A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate Safety and Efficacy of Evolocumab (AMG 145) in Addition to Optimal Stable Background Statin Therapy in Chinese Subjects With Primary Hypercholesterolemia and Mixed Dyslipidemia
Phase: PHASE3
Conditions: Primary Hypercholesterolemia, Mixed Dyslipidemia
Sponsor: Amgen

Product:  Evolocumab 
Protocol Number:  20150172 
Date:  06 June 2016 
Page 1 of 78 
CONFIDENTIAL 
Title:  A Double-blind, Randomized, Placebo-controlled, Multicenter Study to 
Evaluate Safety and Efficacy of Evolocumab (AMG 145) in addition to Optimal 
Stable Background Statin Therapy in Chinese Subjects with Primary 
Hypercholesterolemia and Mixed Dyslipidemia 
Amgen Protocol Number (Evolocumab) 20150172 
Clinical Study Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
+1 805-447-1000
Key Sponsor Contact(s): 
 
Amgen Inc. 
Thousand Oaks, CA 91320 
Date: 
06 June 2016 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  Amgen’s general number in the 
US (1-805-447-1000).  
Approved
NCT Number: NCT03433755
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov
PPD
PPD
PPD

Product:  Evolocumab 
Protocol Number:  20150172 
Date:  06 June 2016 
Page 2 of 78 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled, “A Double-blind, Randomized, 
Placebo-controlled, Multicenter Study to Evaluate Safety and Efficacy of Evolocumab 
(AMG 145) in addition to Optimal Stable Background Statin Therapy in Chinese Subjects 
with Primary Hypercholesterolemia and Mixed Dyslipidemia”, dated 06 June 2016, and 
agree to abide by all provisions set forth therein.   
I agree to comply with the International Conference on Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines.  
I agree to ensure that Financial Disclosure Statements will be completed by: 
• 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
• 
my sub investigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
at the start of the study and for up to one year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc.  
 
 
 
Signature 
 
 
Name of Investigator 
 
Date (DD Month YYYY) 
 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20150172 
Date:  06 June 2016 
Page 3 of 78 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate Safety and 
Efficacy of Evolocumab (AMG 145) in addition to Optimal Stable Background Statin Therapy in 
Chinese Subjects with Primary Hypercholesterolemia and Mixed Dyslipidemia 
Study Phase:  3 
Indication:  Primary Hypercholesterolemia and mixed dyslipidemia 
Primary Objective:  To evaluate the effect of 12 weeks of subcutaneous (SC) evolocumab every 
2 weeks or every 4 weeks, compared with placebo, on percent change from baseline in 
low-density lipoprotein cholesterol (LDL-C) when used in addition to optimal stable background 
statin therapy in Chinese subjects with primary hypercholesterolemia and mixed dyslipidemia. 
Secondary Objective(s):  To evaluate the effect of 12 weeks of SC evolocumab Q2W or QM, 
compared with placebo, on change from baseline in LDL-C, achievement of target LDL-C 
< 70 mg/dL (1.8 mmol/L), LDL-C response (50% reduction of LDL-C from baseline) and percent 
change from baseline in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B 
(ApoB), total cholesterol, lipoprotein(a) [Lp(a)], triglycerides, HDL-C, very low-density lipoprotein 
cholesterol (VLDL-C) when used in addition to optimal stable background statin therapy in 
Chinese subjects with primary hypercholesterolemia and mixed dyslipidemia. 
Hypotheses:  The hypothesis is the dosing regimens of evolocumab SC 140 mg Q2W and 
420 mg QM will be well tolerated and will result in greater reduction of LDL-C, as defined by the 
mean percent change from baseline at weeks 10 and 12 and percent change from baseline at 
week 12, than placebo when used in combination with optimal stable background statin therapy in 
Chinese subjects with primary hypercholesterolemia and mixed dyslipidemia. 
Co-Primary Endpoints:   
• 
Mean percent change from baseline in LDL-C at weeks 10 and 12  
• 
Percent change from baseline in LDL-C at week 12 
Secondary Endpoint(s):   
• 
The mean of weeks 10 and 12 and for week 12 for the following:  
Tier 1: 
• 
Change from baseline in LDL-C  
• 
Percent change from baseline in non-HDL-C  
• 
Percent change from baseline in ApoB  
• 
Percent change from baseline in total cholesterol  
• 
Achievement of target LDL-C < 70 mg/dL (1.8 mmol/L)  
• 
LDL-C response (50% reduction of LDL-C from baseline)  
Tier 2:  
• 
Percent change from baseline in Lp(a)  
• 
Percent change from baseline in triglycerides  
• 
Percent change from baseline in HDL-C  
• 
Percent change from baseline in VLDL-C  
Study Design:  This is a phase 3, multicenter, double-blind, randomized, placebo-controlled 
study of evolocumab in Chinese subjects with hypercholesterolemia and mixed dyslipidemia.  
Subjects who have signed the informed consent form (ICF), will have fasting lipids measured and 
all inclusion and exclusion criteria assessed.  Subjects should maintain their current diet and 
exercise regimen.  Subjects who, in the opinion of the investigator, require statin up-titration or 
dietary adjustment can be rescreened after 1 month. Subjects can only be rescreened once.  
Statins may not be down-titrated with subsequent rescreened.  Baseline statin therapy is 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20150172 
Date:  06 June 2016 
Page 4 of 78 
CONFIDENTIAL 
 
 
expected to be continued unchanged throughout the study.  Subjects will be randomized 2:2:1:1 
into the following treatment arms:  
• 
evolocumab SC 140 mg Q2W,  
• 
evolocumab SC 420 mg QM,  
• 
placebo SC Q2W, or  
• 
placebo SC QM.   
Randomization will be stratified by entry cardiovascular (CV) risk (high/very high CV risk vs not 
high/very high CV risk).   
The overall sample size will be approximately 450 subjects (150 subjects for each evolocumab 
dosing regimen).  The sample size for each placebo will be approximately 75 subjects. 
Evolocumab and placebo will be administered SC at the study site or in an appropriate non-clinic 
setting (eg, at home) by spring based prefilled autoinjector/pen (AI/Pen).  The dose frequencies of 
Q2W and QM will not be blinded but the identity of investigational product evolocumab or 
matching SC placebo) will be blinded.   
Subjects must tolerate a SC injection of placebo with a prefilled autoinjector/pen device to be 
used during the study prior to randomization.  
All central laboratory results of Apolipoprotein (Apo) A1, ApoB, Lp (a), PCSK9, high sensitivity 
C-reactive protein (hsCRP) will be blinded until unblinding of the clinical database and will not be 
reported to the investigator. Post-investigational product treatment central laboratory results of 
the lipid panel will be blinded until unblinding of the clinical database and will not be reported to 
the investigator. Investigators should not perform non protocol testing of these analytes during a 
subject’s study participation and until at least 12 weeks after last investigational product 
administration, or the subject’s end of study (EOS), whichever is later. 
Approximately 40 sites in China will participate in this study.  Treatment and follow-up period will 
be 12 weeks with an additional phone call or other subject contact at week 14 for subjects 
receiving investigational product Q2W.  The EOS for subjects on QM investigational product is at 
the week 12 visit which must be at least 30 days post last dose of investigational product. The 
EOS for subjects on Q2W investigational product is a telephone call from the site at week 14 (and 
at least 30 days post last dose of investigational product) for any potential adverse events, 
adverse device effects (ADEs), serious adverse events and disease related events.  Subjects will 
be encouraged to complete all planned visits regardless of their adherence to investigational 
product administration. 
The primary completion is when all subjects have completed study treatment and have had the 
opportunity to complete the 12 week visit. 
End of trial will occur when the last subject has completed or discontinues study treatment and 
has had the opportunity to complete the safety follow-up visit. 
Sample Size:  A total 450 subjects are planned to be enrolled in this study. 
Summary of Subject Eligibility Criteria:  Males and females, ≥ 18 to years of age are eligible 
for this study.  Subject must be on an approved statin for at least 4 weeks, before LDL-C 
screening and, in the opinion of the investigator, not require uptitration. Subject must have fasting 
LDL-C ≥ 80mg/dL at screening, and meet one of the criteria listed in Section 4.1.1 to be 
considered high/very high CV risk.  Subject must have fasting triglycerides ≤ 400 mg/dL 
(4.5 mmol/L) at screening, and be able to tolerate a screening placebo injection 
Major exclusions are myocardial infarction, unstable angina, percutaneous coronary intervention 
(PCI), coronary artery bypass graft (CABG) within the last 3 months, planned coronary or other 
revascularization within 20 weeks of screening, New York Heart Association (NYHA) III or IV 
heart failure, uncontrolled serious cardiac arrhythmia, diabetes, or hypertension, and severe renal 
dysfunction. 
For a full list of eligibility criteria, please refer to Section 4.1.  
Investigational Product 
Amgen Investigational Product Dosage and Administration:  Evolocumab and matched 
placebo will be administered SC using a spring-based prefilled AI/Pen.  Each prefilled AI/Pen 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20150172 
Date:  06 June 2016 
Page 5 of 78 
CONFIDENTIAL 
 
 
contains 1.0 mL of deliverable volume.  The Q2W administration will occur via 1 AI/Pen, while the 
QM administration will occur via 3 AI/Pens. 
Non-investigational Product 
Amgen Non-investigational Product Dosage and Administration:  None  
Non-Amgen Non-investigational Product Dosage and Administration:  All eligible subjects 
must be taking a maximum appropriate dose of an approved statin, not requiring uptitration. 
All other lipid lowering drugs that are allowed per protocol and that the subject may be taking, 
must be commercially available. Subjects must be on an approved statin with maximum 
appropriate (optimal) stable daily dose with or without ezetimibe for at least 4 weeks before 
LDL-C screening and, in the opinion of the investigator, not requiring uptitration. 
They must remain on the same daily statin background therapy (drug and dose), with or without 
ezetimibe, throughout the study from signing of the ICF until the EOS. If statin therapy is 
discontinued, or changed during the study, the reason for adjusting medication (eg. adverse 
event, noncompliance, etc) should be recorded. 
Procedures:  Subjects being considered for participation and who have signed informed consent, 
will be assessed for inclusion and exclusion criteria.  Medical and medication history will be 
obtained.  During screening, all subjects will undergo physical examination, and central labs 
including fasting lipids will be collected. If a subject has not met all eligibility criteria at the end of 
the 4-week window, the subject will be registered as a screen fail.  Subjects who screen fail due 
to the LDL-C below the limit for eligibility during final screening cannot be rescreened for this 
study. Suitable subjects who are ineligible at the initial screening for other reasons and have not 
been randomized can be re-consented and rescreened once at a later time unless they withdraw 
from screening, provided the study is still enrolling subjects. Subjects will undergo SC placebo 
injection prior to randomization with a device to be used during the study (AI/pen).  Subjects who 
tolerate the placebo injection, complete all screening procedures, and successfully meet all 
eligibility criteria at the end of screening will be randomized and will return to the study site for 
Day 1 procedures while continuing their background lipid lowering treatment (if applicable).  The 
dosing regimens are evolocumab 140 mg SC Q2W or 420 mg SC QM. Study visits will occur at 
screening, baseline (Day 1), Week 8, Week 10, Week 12, and Week 14 (Q2W subjects only). 
Fasting lipids will be tested for all subjects at baseline, Week 8, Week 10, and Week 12 towards 
analysis of primary and secondary endpoints. Safety data will be collected at all time points as 
indicated in the Schedule of Assessments (Table 2).   
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments (Table 2).   
Statistical Considerations:   
 
