Vital Signs 
Systolic and diastolic blood pressure and heart rate will be summarized using descriptive 
statistics at each scheduled visit based on the OLE Safety Analysis Set for the OLE 
study period. 
  
9.6.3 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to investigational product 
for both the overall OLE study period and combined parent and OLE study 
periods using the OLE Safety Analysis Set. 
9.6.4 
Exposure to Other Protocol-specified Treatment 
The number and proportion of subjects receiving protocol specified lipid regulating 
medications captured on the related concomitant medication eCRF will be 
summarized. The subject incidence of changes in protocol specified background lipid 
regulating medications during the treatment period will also be provided for the overall 
OLE study period using the OLE Safety Analysis Set (Appendix D). 
9.6.5 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving therapies of interest will be 
summarized by preferred term or category as coded by the World Health Organization 
Drug (WHO DRUG) dictionary using the OLE Safety Analysis Set.   


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9.7 
Other Analyses 
A listing will be provided for events which occurred in the time between the subject’s 
EOS date in the parent study and the enrolment date of the OLE (recorded on the 
medical history eCRF for the OLE). 
10. 
Changes From Protocol-specified Analyses 
Removed long-term safety analysis set and related analysis from SAP. 
Rationale: The pre-specified planned analyses in the SAP focus on the long term 
safety data in the subjects who enrolled into this OLE study (i.e., OLE safety 
analysis set) rather than the long-term safety analysis set which also includes the 
subjects from the parent study who did not enroll into this OLE study. 
 
11. 
Literature Citations / References 
There are no references in this document. 


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12. 
Appendices 


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Appendix A.  Analytical Study Week Assignments 
Selected endpoints will be summarized by scheduled study visits in descriptive analyses. 
Since the actual visits may not exactly coincide with their scheduled visit day, the actual 
visit day is mapped to the study visit generally by non-overlapping consecutive intervals 
covering the entire time continuum. The mapping intervals for all distinct schedules are 
summarized in the following table. 
If there is more than one record in a given analytical window, the analytical record for 
that scheduled visit will be defined as the record closest to the scheduled visit day 
(7 days x Number of Study Weeks + 1) for that scheduled visit. If two records are 
equidistant from the scheduled visit day, then the earlier record will be chosen. If there 
are multiple records on the same day, the last record will be used. 
 


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          Vital signs 
 
 
Analytical Study Week 
Scheduled Visit Day 
        Body weight 
Laboratory (lipid panel, 
ApoA1, ApoB, Lp(a), and 
serum pregnancy) 
Concomitant therapy 
Physical 
 exam 
Week 12 
85 
(1, 126] 
(1, 126] 
 
Week 24 
169 
(126, 252] 
(126, 252] 
 
Week 48 
337 
(252, 420] 
(252, 420] 
 
Week 72 
505 
(420, 588] 
(420, 588] 
 
Week 96 
673 
(588, 756] 
(588, 756] 
 
Week 120 
841 
(756, 924] 
(756, 924] 
 
Week 144 
1009 
(924, 1092] 
(924, 1092] 
 
Week 168 
1177 
(1092, 1260] 
(1092, 1260] 
 
Week 192 
1345 
(1260, 1428] 
(1260, 1428] 
 
Week 216 
1513 
(1428, 1666] 
(1428, 1596] 
 
Week 240 
1681 
 
(1596, 1750] 
 
Week 260 
1821 
(1666, EOS] 
(1750, 1836] 
 1 
EOS 
1851 
 
 1836 
 
 


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Appendix B.  Common Terminology Criteria for AEs (CTCAE) 
Refer to the NCI Common Terminology Criteria for AEs (CTCAE) Version 4.03, 
published: May 28, 2009 (v4.03: June 14, 2010) for AEs and lab shift grading and 
information. The CTCAE is available at the following link: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
 
 
 
 
 
 
 


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Appendix C. Mortality Endpoints Censoring 
 
 
 


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Appendix D.  Lipid Modifying Background Therapy 
Based on ACC/AHA 2018 guidelines:  
HIGH-
INTENSITY 
STATIN 
THERAPY 
MODERATE-
INTENSITY 
STATIN 
THERAPY 
LOW-
INTENSITY 
STATIN 
THERAPY 
Atorvastatin 
equivalent 
factor 
Atorvastatin 
 40 mg QD 
10 –  40 mg QD 
 10 mg QD 
1 
Rosuvastatin 
 20 mg QD 
5 –  20 mg QD 
 5 mg QD 
2 
Simvastatin 
 80 mg QD 
20 –  80 mg QD 
 20 mg QD 
0.5 
Pravastatin 
 40 mg QD 
 40 mg QD 
0.25 
Lovastatin 
 40 mg QD 
 40 mg QD 
0.25 
Fluvastatin* 
80 mg QD 
 80 mg QD 
0.125 
Pitavastatin 
1 – 4 mg QD 
1 mg QD 
10 
   * includes immediate-release capsules and prolonged-release tablets 
High-intensity lipid-lowering regimen is defined as: 
 
A high intensity statin (e.g. atorvastatin  40 mg QD, rosuvastatin  20 mg 
QD, or simvastatin  80 mg QD); or  
 
A combination of any statin at any approved daily dose plus ezetimibe  
10mg QD