Analysis Sets 
The full analysis set (FAS) includes all randomized subjects who received at least 1 dose of 
investigational product. This analysis set will be used in both efficacy and safety analyses. In 
efficacy analyses, subjects will be grouped according to their randomized treatment group 
assignment. For safety analyses, subjects will be grouped according to their randomized 
treatment group assignment with the following exception:  if a subject receives treatment 
throughout the study that is different than the randomized treatment group assignment, then the 
subject will be grouped by the actual treatment group.  
The completer analysis set (CAS) includes subjects in the FAS who adhered to the scheduled 
investigational product regimen and have observed values for the co-primary endpoints. 
General Considerations 
Efficacy and safety analyses will be performed on the FAS. Unless specified otherwise, the FAS 
will be the default analysis set in this study and data will be summarized by randomized treatment 
group. Analyses will be performed separately by each dose frequency (Q2W and QM) unless 
specified otherwise. The superiority of evolocumab to placebo will be assessed for all efficacy 
endpoints. 
Subject disposition, demographics, baseline characteristics, and exposure to investigational 
product will be summarized. 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20150172 
Date:  06 June 2016 
Page 6 of 78 
CONFIDENTIAL 
 
 
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. 
Missing data will not be imputed for safety endpoints.   
Analysis of Co-Primary Efficacy Endpoints 
To assess the co-primary endpoints of the mean percent change from baseline in LDL-C at 
weeks 10 and 12 and the percent change in LDL-C from baseline at week 12, a repeated 
measures linear effects model will be used on the FAS in each dose frequency to compare the 
efficacy of evolocumab with placebo. The repeated measures model will include terms for 
treatment group, stratification factor, scheduled visit and the interaction of treatment with 
scheduled visit. 
Subgroup Analysis 
If applicable, subgroup analyses on the co-primary efficacy endpoints will be conducted using the 
stratification factor and baseline covariates. 
Secondary Efficacy Endpoint(s) 
The statistical model and testing of the tier 1 secondary efficacy endpoints will be similar to the 
primary analysis of the co-primary endpoints. The secondary efficacy endpoints of LDL-C 
response (achievement of LDL-C < 70 mg/dL and achievement of > 50% LDL-C reduction from 
baseline) will be analyzed using the Cochran-Mantel Haenszel (CMH) test adjusted by the 
stratification factor. 
Analyses of the tier 2 secondary efficacy endpoints will use the same analysis model 
as the tier 1 endpoints, and testing will use a union-intersection test. 
Safety Endpoints 
The current Medical Dictionary for Regulatory Activities (MedDRA) version at the time of the data 
lock will be used to code all adverse events to a system organ class and a preferred 
term. Subject incidence of all treatment emergent adverse events will be tabulated by system 
organ class and preferred term. Tables of fatal adverse events, serious adverse events, 
adverse events leading to withdrawal from investigational product, device-related adverse events, 
and significant treatment-emergent adverse events will also be provided. Subject incidence of 
disease-related events and fatal disease-related events will be tabulated by system organ class 
and preferred term. 
Measurements of selected laboratory parameters and vital signs will be summarized over time. 
The incidence and percentages of subjects who develop anti-evolocumab antibodies (binding and 
neutralizing) at any time will be tabulated. 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen 
Data Element Standards 
Version(s)/Date(s):  
  5: 20 March 2015   
 
Approved 
 
 

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Product:  Evolocumab 
Protocol Number:  20150172 
Date:  06 June 2016 
Page 8 of 78 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ADE 
adverse device effect 
AE 
adverse event 
AI/Pen 
autoinjector/pen 
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) 
BAS 
bile acid sequestrants 
BP 
blood pressure 
CABG 
coronary artery bypass graft 
CAS 
completer analysis set 
CBC 
complete blood count 
CHD 
coronary heart disease 
CK 
creatine kinase 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for adverse events 
CTT 
Cholesterol treatment trialists 
CV 
cardiovascular 
CVD 
cardiovascular disease 
CYP3A4 
Cytochrome P450 A4 
Day 1 
defined as the first day that protocol-specified investigational product 
is administered to the subject at the beginning of each study part 
DBP 
diastolic blood pressure 
DILI 
drug-induced liver injury 
DNA 
deoxyribonucleic acid 
DRE 
disease related event 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate; eGFR will be calculated by the 
central laboratory and provided to the investigator. 
End of study 
The end of the study is defined as when the last subject has 
completed or discontinued study treatment and has had the 
opportunity to complete the safety follow-up visit. 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20150172 
Date:  06 June 2016 
Page 9 of 78 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
End of study for individual 
subject 
Defined as the last day that protocol-specified procedures are 
conducted for an individual subject or the day the subject withdraws 
from study early.  
End of treatment 
Defined as the day a subject receives the last treatment with 
investigational product before the subject completes the study or 
ends the treatment early. 
Enrollment 
A subject is considered enrolled upon randomization   
EOS 
end of study (for individual subject) 
EU 
European Union 
FAS 
full analysis set 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
HbA1c 
hemoglobin A1c 
HCV 
Hepatitis C virus 
HDL-C 
high density lipoprotein cholesterol 
HepBsAg 
Hepatitis B surface antigen 
HepBcAb 
Hepatitis B core antibody 
HR 
heart rate 
HRT 
Hormone replacement therapy 
hsCRP 
high sensitivity CRP 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC/IRB 
Independent Ethics Committee / Institutional Review Board 
IFU 
instructions for use 
INR 
international normalized ratio 
IMP 
investigational medicinal product 
IP 
investigational product (evolocumab and placebo, administered with 
the medical device used in this study – the prefilled autoinjector/pen 
[AI/pen]) 
IPIM 
investigational product instruction manual 
IUD 
intrauterine device 
IUS 
Intrauterine hormone releasing system 
IVRS/IWRS 
interactive voice response system / interactive web response system 
IV 
intravenous 
LDH 
lactate dehydrogenase 
LDL-C 
low-density lipoprotein cholesterol 
l 
lipoprotein(a) 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20150172 
Date:  06 June 2016 
Page 10 of 78 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
MedDRA 
medical dictionary for regulatory activities 
PCI 
percutaneous coronary intervention 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
PCR 
polymerase chain reaction 
PKPD 
pharmacokinetic / pharmacodynamic 
Q2W 
Q2W is defined as every 2 weeks with a window of ± 3 days for each 
visit 
QM 
QM is defined as every 4 weeks with a window of ± 3 days for each 
visit 
Randomized 
Assignment to treatment group based on computer-generated 
randomization schedules prepared by Amgen before the start of the 
study 
RBC 
red blood cells 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SC 
subcutaneous 
SD 
standard deviation 
SEC 
self-evident correction 
Source Data 
Information from an original record or certified a 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 ID, 
Randomization ID, and Stratification Value. 
TBL 
total bilirubin 
ULN 
upper limit of normal 
VLDL-C 
very low-density lipoprotein cholesterol 
WBC 
white blood cell 
 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20150172 
Date:  06 June 2016 
Page 11 of 78 
CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................. 3 
Study Design and Treatment Schema .............................................................................. 7 
Study Glossary .................................................................................................................. 8 
1. 
OBJECTIVES ......................................................................................................... 15 
1.1 
Primary ....................................................................................................... 15 
1.2 
Secondary .................................................................................................. 15 
1.3 
Exploratory ................................................................................................. 15 
1.4 
Safety ......................................................................................................... 15 
2. 
BACKGROUND AND RATIONALE ........................................................................ 15 
2.1 
Disease ....................................................................................................... 15 
2.2 
Amgen Investigational Product Background ............................................... 17 
2.3 
Rationale .................................................................................................... 17 
2.4 
Clinical Hypotheses .................................................................................... 18 
3. 
EXPERIMENTAL PLAN ......................................................................................... 19 
3.1 
Study Design .............................................................................................. 19 
3.2 
Number of Sites .......................................................................................... 20 
3.3 
Number of Subjects .................................................................................... 20 
3.4 
Replacement of Subjects ............................................................................ 20 
3.5 
Estimated Study Duration ........................................................................... 20 
3.5.1 
Study Duration for Subjects ........................................................ 20 
3.5.2 
End of Study ............................................................................... 21 
4. 
SUBJECT ELIGIBILITY .......................................................................................... 21 
4.1 
Inclusion and Exclusion Criteria ................................................................. 21 
4.1.1 
Inclusion Criteria ......................................................................... 21 
4.1.2 
Exclusion Criteria ........................................................................ 22 
5. 
SUBJECT ENROLLMENT ..................................................................................... 24 
5.1 
Randomization/Treatment Assignment ...................................................... 25 
5.2 
Site Personnel Access to Individual Treatment Assignments .................... 26 
6. 
TREATMENT PROCEDURES ............................................................................... 26 
6.1 
Classification of Product(s) and/or Medical Device(s) ................................ 26 
6.2 
Investigational Product ............................................................................... 27 
6.2.1 
Amgen Investigational Product [Evolocumab] ............................ 27 
6.2.1.1 
Dosage, Administration, and Schedule .................... 27 
6.2.1.2 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 28 
6.3 
Non-investigational Product(s) ................................................................... 29 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20150172 
Date:  06 June 2016 
Page 12 of 78 
CONFIDENTIAL 
 
 
6.3.1 
Non-Amgen Non-investigational Product(s) ............................... 29 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules ........................................ 29 
6.4.1 
Criteria for Withholding and/or Permanent 
Discontinuation of Amgen Investigational Product and 
Other Protocol-required Therapies due to Potential 
Hepatotoxicity ............................................................................. 29 
6.4.2 
Criteria for Rechallenge of Amgen Investigational 
Product and Other Protocol-required Therapies After 
Potential Hepatotoxicity .............................................................. 31 
6.5 
Concomitant Therapy ................................................................................. 31 
6.6 
Medical Devices ......................................................................................... 32 
6.7 
Product Complaints .................................................................................... 32 
6.8 
Excluded Treatments, Medical Devices, and/or Procedures 
During Study Period ................................................................................... 33 
6.9 
Contraceptive Requirements ...................................................................... 33 
6.9.1 
Female Subjects ......................................................................... 33 
6.9.2 
Unacceptable Methods of Birth Control for Female 
Subjects ..................................................................................... 34 
7. 
STUDY PROCEDURES ......................................................................................... 34 
7.1 
Schedule of Assessments .......................................................................... 35 
7.2 
General Study Procedures ......................................................................... 38 
7.2.1 
Study Visit Definitions and Windows .......................................... 38 
7.2.2 
Description of Study Procedures ................................................ 38 
7.2.2.1 
Informed Consent .................................................... 38 
7.2.2.2 
Medical History ........................................................ 38 
7.2.2.3 
Measurement of Vital Signs ..................................... 39 
7.2.2.4 
Measurement of Waist Circumference ..................... 39 
7.2.2.5 
Prior Therapies, Substance use History, 
and Concomitant Medications .................................. 39 
7.2.2.6 
Pregnancy Test ........................................................ 40 
7.2.2.7 
Laboratory Assessments ......................................... 40 
7.2.3 
Screening Enrollment and/or Randomization ............................. 42 
7.2.3.1 
Rescreening ............................................................. 43 
7.2.4 
Treatment ................................................................................... 43 
7.2.4.1 
Baseline (Day 1): All Subjects .................................. 43 
7.2.4.2 
Week 8: All Subjects ................................................ 44 
7.2.4.3 
Week 10: All Subjects .............................................. 45 
7.2.4.4 
Week 12: All Subjects .............................................. 45 
7.2.4.5 
Week 14: Q2W Subjects Only ................................. 46 
7.2.5 
Early Termination Visit ................................................................ 46 
7.3 
Antibody Testing Procedures ..................................................................... 46 
7.4 
Sample Storage and Destruction ................................................................ 47 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 48 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20150172 
Date:  06 June 2016 
Page 13 of 78 
CONFIDENTIAL 
 
 
8.1 
Subjects’ Decision to Withdraw .................................................................. 48 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 49 
8.3 
Reasons for Removal From Treatment ...................................................... 49 
8.3.1 
Reasons for Removal From Treatment ...................................... 49 
8.3.2 
Reasons for Removal From Study ............................................. 49 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 50 
9.1 
Definition of Safety Events ......................................................................... 50 
9.1.1 
Disease Related Events ............................................................. 50 
9.1.2 
Adverse Events .......................................................................... 50 
9.1.3 
Serious Adverse Events ............................................................. 51 
9.2 
Safety Event Reporting Procedures ........................................................... 52 
9.2.1 
Reporting Procedures for Disease Related Events .................... 52 
9.2.2 
Adverse Events .......................................................................... 52 
9.2.2.1 
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria ............................ 52 
9.2.2.2 
Reporting Procedures for Serious Adverse 
Events ...................................................................... 54 
9.2.2.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 55 
9.2.2.4 
Reporting a Safety Endpoint as a Study 
Endpoint ................................................................... 56 
9.3 
Pregnancy and Lactation Reporting ........................................................... 56 
10. 
STATISTICAL CONSIDERATIONS ....................................................................... 57 
10.1 
Study Endpoints, Analysis Sets, and Covariates ........................................ 57 
10.1.1 
Study Endpoints ......................................................................... 57 
10.1.1.1 
Co-Primary Endpoints .............................................. 57 
10.1.1.2 
Secondary Endpoints ............................................... 57 
10.1.1.3 
Safety Endpoints ...................................................... 57 
10.1.1.4 
Exploratory Endpoint(s) ........................................... 58 
10.1.2 
Analysis Sets .............................................................................. 58 
10.1.3 
Covariates and Sub-groups ........................................................ 58 
10.2 
Sample Size Considerations ...................................................................... 59 
10.3 
Access to Individual Subject Treatment Assignments by Amgen 
or Designees .............................................................................................. 60 
10.4 
Planned Analyses ....................................................................................... 60 
10.4.1 
Primary Analysis ......................................................................... 60 
10.5 
Planned Methods of Analysis ..................................................................... 60 
10.5.1 
General Considerations .............................................................. 60 
10.5.2 
Co-Primary Efficacy Endpoints ................................................... 62 
10.5.2.1 
Primary Analysis ...................................................... 62 
10.5.2.2 
Subgroup Analysis ................................................... 62 
10.5.3 
Secondary Efficacy Endpoint(s) ................................................. 62 
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10.5.4 
Safety Endpoints ........................................................................ 62 
10.5.4.1 
Treatment Emergent Adverse Events ...................... 62 
10.5.4.2 
Laboratory Parameters ............................................ 63 
10.5.4.3 
Vital Signs ................................................................ 63 
10.5.4.4 
Concomitant Medications ......................................... 63 
10.5.4.5 
Anti-evolocumab antibody ........................................ 63 
11. 
REGULATORY OBLIGATIONS ............................................................................. 63 
11.1 
Informed Consent ....................................................................................... 63 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 64 
11.3 
Subject Confidentiality ................................................................................ 64 
11.4 
Investigator Signatory Obligations .............................................................. 65 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................... 65 
12.1 
Protocol Amendments and Study Termination ........................................... 65 
12.2 
Study Documentation and Archive ............................................................. 66 
12.3 
Study Monitoring and Data Collection ........................................................ 67 
12.4 
Investigator Responsibilities for Data Collection ........................................ 68 
12.5 
Language.................................................................................................... 68 
12.6 
Publication Policy ....................................................................................... 68 
12.7 
Compensation ............................................................................................ 69 
13. 
REFERENCES ....................................................................................................... 70 
14. 
APPENDICES ........................................................................................................ 71 
 
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 ............................................... 31 
Table 2.  Schedule of Assessments ................................................................................ 36 
Table 3.  Lists of Analytes ............................................................................................... 41 
 
List of Appendices 
Appendix A.  Additional Safety Assessment Information ................................................ 72 
Appendix B.  Sample eSerious Event Contingency Form ............................................... 74 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................... 77 
 
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1. 
OBJECTIVES 
1.1 
Primary 
• 
To evaluate the effect of 12 weeks of subcutaneous (SC) evolocumab every 
2 weeks or every 4 weeks, compared with placebo, on percent change from 
baseline in low-density lipoprotein cholesterol (LDL-C) when used in addition to 
optimal stable background statin therapy in Chinese subjects with primary 
hypercholesterolemia and mixed dyslipidemia.  
1.2 
Secondary 
• 
To evaluate the effect of 12 weeks of SC evolocumab Q2W or QM, compared 
with placebo, on change from baseline in LDL-C, achievement of target LDL-C  
< 70 mg/dL (1.8 mmol/L), LDL-C response (50% reduction of LDL-C from 
baseline) and percent change from baseline in non-high-density lipoprotein 
cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol, lipoprotein(a) 
[Lp(a)], triglycerides, HDL-C, very low-density lipoprotein cholesterol (VLDL-C) 
when used in addition to optimal stable background statin therapy in Chinese 
subjects with primary hypercholesterolemia and mixed dyslipidemia. 
1.3 
Exploratory 
• 
To evaluate the effect of 12 weeks of SC evolocumab Q2W or QM, compared 
with placebo on change from baseline high sensitivity C-reactive protein (hsCRP) 
and on percent change from baseline in apolipotrotein A1 (Apo A1) when used in 
addition to optimal stable background statin therapy in Chinese subjects with 
primary hypercholesterolemia and mixed dyslipidemia. 
• 
To evaluate the effect over time of SC evolocumab  Q2W or QM, compared with 
placebo, on change from baseline in proprotein convertase subtilisin/kexin 
type 9 (PCSK9) levels and on change from baseline and percent change from 
baseline of LDL-C, total cholesterol, non-HDL-C, apolipotrotein B (ApoB), 
VLDL-C, HDL-C, ApoA1, triglycerides and Lp(a) when used in addition to optimal 
stable background statin therapy in Chinese subjects with primary 
hypercholesterolemia and mixed dyslipidemia. 
1.4 
Safety 
• 
To evaluate the safety and tolerability of SC evolocumab Q2W and QM when 
used in combination with optimal stable background statin therapy in Chinese 
subjects with primary hypercholesterolemia and mixed dyslipidemia 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
In China, about 230 million people, 1 in 5 adults, have cardiovascular disease (CVD).  In 
2010, 154.8 per 100,000 deaths per year are estimated to be associated with CVDs in 
urban areas and 163.1 per 100,000 in rural areas.  This number accounts for 
20.9%/17.9% (urban/rural) of China's total number of deaths per year.  In China, heart 
attacks and strokes account for the number 1 and 3 causes of death.  China now ranks 
among the top 10 countries in the world for total incidence of CVD.  Projected annual 
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cardiovascular events are predicted to increase by 50% between 2010 and 2030 based 
on population aging and growth alone in China.  
These trends are thought to result from growing urbanization and industrialization which 
has resulted in a rise in cardiovascular risk factors such as glucose intolerance, 
dyslipidemia, and hypertension.  The rationale for treatment of dyslipidemia, particularly 
elevated LDL-C, extends from extensive clinical study data in both primary and 
secondary prevention that demonstrates the reduction in total cholesterol, non-HDL-C, 
and most importantly, LDL-C through pharmacological therapies, particularly statins, 
lowers the risk of CVD events. 
A recent Cholesterol Treatment Trialists’ (CTT) Collaboration meta-analysis 
(CTT Collaboration, 2010), which included 21 randomized controlled studies of statin 
versus control involving nearly 170,000 patients, showed that for every ~ 1 mmol/L 
reduction in LDL-C, there was an approximately 20% reduction in the risk of major 
vascular events (coronary death, non-fatal myocardial infarction, coronary 
revascularization, or stroke).  Importantly, this meta-analysis, which evaluated 5 studies 
that compared more versus less intensive statin therapy, did not find a LDL-C threshold; 
additional vascular risk reduction is possible in patients with low LDL-C. 
Statins are the most commonly used drugs for treating dyslipidemia.  However, the 
current status of lipid lowering therapy in China is unsatisfactory.  Several studies found 
that there is a low rate of achieving goal LDL-C levels among Chinese patients in 
general, and that this is particularly true in those at high risk or very high risk who require 
intensive LDL-C lowering therapy.  For example, results from China Cholesterol 
Education Program indicate that after moderate statin treatment (ie, 10-20 mg 
atorvastatin or 20-40 mg simvastatin), the rates of LDL-C goal achievement are only 
10.9% (< 70mg/dL) and 36.2% (< 100 mg/dL) and among outpatients at very high risk 
and high risk, respectively (Hu et al, 2008).  Results of the dyslipidemia international 
study (DYSIS) China study showed that 39.7% of coronary heart disease (CHD) patients 
with diabetes achieved LDL-C control far lower than in subjects with either CHD or 
diabetes alone (Zhao S et al, 2014).  Poor control rate of LDL-C is associated with 
increased risk of cardiovascular events, which leads to a heavy burden on families and 
society. 
There are certain limitations of statins.  Some Chinese patients respond poorly to the 
statin therapy. 
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As an example, the clinical study HPS2-THRIVE showed that almost 9.8% of Chinese 
patients were reported to have an LDL-C level > 2.0 mmol/L (77mg/dL), and 48.9% 
exceeded 1.5 mmol/L (58mg/dL) even with a dose of statin such as 40 mg/day 
simvastatin (HPS2 THRIVE Collaborative Group, 2013).  Although increasing the statin 
dose could help more patients to achieve their LDL-C goal, it is not wise to achieve a 
higher goal attainment rate by only using high-dose statin, as there is a "Rule of Six%" 
principle:  For each doubling of the statin dose, only an additional 6% further lowering of 
LDL C is achieved (Knopp, 1999). 
Meanwhile, high dose statins lead to increasing adverse effects, including increased liver 
and muscle related adverse effects (Silva et al, 2007) and a potential increased risk 
higher of new onset diabetes (Preiss et al, 2011).  This is particularly obvious in the 
Chinese population.  The HSP2-THRIVE study, which randomized 10932 Chinese 
patients, demonstrated a higher rate of adverse events in Chinese subjects who 
received only LDL-C lowering therapy (namely they were allocated into controlled arm 
receiving simvastatin or simvastatin plus ezetimibe) than in European patients who 
underwent the same treatment (HPS2-THRIVE Collaborative Group, 2013).  Statin 
related adverse effects are considered to be the main reason of the discontinuation of 
the drug.  The Clinical Pathways for Acute Coronary Syndromes in China study 
suggested that side effects were accountable for discontinuation of statin therapy in 23% 
of patients discharged from hospitals with a diagnosis of acute coronary syndrome 
(Bi et al, 2009).  Drug discontinuation due to adverse effects and poor patient 
compliance further impact attainment of LDL-C goals; consequently, this will lead to high 
incidence of cardiovascular events. 
2.2 
Amgen Investigational Product Background 
For further details on evolocumab efficacy and safety results refer to the Evolocumab 
Investigator’s Brochure. 
2.3 
Rationale 
Despite achieving their LDL-C goals, approximately two-thirds of Chinese patients on 
lipid reduction therapy still have cardiovascular events (Libby, 2005).  While it is unlikely 
that this residual risk is entirely due to LDL-C concentrations above the goal articulated 
in recent treatment guidelines (Grundy et al, 2004; NCEP, 2002;), CTT Collaboration 
meta-analysis which assessed the relationship between LDL-C reduction and the 
cardiovascular events concluded that the relative risk decreases by 1% for every 
1.8 mg/dL reduction in LDL-D (CTT Collaboration, 2010).  Furthermore, therapies are 
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needed for individuals who are intolerant to statin therapy and cannot achieve their 
respective LDL C goals (Bruckert et al, 2005; Franc et al, 2003). 
Non-statin treatment options are currently available to lower LDL-C but their potency is 
limited, such that LDL-C reductions occur on the order of 15% to 20%.  Considering the 
remaining cardiovascular risk despite the availability of statin therapy, and given that 
non-statin treatment options have modest efficacy (ezetimibe, bile acid sequestrants 
[BAS], plant stanols) and/or are poorly tolerated (niacin and BAS), 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.  Based on the current 
data, evolocumab, a fully human monoclonal antibody to PCSK9, may fulfill this need 
and may provide an important addition to the treatment of hyperlipidemia/dyslipidemia 
for individuals with hyperlipidemia. 
The rationale for the study design and study population is to investigate the effect of 
evolocumab on LDL across different levels of cardiovascular risk and baseline LDL 
levels.  The 2007 China Guideline on Prevention and Treatment of Dyslipidemia in 
Adults categorizes patients as high risk if they have coronary heart disease or coronary 
heart disease equivalent (documented atherosclerosis other than in the coronary 
arteries, diabetes mellitus or multiple cardiovascular risk factors).  The target LDL levels 
for these patients is < 80mg/dL for those with a history of acute coronary syndrome or 
both documented atherosclerosis and diabetes mellitus.  The target LDL for other high 
risk subjects was < 100mg/dL.  However since the release of subsequent international 
guidelines in 2007 the target for the latter high risk patients has in practice been moving 
lower.  Patients without very high or high risk features but receiving optimal stable 
background statin therapy in China are generally of moderate risk for which the 2007 
guidelines recommend a target LDL of < 130 mg/dL.  For these reasons the recruitment 
criteria for this trial is based on level of risk with high and very high risk subjects 
requiring an LDL at screening of at least 80mg/dL on optimal stable background statin 
therapy and the subjects without high risk features requiring an LDL of at least 
130 mg/dL. 
2.4 
Clinical Hypotheses 
The hypothesis is the dosing regimens of evolocumab SC 140 mg Q2W and 420 mg QM 
will be well tolerated and will result in greater reduction of LDL-C, as defined by the 
mean percent change from baseline at weeks 10 and 12 and percent change from 
baseline at week 12, than placebo when used in combination with optimal stable 
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background statin therapy in Chinese subjects with primary hypercholesterolemia and 
mixed dyslipidemia.  
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
The overall study design is described by a study schema at the end of the 
protocol synopsis section. 
This is a phase 3, multicenter, double-blind, randomized, placebo-controlled study of 
evolocumab in Chinese subjects with hypercholesterolemia and mixed dyslipidemia.  
Subjects who have signed the informed consent form (ICF), will have fasting lipids 
measured and all inclusion and exclusion criteria assessed.  Subjects should maintain 
their current diet and exercise regimen.  Subjects who, in the opinion of the investigator, 
require statin up-titration or dietary adjustment can be rescreened after 1 month.  
Subjects can only be rescreened once.  Statins may not be down-titrated with 
subsequent rescreened.  Baseline statin therapy is expected to be continued unchanged 
throughout the study.  Subjects will be randomized 2:2:1:1 into the following treatment 
arms:  
• 
evolocumab SC 140 mg Q2W,  
• 
evolocumab SC 420 mg QM,  
• 
placebo SC Q2W, or  
• 
placebo SC QM.   
Randomization will be stratified by entry CV risk (high/very high CV risk vs not high/very 
high CV risk).   
The overall sample size will be approximately 450 subjects (150 subjects for each 
evolocumab dosing regimen).  The sample size for each placebo will be approximately 
75 subjects. 
Evolocumab and placebo will be administered SC at the study site or in an appropriate 
non-clinic setting (eg, at home) by spring based prefilled autoinjector/pen (AI/Pen).  
Observed, in-clinic dosing will occur at Day 1 and Week 8 (± 3 days).  Subjects 
randomized to QM will self-administer in an appropriate non-clinic setting (eg, at home) 
at Week 4 (± 3 days).  Subjects randomized to Q2W will self-administer in an 
appropriate non-clinic setting (eg, at home) at Week 2, 4 and 6 (± 3 days).  The dose 
frequencies of Q2W and QM will not be blinded but the identity of investigational product 
(evolocumab or matching SC placebo) will be blinded.   
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Subjects must tolerate a SC injection of placebo with a prefilled AI/Pen device to be 
used during the study prior to randomization.  
All central laboratory results of ApoA1, ApoB, lipoprotein(a), PCSK9, hsCRP will be 
blinded until unblinding of the clinical database and will not be reported to the 
investigator.  Post-investigational product treatment central laboratory results of the lipid 
panel will be blinded until unblinding of the clinical database and will not be reported to 
the investigator.  Investigators should not perform non protocol testing of these analytes 
during a subject’s study participation and until at least 12 weeks after last investigational 
product administration, or the subject’s end of study (EOS), whichever is later. 
Approximately 40 sites in China will participate in this study.  Treatment and follow-up 
period will be 12 weeks with an additional phone call or other subject contact at week 14 
for subjects receiving investigational product Q2W.  The EOS for subjects on QM 
investigational product is at the week 12 visit which must be at least 30 days post last 
dose of investigational product.  The EOS for subjects on Q2W investigational product is 
a telephone call from the site at week 14 (and at least 30 days post last dose of 
investigational product) for any potential adverse events, adverse device effects (ADEs), 
serious adverse events and disease related events (DREs).  Subjects will be 
encouraged to complete all planned visits regardless of their adherence to 
investigational product administration. 
The study endpoints are defined in Section 10.1.1. 
3.2 
Number of Sites 
Approximately 40 sites in China will participate in this study.   
Sites that do not enroll subjects within 3 months of site initiation may be closed.   
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”. 
A total of 450 subjects are planned to be enrolled in this study. 
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 
After signing the ICF, subjects should be randomized within 4 weeks.  The maximal total 
duration of study participation for a subject on QM investigational product schedule will 
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be 16 weeks (approximately 4 months) which includes screening, study treatment, and 
safety follow-up. For a subject on Q2W investigational product schedule, the maximum 
study duration will be 18 weeks (approximately 4.5 months), including a telephone 
contact by the site at week 14 to obtain potential adverse events, adverse device effects, 
serious adverse events and disease related events information. 
3.5.2 
End of Study 
Primary Completion:  is when all the randomized subjects in the study have completed 
study treatment and have had the opportunity to complete the 12 week visit. 
End of Trial:  is when the last subject has completed or discontinued study treatment and 
has had the opportunity to complete the safety follow-up visit. 
4. 
SUBJECT ELIGIBILITY 
Study sites will be expected to maintain a screening log of all potential study subjects 
that includes limited information about the potential subject (eg, date of screening).  
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1).   
4.1 
Inclusion and Exclusion Criteria  
4.1.1 
Inclusion Criteria  
101 
Male or female ≥ 18 years of age at signing of informed consent form 
102 
On an approved statin, with or without ezetimibe, at optimal stable daily dose(s) 
for at least 4 weeks before LDL-C screening and, in the opinion of the 
investigator, not requiring uptitration 
103 
Fasting LDL-C as determined by central laboratory at screening ≥ 80 mg/dL  
104 
Subject meets at least one of the following criteria for high/very high CV risk： 
 
history of coronary artery disease 
 
history of ischemic stroke  
 
diagnosis of peripheral artery disease  
 
an estimated glomerular filtration rate (eGFR) as determined by central 
laboratory at screening of ≥ 30 but < 60 ml/min/1.73m2  
 
diagnosis of diabetes mellitus type 2 
 
presence of ≥ 3 of the following risk factors:  
o ≥ 45 years of age if male, ≥ 55 years of age if female 
o hypertension  
o smoking 
o family history of premature CVD (1st degree of relative:  male < 55yr, 
female < 65yr) 
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 
HDL cholesterol < 40 mg/dL  
 
obesity(BMI ≥ 28 kg/m2) 
OR  
Subject does not meet high/very high CV risk criteria but fasting LDL-C as 
determined by central laboratory at screening ≥ 130 mg/dl  
105 
Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) by determined by central 
laboratory at screening 
106 
Subject tolerates a screening placebo injection  
4.1.2 
Exclusion Criteria  
201. 
Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), 
coronary artery bypass graft (CABG) or stroke within 3 months prior to 
randomization  
202. 
Planned coronary or other revascularization within 20 weeks of screening  
203. 
New York Heart Association (NYHA) III or IV heart failure, or last known left 
ventricular ejection fraction < 30 
204. 
Uncontrolled serious cardiac arrhythmia defined as recurrent and highly 
symptomatic ventricular tachycardia, atrial fibrillation with rapid ventricular 
response, or supraventricular tachycardia that are not controlled by medications, 
in the past 3 months prior to randomization 
205. 
Type 1 diabetes, new-onset (hemoglobin [Hb]A1c ≥ 6.5% or fasting plasma 
glucose (FPG) ≥ 126 mg/dL at screening without known diagnosis) or poorly 
controlled (HbA1c ≥ 8.5% ) type 2 diabetes, as determined by central laboratory 
at screening  
206. 
Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) 
> 180 mmHg or diastolic blood pressure (DBP) > 110 mmHg  
207. 
Subject has taken a cholesterylester transfer protein (CETP) inhibitor in the 
12 months prior to randomization  
208. 
Subject has taken in the 6 weeks prior to LDL - C screening: red yeast rice, 
> 200 mg/day niacin, > 1000 mg/day omega-3 fatty acids (eg, dihydroxyacetone 
docosahexaenoic acid and eicosapentaenoic acid), stanols or prescription 
lipid-regulating drugs (eg, bile-acid sequestering resins, fibrates and derivatives) 
or other cholesterol lowering drugs or lipid-lowering dietary supplements or food 
additives other than statins and ezetimibe  
209. 
Treatment 3 months prior to LDL-C screening with any of the following drugs: 
systemic cyclosporine, systemic steroids , (intravenous [IV], intramuscular [IM], 
or PO) (Note: hormone replacement therapy is permitted), vitamin A derivatives 
and retinol derivatives for the treatment of dermatologic conditions 
(eg, Accutane) (Note: vitamin A in a multivitamin preparation is permitted)  
210. 
Uncontrolled hypothyroidism or hyperthyroidism as defined by thyroid stimulating 
hormone (TSH) < 1.0 time the lower limit of normal (LLN) or > 1.5 times the 
upper limit of normal (ULN), respectively, at screening  
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211. 
Severe renal dysfunction, defined as an eGFR < 30 ml/min/1.73m2 at screening 
as estimated by Cockcroft-Gault method 
212. 
Active liver disease or hepatic dysfunction, defined as aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the ULN as 
determined by central laboratory analysis at screening 
213. 
Creatinine Kinase (CK) > 5 times the ULN at screening 
214. 
Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, 
breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 
5 years prior to randomization  
215. 
Subject has previously received evolocumab or any other therapy to inhibit 
PCSK9  
216. 
Subject has known sensitivity to any of the active substances or their excipients 
to be administered during dosing, eg, carboxymethylcellulose  
217. 
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.  
218. 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures or completion. 
219. 
Currently receiving treatment in another investigational device or drug study, or 
less than 30 days before randomization since ending treatment on another 
investigational device or drug study(s) or planning to receive other investigational 
procedures while participating in this study  
220. 
Female subject of childbearing potential not willing to use an acceptable 
method(s) of effective birth control during treatment with investigational product 
and for an additional 15 weeks after the end of treatment with investigational 
product (Refer to Section 6.9.1 for specific contraceptive information).  
Female subjects of non-childbearing potential who are not required to use 
contraception during the study and include those who have had a:  
• 
hysterectomy 
• 
bilateral salpingectomy 
• 
bilateral oophorectomy 
or  
• 
who are postmenopausal.  
i. 
A postmenopausal state is defined as no menses for 12 months 
without an alternative medical cause.  [A high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used 
to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT).  However, 
in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.] 
ii. 
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 
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the study.  Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.  
Acceptable methods of effective birth control include:  
• 
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.  
[Periodic abstinence (eg., calendar, ovulation, symptothermal, 
postovulation methods), declaration of abstinence for the duration of a 
study, and withdrawal are not acceptable methods of contraception]) 
• 
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) 
• 
use of hormonal birth control methods (oral, intravaginal (eg. vaginal 
ring(s), transdermal, injectable, or implantable) 
• 
intrauterine devices (IUDs) 
• 
intrauterine hormonal releasing system (IUS) 
• 
2 barrier methods (each partner must use 1 barrier method) the male 
uses a condom and the female must choose either a diaphragm, OR 
cervical cap, OR contraceptive sponge with spermicide.  If spermicide is 
not commercially available in the country or region, the 2 barrier method 
without spermicide is acceptable.  (A female condom is not an option due 
to the risk of tearing when both partners use a condom.) 
Note: Additional medications given during treatment with investigational product 
may alter the contraceptive requirements.  These additional medications may 
require a change in the type of contraceptive methods and/or length of time that 
contraception is to be utilized and/or length of time breastfeeding (nursing) is to 
be avoided.  The investigator is to discuss these contraceptive changes with the 
study subject.  
221. 
Female subject is pregnant or breast feeding (nursing), planning to become 
pregnant or planning to breastfeed (nurse) during treatment with investigational 
product and/or within 15 weeks after the end of treatment with investigational 
product.  
5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, ICF, and all other subject information 
and/or recruitment material, if applicable (see Section 11.2).  All subjects must 
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personally sign and date the ICF before commencement of study specific 
activities/procedures. 
Upon completion of the screening period the subject is evaluated by the investigator and 
providing the subject continues to meet the inclusion/exclusion criteria, the subject is 
subsequently eligible to be enrolled in the study.  The investigator is to document this 
decision and date, in the subject’s medical record and in/on the enrollment case report 
form (CRF). 
Each subject who enters into the screening period for the study (defined as the point at 
which the subject signs the ICF) receives a unique subject identification number before 
any study-related activities/procedures are performed.  The subject identification number 
will be assigned by the interactive voice response system / interactive web response 
system (IVRS/IWRS).  This number will be used to identify the subject throughout the 
clinical study and must be used on all study documentation related to that subject.  
Subjects who, in the opinion of the investigator, require statin up-titration or dietary 
adjustment can be rescreened after 1 month.  Subjects can only be rescreened once.   
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.  This number will not necessarily be the same as the randomization number 
assigned for the study.   
5.1 
Randomization/Treatment Assignment 
Subjects will be considered enrolled on the day they are randomized.  Assignment to the 
4 treatment arms will be based on a computer-generated randomization schedule 
prepared by Amgen before the start of the study. 
Each subject will receive a unique randomization number.  Randomization will be 
stratified by entry CV risk (high/very high CV risk vs not high/very high CV risk). 
Once a subject has completed screening and continues to meet all eligibility criteria, a 
site representative will make the randomization call to the IVRS/IWRS to assign a 
randomization number to the subject.  The randomization call to the IVRS/IWRS is 
accomplished by entering the pertinent information detailed in the IVRS/IWRS user 
manual.  A confirmation fax or email will be sent to the site to verify that the correct 
information has been entered and to confirm the assignment of a randomization number.  
A subject will be considered randomized into the study when a randomization number is 
assigned.   
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The randomization date is to be documented in the subject’s medical record and on the 
enrollment CRF.  Randomization numbers will be provided to the site through an 
IVRS/IWRS. 
5.2 
Site Personnel Access to Individual Treatment Assignments 
A subject’s treatment assignment should only be unblinded when knowledge of the 
treatment is essential for the further management of the subject on this study. 
Unblinding at the study site for any other reason will be considered a protocol deviation. 
The investigator is strongly encouraged to contact the Amgen Clinical Trial Manager 
before unblinding any subject’s treatment assignment, but must do so within 1 working 
day after the event. 
6. 
TREATMENT PROCEDURES 
The Amgen investigational product used in this study is evolocumab and placebo 
(Amgen investigational medicinal product) in a prefilled Autoinjector/Pen (AI/Pen) 
(Amgen investigational medical device).  In several countries, investigational product is 
referred to as Investigational Medicinal Product (IMP).  In this document, IMP will be 
referred to as investigational product.  
An Investigational Product Instruction Manual (investigational productIM) containing 
detailed information regarding the storage, preparation, and administration of 
investigational product will be provided separately. 
Refer to Section 6.1 and Section 6.2 for details regarding investigational product and its 
dosage and administration.   
6.1 
Classification of Product(s) and/or Medical Device(s) 
The Amgen Investigational Product(s) and/or matched placebo (except if required by 
local regulation) used in this study include(s): evolocumab and placebo.   
The IPIM, a document external to this protocol, contains detailed information regarding 
the storage, preparation, destruction, and administration of evolocumab and matched 
placebo.  
The medical device(s) used in this study include(s): Prefilled AI/pen. 
Note:  Non-investigational medical device(s) (ie, medical device(s) not under study) or 
products will be described in Section 6.6.  
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Additional details regarding the use of the AI/Pen is provided in the IPIM and in the 
Instructions for Use (IFU). 
In several countries, investigational product is referred to as IMP.  In this document, IMP 
will be referred to as investigational product.   
6.2 
Investigational Product 
6.2.1 
Amgen Investigational Product [Evolocumab] 
Evolocumab and respective placebo will be manufactured and packaged by Amgen Inc. 
and distributed using Amgen clinical investigational product distribution procedures.   
Evolocumab will be presented as a sterile, preservative-free solution in a single use, 
disposable, handheld mechanical (spring-based) 1.0 mL prefilled AI/Pen for fixed dose, 
subcutaneous injection.  The prefilled AI/Pen contains a 1.0 mL deliverable volume of 
140 mg/mL evolocumab in 220 mM proline, 20 mM acetate, 0.01% (w/v) polysorbate 80, 
pH 5.0.   
Placebo will be presented in a prefilled AI/Pen containing a 1.0 mL deliverable volume of 
1.1% (w/v) sodium carboxymethylcellulose, 250 mM proline, 10 mM acetate, and 
0.01% (w/v) polysorbate 80, pH 5.0. 
Evolocumab should be stored protected from light and according to the storage and 
expiration information (where required) provided on the label.  Evolocumab should be 
handled per the instructions provided in the IPIM.  AI/pens should be checked for cracks 
or damage that may occur during shipment or if not handled properly.  Damaged product 
should not be administered.  Further details are provided in the IPIM.   
6.2.1.1 
Dosage, Administration, and Schedule 
Investigational product will be administered SC (evolocumab or matched placebo) at the 
investigator site by a qualified staff member in accordance with instructions in the IPIM.  
Investigational product administration by SC injection at each visit must be done after 
vital signs, electrocardiogram (ECG), and blood draw procedures, if applicable.  The 
date, time, and amount of evolocumab or placebo  will be recorded on the individual 
subject’s worksheet and/or electronic case report form (eCRF).  The box number of 
investigational product (active drug or placebo) is to be recorded on each subject’s Drug 
Administration electronic case report form (eCRF).  
After investigational product administration at each dosing visit, subjects should be 
observed for at least 30 minutes before being discharged. 
Approved 
 
 

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In the Q2W regimen, 140 mg of AMG 145 will be administered subcutaneously every 
2 weeks via one 1.0 mL prefilled AI/pen. 
In the QM regimen, 420 mg of evolocumab will be administered subcutaneously once a 
month via three 1.0 mL prefilled AI/pens.  The prefilled AI/pens injections should be 
administered in a consecutive fashion with all injections completed within 30 minutes.   
Details of preparing and administering investigational product are included in the IPIM 
provided by Amgen at the start of the study.  The dosing schedule is described by a 
schema in the protocol synopsis. 
6.2.1.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation  
There will be no dose adjustments in this study.  If, in the opinion of the investigator, a 
subject is unable to tolerate a specific dose of investigational product, that subject will 
discontinue investigational product but will return for all other study procedures and 
measurements until the end of the study. 
If a subject is late for administration of investigational product, administration should 
occur as soon as possible.  
A QM dose of investigational product should not be administered within less than 7 days 
of a previous dose.  If a QM subject arrives for a visit with investigational product 
administration and investigational product was administered within the prior 7 days, the 
dose should not be administered but all other study procedures should be conducted.  
Administration of investigational product should occur as soon as possible but at least 
7 days after the previous administration.   
Not more than 2 Q2W doses should be administered within any 7-day period.  If a Q2W 
subject arrives for a visit with investigational product administration and more than 
1 dose of investigational product was administered within the prior 7 days, the dose 
should not be administered but all other study procedures should be completed.  
Administration of investigational product should occur as soon as possible but at least 
7 days after the most recent previous administration. 
Subjects who completely miss a dose of investigational product will continue in the study 
and receive the next dose of investigational product per their schedule of administration. 
Approved 
 
 

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6.3 
Non-investigational Product(s) 
6.3.1 
Non-Amgen Non-investigational Product(s) 
All eligible subjects must be taking a maximum appropriate dose of an approved statin, 
not requiring uptitration. 
All other lipid lowering drugs that are allowed per protocol and that the subject may be 
taking, must be commercially available and are not provided or reimbursed by Amgen 
(except if required by local regulation).  The investigator will be responsible for obtaining 
supplies of these drugs.   
Subjects must be on an approved statin with maximum appropriate (optimal) stable daily 
dose with or without ezetimibe for at least 4 weeks before LDL-C screening and, in the 
opinion of the investigator, not requiring uptitration. 
They must remain on the same daily statin background therapy (drug and dose), with or 
without ezetimibe, throughout the study from signing of the ICF until the EOS.  If statin 
therapy is discontinued, or changed during the study, the reason for adjusting 
medication (eg. adverse event, noncompliance, etc.) should be recorded. 
Additional details regarding the product(s) are provided in the IPIM. 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], AST, 
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). 
6.4.1 
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) 
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• 
Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia. 
• 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants and mushrooms 
• 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s 
Syndrome,Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation 
(eg, indinavir, atazanavir) 
• 
Alpha-one antitrypsin deficiency 
• 
Alcoholic hepatitis 
• 
Autoimmune hepatitis 
• 
Wilson’s disease and hemochromatosis 
• 
Nonalcoholic Fatty Liver Disease including Steatohepatitis (NASH) 
• 
Non-hepatic causes (eg, rhabdomylosis, hemolysis) 
If investigational product is 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 6.4.2). 
Approved 
 
 

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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 
-- 
Abbreviations: ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate 
aminotransferase; INR=international normalized ratio; TBL=total bilirubin; ULN=upper limit of normal 
6.4.2 
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 investigational product should be 
permanently discontinued.  Subjects who clearly meet the criteria for permanent 
discontinuation (as described in Table 1) should never be rechallenged. 
6.5 
Concomitant Therapy 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.8. 
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6.6 
Medical Devices 
Investigational product will be administered per prefilled AI/Pen, provided by Amgen.  
The AI/pen is a single use disposable, handheld mechanical "spring-based" device for 
fixed dose subcutaneous injection of 1.0 mL deliverable volume.Additional details 
regarding the use of the AI/Pen is provided in the IPIM and in the IFU.  Other 
non-investigational medical devices may be used in the conduct of this study as part of 
standard care.  These other medical devices (eg, syringes, sterile needles, alcohol prep 
pads), that are commercially available are not usually provided or reimbursed by Amgen 
(except, for example, if required by local regulation).  The investigator will be responsible 
for obtaining supplies of these devices.   
6.7 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material.  
This includes any drug(s), device(s) or combination product(s) provisioned and/or 
repackaged /modified by Amgen.  Drug(s) or device(s) includes investigational product.   
Examples of potential product complaints that need to be reported to Amgen include, but 
are not limited to: 
• 
broken container or cracked container, 
• 
subject or healthcare provider cannot appropriately use the product despite training 
(eg., due to malfunction of the prefilled AI/pen), 
• 
missing labels, illegible labels, incorrect labels, and/or suspect labels,  
• 
change in investigational product appearance, for example color change or visible 
presence of foreign material, 
• 
unexpected quantity or volume, for example amount of fluid in the prefilled AI/pen, or 
• 
evidence of tampering or stolen material. 
If possible, please have the prefilled AI/pen available for visual examination when 
making a product complaint.  Maintain the prefilled AI/pen at appropriate storage 
conditions until further instructions are received from Amgen.   
The investigator is responsible for ensuring that all product or device complaints 
observed by the investigator or reported by the subject that occur after signing of the 
ICF through 30 days after the last dose of investigational product or EOS, whichever is 
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later, are reported to Amgen within 24 hours of discovery or notification of the product 
and/or device complaint.  
Any product complaint(s) associated with an investigational product(s) or 
non-investigational product(s) or device(s) supplied by Amgen are to be reported 
according to the instructions provided in the IPIM. 
6.8 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
The following treatments are not permitted during the study: 
• 
any investigational therapies other than study provided investigational product 
• 
any lipid lowering therapies not taken at the time of screening and enrollment 
Please contact the Amgen medical monitor or designee if any of these therapies should 
be initiated during the blinded portion of the study.  Note that a change in lipid lowering 
therapy does not necessarily require ending investigational product. 
The following treatments are not recommended in subjects treated with statins 
metabolized by CYP3A4 (eg simvastatin or atorvastatin) because of their potential 
impact on metabolism of certain statins:  
Medications or foods that are known potent inhibitors of cytochrome P450 A4 
(CYP3A) eg, itraconazole, ketoconazole, and other antifungal azoles, macrolide 
antibiotics erythromycin, clarithromycin, and the ketolide antibiotic telithromycin, 
HIV or Hepatitis C virus (HCV) protease inhibitors, antidepressant nefazodone 
and grapefruit juice in large quantities (> 1 quart daily [approximately 1 Liter]) 
should not be used during the study or other cholesterol lowering drugs or lipid 
lowering dietary supplements or food additives other than statins and ezetimibe. 
6.9 
Contraceptive Requirements 
6.9.1 
Female Subjects  
Female subjects of childbearing potential must agree to practice true sexual abstinence 
(refrain from heterosexual intercourse) or use effective method(s) of contraception 
during treatment and for an additional 15 weeks after the last dose of protocol-required 
therapies.   
Acceptable methods of effective contraception include: Hormonal (Combined estrogen 
and progestogen or progesterone-only hormonal contraception given via oral, 
intravaginal, transdermal, injectable, or implantable route); Intrauterine device (IUD); 
Intrauterine hormonal-releasing system (IUS); Bilateral tubal occlusion/ligation; 
Approved 
 
 

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Vasectomized partner (provided that partner is the sole sexual partner of the female 
subject who is of childbearing potential and that the vasectomized partner has received 
medical assessment of the surgical success); Two barrier methods (one by each 
partner) and the female partner must use spermicide (if spermicide is commercially 
available) with the barrier method [the male must use a condom (latex or other synthetic 
material) and the female may select either a diaphragm, cervical cap or contraceptive 
sponge].  A female condom is not an option because there is a risk of tearing when both 
partners use a condom.  The reliability of true sexual abstinence must be evaluated by 
the investigator and be the preferred and usual lifestyle of the subject.   
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.   
Females not of childbearing potential are defined as:  Any female who is has had a 
hysterectomy, OR bilateral salpingectomy, OR bilateral oophorectomy, OR are 
post-menopausal.  Post-menopausal women are: 
• 
Age > 55 years with cessation of menses for 12 or more months  
• 
Age < 55 years but no spontaneous menses for at least 2 years 
• 
Age < 55 years and spontaneous menses within the past 1 year, but currently 
amenorrheic (eg, spontaneous or secondary to hysterectomy), AND with 
follicle-stimulating hormone levels > 40 IU/L, or postmenopausal estradiol levels 
< 5 ng/dL, or according to the definition of "postmenopausal range" for the laboratory 
involved. 
6.9.2 
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 amenorrhoea method. 
7. 
STUDY PROCEDURES 
Screening assessments and study procedures outlined in this section and in Table 2 can 
only be performed after obtaining a signed informed consent.  This includes any 
discontinuation of the subject’s medication for the purpose of participation in this study. 
It is very important to attempt to perform study procedures and obtain samples at the 
precise timepoints stipulated in Table 2.  When it is not possible to perform the study 
visit at the exact timepoint, the visit may be performed within the acceptable visit window 
Approved 
 
 

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as defined in Table 2.  If a study visit is missed or late, including visits outside the visit 
window, subsequent visits should resume on the original visit schedule. 
Any assessments at prior visits should not be duplicated at subsequent visits, with the 
exception of screening and rescreening visits, if possible, all study procedures for a visit 
should be completed on the same day.  Subsequent study visits should resume on the 
original schedule.  Missed assessments at prior visits should not be duplicated at 
subsequent visits. 
7.1 
Schedule of Assessments  
 
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Table 2.  Schedule of Assessments 
 
Screening 
Baseline 
Treatment Period 
Early 
Termination 
Study Week 
Week -4 
(Day -28) to 
Day -1 
Day 1 
Week 8 
± 3 days 
Week 10 
± 3 days 
Week 12a 
± 3 days 
Week 14a, b 
± 3 days 
Q2W subjects only 
 
Informed Consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
 
X 
Physical Examination 
X 
X 
 
 
X 
 
X 
Weight and waist circumference 
X 
X 
 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
Pregnancy Test : Serumc 
X 
 
 
 
 
 
 
Pregnancy Test : Urined 
 
X 
 
 
 
 
 
Chemistry 
X 
X 
X 
 
X 
 
X 
Hematology 
X 
X 
X 
 
X 
 
X 
Urinalysis 
X 
X 
X 
 
X 
 
X 
Screening placebo injectione 
X 
 
 
 
 
 
 
HbA1c 
X 
 
 
 
X 
 
X 
Thyroid Stimulating Hormone 
X 
 
 
 
 
 
 
HCVf 
X 
 
 
 
X 
 
X 
Hepatitis C viral loadg 
 
X 
 
 
X 
 
X 
hsCRP 
 
X 
 
 
X 
 
X 
Anti-evolocumab antibodies 
 
X 
 
 
X 
 
X 
Page 1 of 2 
Footnotes defined on the next page 
 
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Table 2.  Schedule of Assessments 
 
Screening 
Baseline 
Treatment Period 
Early 
Termination 
Study Week 
Week -4 
(Day -28) to 
Day -1 
Day 1 
Week 8 
± 3 days 
Week 10 
± 3 days 
Week 12a 
± 3 days 
Week 14a, b 
± 3 days 
Q2W subjects only 
 
Fasting Lipids, ApoA1, ApoB, 
Lp(a) 
X 
X 
X 
X 
X 
 
X 
PCSK9 
 
X 
X 
X 
X 
 
X 
Safety Data 
Collection/Recording/Reportingh 
X 
X 
X 
X 
X 
X 
X 
Concomitant Therapy 
X 
X 
X 
X 
X 
X 
X 
IP dispensation to subject for 
non-clinic administration 
 
X 
 
 
 
 
 
IP administrationi 
 
X 
X 
Xj 
 
 
 
IP reconciliation 
 
 
X 
 
 
 
X 
Page 2 of 2 
Abbreviations: ApoA1= apolipoprotein A1;ApoB= apolipoprotein B1; HbA1C= hemoglobin A1c; hsCRP= high sensitivity CRP; Lp(a)= lipoprotein a; PCSK9= proprotein 
convertase subtilisin/kexin type 9. 
a: End of Study visit for QM subjects (week 12) and visit/phone call for Q2W subjects (Week 14) are to occur no earlier than 30 days post last IP administration  
b: Phone call is acceptable 
c: Only in females of childbearing potential.  Additional pregnancy testing may be performed at the investigators's discretion or as required per local laws and 
regulations. 
d: Only in females of childbearing potential prior to administration of IP/placebo if the serum pregnancy test was performed over 7 days prior to initiation of IP/placebo. 
e: Placebo injection to occur following determination of eligibility for all other screening parameters 
f: HCV antibodies only in high risk subjects (see Section 7), subjects with a positive history of HCV infection, or if ALT or AST > 2x ULN at any time during screening;  
g: Hepatitis C viral load only in HCV positive patients 
h: Including assessment/review for adverse events/serious adverse events/disease related events/adverse device effects.  Only AEs/ADEs 
possibly related to study procedures and serious adverse events are collected during the screening period 
i: During the treatment period, in addition to the in-clinic administration at D1, W8 and W10 (as applicable), subjects randomized to QM are expected to administer 
non-clinic IP at W4 and subjects randomized to Q2W IP are expected to administer non-clinic IP at W2,W4,and W6. 
j: Only for subjects randomized to Q2W IP 
 
 
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7.2 
General Study Procedures  
7.2.1 
Study Visit Definitions and Windows 
After signing the ICF, potential subjects will be evaluated to determine whether they fulfill 
the entry requirements listed in Section 4.1.  At screening, the subject should be 
reminded that participation in the study is contingent upon his or her screening test 
results.  The screening period begins the day the subject signs the ICF, and ends (after 
28 days) when the subject is randomized to receive the first dose of investigational 
product or fails the enrollment criteria. 
Refer to the applicable supplemental central laboratory, IVRS/IWRS, and study manuals 
for detailed collection and handling procedures.   
Subjects should be randomized before or on the day 1 visit, and initiate their first dose of 
investigational product within 5 days of randomization. 
The following visit windows (± 3 days) will apply to all visits during the treatment period 
of the study: 
• 
Week 8 
• 
Week 10  
• 
Week 12  
• 
Week 14 (Q2W subjects only) 
Study procedures for a specific visit may be completed on multiple days as long as all 
the procedures are completed within the visit window. 
7.2.2 
Description of Study Procedures 
The sections below provide a description of the individual study procedures listed in 
Section 7.2.3, Section 7.2.4, and Section 7.2.5.  Details regarding the collection, 
recording and reporting of adverse events, adverse device effects, serious adverse 
events, disease related events and/or other safety findings are provided in Section 9.2. 
7.2.2.1 
Informed Consent 
All subjects or legally acceptable representative must sign and personally date the 
IRB/IEC approved informed consent and provide subject assent if appropriate before 
any study specific procedures are performed. 
7.2.2.2 
Medical History 
The Investigator or designee will collect a complete medical history covering the period 
within 120 days prior to randomization.  Additionally, a targeted cardiovascular and 
diabetes medical history not limited to 120 days prior to randomization will be collected. 
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Targeted cardiovascular history including but not limited to cardiovascular risk factors, 
history of cardiovascular disease, revascularization procedures, family history, and 
diagnostic criteria for familial hypercholesterolemia will be collected.  
7.2.2.3 
Measurement of Vital Signs 
Blood pressure (BP) and heart rate (HR) measurements will be determined after the 
subject has been seated for at least 5 minutes.  The appropriate size cuff should be 
used.  During screening, BP measurements can be repeated if the previous reading is 
outside of the eligibility range.  The repeat BP measure should be taken at least 
2 minutes following the previous measure. 
7.2.2.4 
Measurement of Waist Circumference 
Subjects should wear minimal clothing to ensure that the measuring tape is correctly 
positioned.  Subjects should stand erect with the abdomen relaxed, arms at the sides, 
feet together and with their weight equally divided over both legs.  To perform the waist 
measurement, the lowest rib margin is first located.  The iliac crest is then palpated in 
the midaxillary line.  It is recommended to apply an elastic tape horizontally midway 
between the lowest rib margin and the iliac crest, and tie firmly so that it stays in position 
around the abdomen about the level of the umbilicus.  The elastic tape thus defines the 
level of the waist circumference, which can then be measured by positioning the 
measuring tape over the elastic tape. 
Subjects are asked to breathe normally, and to breathe out gently at the time of the 
measurement to prevent them from contracting their muscles or from holding their 
breath.  Measurements should be performed using the same procedure throughout the 
study.  The reading is taken to the nearest centimeter or ½ inch and entered in the 
source document. 
7.2.2.5 
Prior Therapies, Substance use History, and Concomitant 
Medications 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed above in Excluded Treatments and/or Procedures During Study Period. 
Prior general and targeted therapies (eg, statins and other lipid lowering therapy), taken 
120 days prior to randomization should be collected with the following information: 
therapy name, indication, dose, unit, frequency, route, start date and stop date. 
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If a targeted therapy is begun, discontinued, or changed during study, in addition to 
updates for the above information, the reason for adjusting medication (ie, adverse 
event, worsening of underlying condition, noncompliance etc) should be recorded. 
Concomitant therapies are to be collected from ICF through the EOS.   
7.2.2.6 
Pregnancy Test 
Pregnancy testing will occur in females of childbearing potential only. 
7.2.2.7 
Laboratory Assessments 
Subjects must be fasting overnight (no food or drinks other than water for ≥ 9 hours) 
before each study visit where fasting lipid samples are obtained.  If the subject is not 
fasting for the screening or the day 1 visit, no visit procedures are performed and the 
visit should be rescheduled within the applicable protocol windows.  If subject is not 
fasting after day 1, all procedures except fasting labs and investigational product 
administration, if applicable, will be performed and another visit should be scheduled, 
within the visit window if possible, for fasting labs and investigational product 
administration. 
All laboratory samples will be sent to the central laboratory.  Concentration values are 
provided in mmol/L for investigator convenience.  Conventional concentrations (mg/mL) 
will be used for the protocol, including for eligibility determination.  eGFR will be 
calculated by the central laboratory and will be provided to the site for eligibility 
determination.  Table 3 below outlines the specific analytes to be tested. 
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Table 3.  Lists of Analytes  
Central 
Laboratory 
Chemistry 
 
Central 
Laboratory 
Urinalysis 
Central   
Laboratory 
Hematology 
Other Central 
Laboratory 
Analyses 
Sodium 
Potassium 
Chloride 
Bicarbonate  
Total protein 
Albumin 
Calcium 
Adjusted Calcium 
Magnesium 
Phosphorus 
Fasting Glucose 
BUN or Urea 
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin 
CK 
Alk phos 
LDH 
AST (SGOT) 
ALT (SGPT) 
eGFR 
 
Specific gravity 
pH 
Blood 
Protein  
Glucose 
Bilirubin 
WBC 
RBC 
Epithelial cells 
Bacteria 
Casts 
Crystals 
 
RBC 
Hemoglobin 
Hematocrit 
MCV  
MCH 
MCHC 
RDW 
Platelets 
WBC 
Fasting lipids 
• total cholesterol 
• HDL-C 
• LDL-C 
• triglycerides 
• VLDL-C 
• non-HDL-C 
ApoA1 
ApoB 
Lp(a) 
hsCRP 
PCSK9 
HbA1c 
Serum and urine 
pregnancy tests 
(females of 
childbearing 
potential) 
HCV antibody 
HCV viral load 
Antibodies 
TSH  
Hepatitis C virus (HCV): 
HCV antibodies are measured before initiating treatment with investigational product in 
subjects at high risk for, or with history of, HCV infection and in subjects with ALT or AST 
> 2x ULN at any time during screening. 
High risk subjects for this protocol are those who meet any of the following conditions: 
• 
Intravenous usage of illegal drugs 
• 
History of needle stick injuries as part of career or other reasons (tattoo, punch, 
acupuncture, etc) 
• 
History of iatrogenic exposure 
• 
History of high risk sexual behavior eg multiple sex partners, male homosexual 
• 
Have a known HCV infected sexual partner or family member 
• 
Are known to be infected with HIV or sexual partner of HIV infected person 
• 
Wounded skin or mucosa contaminated with the blood of HCV infected person 
• 
History of blood transfusion or use of blood product before 1993 
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Viral load will be tested in subjects who are positive for HCV antibody. 
Blinding: 
In order to protect the blinding of the double-blind treatment period the following labs will 
be blinded post-investigational product treatment until unblinding of the clinical database 
and not reported to sites as noted below: 
• 
Blinded to the Amgen study team and site staff: lipid panel, ApoA1,ApoB, 
lipoprotein(a), hsCRP, and PCSK9 
Investigators should not perform non-protocol testing of these analytes during a subject’s 
study participation and until at least 12 weeks after last investigational product 
administration, or the subject’s EOS, whichever is later.  
Refer to the IPIM for a description regarding how responsible pharmacists and 
investigators will access treatment information via the IVR/IWR system, in the event that 
there is a need to break the blind.  The investigator is strongly encouraged to contact the 
Clinical Trial Manager before unblinding any subject’s treatment assignment, but must 
do so within 1 working day after the event. 
7.2.3 
Screening Enrollment and/or Randomization 
The following procedures are to be completed during the screening period at time points 
designated in the Schedule of Assessments (Table 2):  
• 
Confirmation that the ICF has been signed  
• 
Demographic data including sex, age, race, and ethnicity will be collected in order to 
study their possible association with subject safety and treatment effectiveness.  
• 
Physical Examination as per standard of care 
• 
Medical/surgical history 
• 
Height, weight, and waist circumference 
• 
Serum pregnancy test (for with childbearing potential) 
• 
Vital signs (eg, BP, HR, respiration rate, temperature) 
• 
Laboratory Assessments (Chemistry, Hematology, and Urinalysis), as applicable 
• 
Assessment of HCV, HbA1c, Thyroid Stimulating Hormone, Fasting Lipids, ApoA1, 
ApoB and Lp(a) 
• 
Serious Adverse Event reporting (AEs possibly related to study procedures, ADEs 
and SAEs are collected during the screening period, from signing of the ICF). 
• 
Adverse Event reporting 
• 
Disease Related Event Reporting 
• 
Adverse Device Effect Reporting  
Approved 
 
 

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• 
Documentation of concomitant medications 
• 
Registration in IVRS/IWRS, as applicable 
• 
Randomization via IVRS/IWRS, as applicable 
ICF must be obtained before completing any other screening procedures.  
The screening period is up to 4 weeks.  If a subject has not met all eligibility criteria at 
the end of the 4-week window, the subject will be registered as a screen fail.  Screen fail 
subjects may be eligible for re-screening once as described in Section 7.2.3.1. 
Subjects will undergo SC placebo injection prior to randomization with a device to be 
used during the study (AI/pen).  Subjects who tolerate the placebo injection, complete all 
screening procedures, and successfully meet all eligibility criteria at the end of screening 
will be randomized via IVRS/IWRS and will return to the study site for day 1 procedures 
while continuing their background lipid lowering treatment (if applicable).  Subjects can 
only be randomized 1 time for this study.  Subjects should be randomized before or on 
the day 1 visit, and initiate their first dose of investigational product within 5 days of 
randomization. 
7.2.3.1 
Rescreening 
Subjects who screen fail due to the LDL-C below the limit for eligibility during final 
screening cannot be rescreened for this study.   
Suitable subjects who are ineligible at the initial screening for other reasons and have 
not been randomized can be re-consented and rescreened once at a later time unless 
they withdraw from screening, provided the study is still enrolling subjects.  For subjects 
who are rescreened, data from the first screening period will not be used for the 
analysis. 
Rescreened subjects will be re-consented and will repeat all screening procedures.  
Rescreened subjects will maintain the originally assigned subject identification number. 
7.2.4 
Treatment  
7.2.4.1 
Baseline (Day 1): All Subjects 
The following procedures will be completed on Day 1 as indicated in the Schedule of 
Assessments (Table 2).   
• 
Vital Signs 
• 
Physical Examination 
• 
Weight and waist circumference 
Approved 
 
 

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• 
Urine pregnancy test (for females with childbearing potential, prior to administration 
of investigational product/placebo if the serum pregnancy test was performed over 
7 days prior to initiation of IP/placebo) 
• 
Laboratory Assessments (Chemistry, Hematology, and Urinalysis), as applicable 
• 
Hepatitis C viral load 
• 
hsCRP 
• 
Antibody testing 
• 
Fasting Lipids, ApoA1, ApoB, Lp(a) 
• 
PCSK9 testing 
• 
Serious Adverse Event reporting 
• 
Adverse Event reporting 
• 
Disease Related Event Reporting 
• 
Adverse Device Effect Reporting  
• 
Documentation of concomitant medications 
• 
Investigational product dispensation to subject for non-clinic administration  
• 
Investigational product administration 
• 
Investigational product reconciliation 
7.2.4.2 
Week 8: All Subjects 
The following procedures will be completed at Week 8 (± 3 days) as indicated in the 
Schedule of Assessments (Table 2).   
• 
Vital Signs 
• 
Laboratory Assessments (Chemistry, Hematology, and Urinalysis), as applicable 
• 
Fasting Lipids, ApoA1, ApoB, Lp(a) 
• 
PCSK9 testing 
• 
Serious Adverse Event reporting 
• 
Adverse Event reporting 
• 
Disease Related Event Reporting 
• 
Adverse Device Effect Reporting  
• 
Documentation of concomitant medications 
• 
Investigational product administration  
• 
Investigational product reconciliation 
Approved 
 
 

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7.2.4.3 
Week 10: All Subjects 
The following procedures will be completed at Week 10 (± 3 days) as indicated in the 
Schedule of Assessments (Table 2).   
• 
Vital Signs 
• 
Fasting Lipids, ApoA1, ApoB, Lp(a) 
• 
PCSK9 testing 
• 
Serious Adverse Event reporting 
• 
Adverse Event reporting 
• 
Disease Related Event Reporting 
• 
Adverse Device Effect Reporting  
• 
Documentation of concomitant medications 
• 
Investigational product administration for Q2W subjects 
7.2.4.4 
Week 12: All Subjects 
The following procedures will be completed at Week 12 (± 3 days) as indicated in the 
Schedule of Assessments (Table 2).   
• 
Vital Signs 
• 
Physical Examination 
• 
Weight and waist circumference 
• 
Laboratory Assessments including local and central laboratories, as applicable 
• 
HbA1C  
• 
HCV 
• 
Hepatitis C viral load 
• 
hsCRP 
• 
Antibody testing 
• 
Fasting Lipids, ApoA1, ApoB, Lp(a) 
• 
PCSK9 testing 
• 
Serious Adverse Event reporting 
• 
Adverse Event reporting 
• 
Disease Related Event Reporting 
• 
Adverse Device Effect Reporting  
• 
Documentation of concomitant medications 
Approved 
 
 

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7.2.4.5 
Week 14: Q2W Subjects Only 
The following procedures will be completed at Week 14 (± 3 days) as indicated in the 
Schedule of Assessments (Table 2).   
• 
Serious Adverse Event reporting 
• 
Adverse Event reporting 
• 
Disease Related Event Reporting 
• 
Adverse Device Effect Reporting  
• 
Documentation of concomitant medications 
7.2.5 
Early Termination Visit 
The following procedures will be completed at the early termination visit as indicated in 
the Schedule of Assessments (Table 2).   
• 
Vital Signs 
• 
Physical Examination 
• 
Weight and waist circumference 
• 
Laboratory Assessments including local and central laboratories, as applicable 
• 
HbA1C 
• 
HCV  
• 
Hepatitis C viral load 
• 
hsCRP 
• 
Antibody testing 
• 
Fasting Lipids, ApoA1, ApoB, Lp(a) 
• 
PCSK9 testing 
• 
Serious Adverse Event reporting 
• 
Adverse Event reporting 
• 
Disease Related Event Reporting 
• 
Adverse Device Effect Reporting  
• 
Documentation of concomitant medications   
7.3 
Antibody Testing Procedures 
Blood sample(s) for Antibody testing are to be collected at baseline, Week 12, and 
during the early termination visit for the measurement of anti-evolocumab binding 
antibodies.  Samples testing positive for binding antibodies will also be tested for 
neutralizing antibodies and may be further characterized for quantity/titer, isotype, affinity 
and presence of immune complexes.  Additional blood samples may be obtained to rule 
out anti-evolocumab antibodies during the study.   
Approved 
 
 

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Sites will be notified of any positive neutralizing antibody results to evolocumab for 
individual subjects at the end of the study for each subject.  If results are not provided, 
no neutralizing antibodies to evolocumab have been detected. 
Subjects who test positive for neutralizing antibodies to evolocumab at the final 
scheduled study visit  will be asked to return for additional follow-up testing.  This testing 
is to occur approximately every 3 months starting from when the site has been notified of 
the positive result, until:  (1) neutralizing antibodies are no longer detectable or (2) the 
subject has been followed for a period of at least 1 year (± 4 weeks) post administration 
of evolocumab.  All follow-up results, both positive and negative will be communicated to 
the sites.  More frequent testing (eg, every month) or testing for a longer period of time 
may be requested in the event of safety-related concerns.  Follow-up testing is not 
required where it is established that the subject did not receive evolocumab. 
Subjects who test positive for binding, non-neutralizing antibodies and have clinical 
sequelae that are considered potentially related to an anti-evolocumab antibody 
response may also be asked to return for additional follow-up testing.   
7.4 
Sample Storage and Destruction  
Any blood sample collected according to the Schedule of Assessments (Table 2) can be 
analyzed for any of the tests outlined in the protocol and for any tests necessary to 
minimize risks to study subjects.  This includes testing to ensure analytical methods 
produce reliable and valid data throughout the course of the study.  This can also 
include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.   
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
scientific questions related to hyperlipidemia and mixed dyslipidemia, metabolic 
disorders, the dose response and/or prediction of response to evolocumab, and 
characterize aspects of the molecule (eg, mechanism of action/target, metabolites).  
Results from this analysis are to be documented and maintained, but are not necessarily 
reported as part of this study.  Samples can be retained for up to 20 years.   
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Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of pharmacogenetic, or other exploratory studies are not 
placed in the subject’s medical record and are not to be made available to the subject, 
members of the family, the personal physician, or other third parties, except as specified 
in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
samples can be located and destroyed.  Samples will be destroyed once all 
protocol-defined procedures are completed.  However, information collected from 
samples prior to the request for destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  See 
Section 11.3 for subject confidentiality. 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects (or a legally acceptable representative) can decline to continue receiving 
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 options for continuation of the Schedule of Assessments 
(Table 2) and collection of data, including endpoints, adverse events, disease related 
events, and device related events, as applicable.  The investigator must document the 
change to the Schedule of Assessments (Table 2) and the level of follow-up that is 
agreed to by the subject (eg, in person, by telephone/mail, through family/friends, in 
Approved 
 
 

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correspondence/communication with other physicians, from review of the medical 
records).   
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publically available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.   
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from 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 
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, including pregnancy in a female 
subject)  
• 
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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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 are at risk or are 
known to have cardiovascular disease.  Therefore, disease-related events potentially 
include manifestations and complications of atherosclerotic vascular disease such as 
coronary artery disease, angina, myocardial infarction, ischemic stroke, transient 
ischemic attack, carotid artery disease, peripheral vascular disease (including 
complications such as claudication), 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 is due to the disease under study; the event is to be recorded on the Event 
CRF. 
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(s)/study treatment/protocol-required therapies and 
disease worsening, this must be reported as an Adverse Event or Serious 
Adverse Event.  
9.1.2 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease 
(eg, diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
Approved 
 
 

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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.   
Resolution of the adverse event will be recorded on the event CRF. 
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.   
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. 
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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 from the time of randomization/ 
after the first dose of investigational medicinal product(s)/study 
treatment/protocol-required therapies through 30 days after the last administration of 
investigational product or the EOS visit/safetyfollow-up visit whichever is later,  are 
recorded on the Event CRF as a Disease Related Event.   
Disease Related Events assessed by the investigator to be more severe than expected 
and/or related to the investigational medicinal product(s)/study 
treatment/protocol-required therapies, and determined to be serious, must be recorded 
on the Event CRF as Serious Adverse Events.   
Additionally, the investigator is required to report a fatal Disease Related Event on the 
Event CRF.   
9.2.2 
Adverse Events 
9.2.2.1 
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
Adverse events possibly related to study procedures, adverse device effects and serious 
adverse events are reported from signing of the ICF.  All other adverse events are 
reported from the time of randomization/first dose of investigational product/study 
treatment/protocol-required therapies.  The investigator is responsible for ensuring that 
all adverse events observed by the investigator or reported by the subject that occur 
from signing of the ICF or from the time of randomization/first dose of investigational 
product/study treatment/protocol-required therapies through 30 days after the last 
administration of investigational product or the EOS visit/safety follow-up visit or  
whichever is later, are reported using the Event CRF.   
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The investigator must assign the following adverse event attributes: 
• 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
• 
Dates of onset and resolution (if resolved), 
• 
Severity [and/or toxicity per protocol], 
• 
Assessment of relatedness to investigational product  (evolocumab/placebo  and/or 
the device (the prefilled Autoinjector/Pen), (AI/Pen) or other protocol-required 
therapies or study mandated procedures or activity 
• 
Action taken. 
The adverse event grading scale used will be the Common Terminology Criteria for 
Adverse Events (CTCAE).  The grading scale used in this study is described in 
Appendix A.   
The investigator must assess whether the adverse event is possibly related to 
investigational medicinal product (IMP) (evolocumab or placebo).  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 evolocumab or placebo (investigational 
medicinal product)?   
The investigator must assess whether the adverse event is possibly related to the 
prefilled Autoinjector/Pen investigational device used to administer evolocumab or 
placebo.  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, device(s) and/or procedure (including any screening procedure(s)).  This 
relationship is indicated by a “yes” or “no” response to the question:  “Is there a 
reasonable possibility that the event may have been caused by a study activity 
(eg, administration of SC placebo”?  
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record a single event for each level of severity on the Event CRF. 
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the investigator's judgment) are not to be 
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recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. 
The Investigator is expected to follow reported adverse events until stabilization or 
reversibility.  
9.2.2.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the ICF through 
30 days after the last administration of investigational product or the EOS/ safety 
follow-up visit, whichever is later, are recorded in the subject’s medical record and are 
submitted to Amgen.  This study will be utilizing electronic data capture for serious 
adverse events.  All serious adverse events must be submitted to Amgen within 
24 hours following the investigator’s knowledge of the event via the Event CRF.   
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
serious adverse event Contingency Report Form within 24 hours of the investigator’s 
knowledge of the event.  See Appendix B for a sample of the electronic Serious Adverse 
Event Contingency Report Form.  For EDC studies where the first notification of a 
serious adverse event is reported to Amgen via the eSerious Adverse Event 
Contingency Report Form, the data must be entered into the EDC system when the 
system is again available. 
The investigator must assess whether the serious adverse event is possibly related to 
investigational medicinal product (IMP) (evolocumab or placebo).  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 evolocumab or placebo (investigational 
medicinal product)?   
The investigator must assess whether the serious adverse event is possibly related to 
the prefilled Autoinjector/Pen investigational device used to administer evolocumab or 
placebo.  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?   
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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, device(s) and/or procedure (including any screening 
procedure(s)).  This relationship is indicated by a “yes” or “no” response to the question:  
“Is there a reasonable possibility that the event may have been caused by a study 
activity (eg, (eg, administration of investigational product, protocol-required therapies, 
device(s), 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 CRF. 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities.   
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and good 
clinical practice.  
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local 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 end of study.  However, these serious 
adverse events can be reported to Amgen.  In some countries (eg, European Union [EU] 
Approved 
 
 

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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.  
9.2.2.4 
Reporting a Safety Endpoint as a Study Endpoint 
Safety endpoints (eg, treatment emergent adverse events) that are study  endpoints are 
reported on an Event CRF.   
9.3 
Pregnancy and Lactation Reporting 
If a female subject becomes pregnant, or a male subject fathers a child, 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 
monitor for pregnancies that occur after the last dose of protocol-required therapies and 
for an additional 15 weeks after the end of treatment with investigational product, report 
the pregnancy to Amgen as specified below. 
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 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.   
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.  
In addition to reporting a lactation case during the study, investigators should report 
lactation cases that occur 15 weeks  after the last dose of protocol-required therapies.  
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. 
10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Co-Primary Endpoints 
• 
Mean percent change from baseline in LDL-C at weeks 10 and 12  
• 
Percent change from baseline in LDL-C at week 12  
10.1.1.2 
Secondary Endpoints 
• 
The mean of weeks 10 and 12 and for week 12 for the following:  
Tier 1: 
• 
Change from baseline in LDL-C  
• 
Percent change from baseline in non-HDL-C  
• 
Percent change from baseline in ApoB  
• 
Percent change from baseline in total cholesterol  
• 
Achievement of target LDL-C < 70 mg/dL (1.8 mmol/L)  
• 
LDL-C response (50% reduction of LDL-C from baseline)  
Tier 2:  
• 
Percent change from baseline in Lp(a)  
• 
Percent change from baseline in triglycerides  
• 
Percent change from baseline in HDL-C  
• 
Percent change from baseline in VLDL-C  
10.1.1.3 
Safety Endpoints 
• 
Subject incidence of treatment emergent adverse events  
• 
Safety laboratory values and vital signs at each scheduled assessment  
• 
Incidence of anti-evolocumab antibody (binding and neutralizing) formation  
Approved 
 
 

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10.1.1.4 
Exploratory Endpoint(s) 
• 
Mean percent change from baseline in ApoA1 at weeks 10 and 12 
• 
Percent change from baseline in ApoA1 at week 12 
• 
Change from baseline in hsCRP 
• 
PCSK9 change from baseline at each scheduled assessment 
• 
Change and percent change from baseline at each scheduled assessment in 
each of the following parameters: 
− 
LDL-C  
− 
total cholesterol 
− 
non-HDL-C  
− 
ApoB 
− 
VLDL-C  
− 
HDL-C  
− 
ApoA1 
− 
triglycerides 
− 
Lp(a) 
10.1.2 
Analysis Sets 
The full analysis set (FAS) includes all randomized subjects who received at least 
1 dose of investigational product.  This analysis set will be used in both efficacy and 
safety analyses.  In efficacy analyses, subjects will be grouped according to their 
randomized treatment group assignment.  For safety analyses, subjects will be grouped 
according to their randomized treatment group assignment with the following exception: 
if a subject receives treatment throughout the study that is different than the randomized 
treatment group assignment, then the subject will be grouped by the actual treatment 
group.   
The completer analysis set (CAS) includes subjects in the FAS who adhered to the 
scheduled investigational product regimen and have observed values for the co-primary 
endpoints. 
10.1.3 
Covariates and Sub-groups 
Baseline covariates and sub-groups include, but are not limited to: 
• 
Stratification factors: 
o entry CV risk (high/very high CV risk vs not high/very high CV risk). 
• 
Age: < 65 year, ≥ 65 years 
• 
Sex 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20150172 
Date:  06 June 2016 
Page 59 of 78 
CONFIDENTIAL 
 
 
• 
Medical history of Diabetes (yes/no) 
• 
Study baseline LDL-C: < median / ≥ median 
• 
Family history of premature coronary heart disease (yes/no) 
• 
Baseline PCSK9  
• 
Diagnosis of HeFH according to protocol defined criteria 
Missing data will not be imputed for safety endpoints.   
10.2 
Sample Size Considerations 
The sample size for this study has been considered to meet the requirement from 
regulatory authority (Drug Registration Regulation No 28; Oct 2007).   
The planned total sample size is 450 subjects (150 randomized to evolocumab SC 
140 mg Q2W, 150 randomized to evolocumab SC 420 mg QM, 75 randomized to 
placebo Q2W and 75 randomized to placebo QM).  The primary analysis will require the 
tests of each co-primary endpoint to be significant at level of 0.05.  The sample size 
should provide adequate power to determine the superiority of evolocumab (either Q2W 
or QM) relative to respective placebo (Q2W or QM) as measured by the co-primary 
endpoints.  
From the phase 3 study 20120122 and phase 2 study 20110155, the mean treatment 
effect of evolocumab 140 mg Q2W and 420 mg QM compared to placebo in percent 
change from baseline in LDL-C at week 12 was at least -50.3%, with the smallest 
treatment effect of -44.6% estimated from 95% confidence intervals.  For the co-primary 
endpoint of mean percent change from baseline in LDL-C at weeks 10 and 12, the mean 
treatment effect of evolocumab 140 mg Q2W and 420 mg QM compared to placebo was 
at least -62.4%, with the smallest treatment effect of -57.2% estimated from 95% 
confidence intervals.  
The assumed treatment effect of evolocumab in LDL-C reduction is 40%, with a common 
SD of 25%.  As the co-primary endpoints are correlated, the planned sample size will 
provide approximately at least 98% (99% x 99%) power in testing the superiority of each 
evolocumab dosing regimen over placebo on the co-primary endpoints, assuming a 10% 
drop out rate.   
Since the testing statistics from Q2W and QM groups are independent, there is a 96% 
chance (98% x 98%) to show the superiority of both evolocumab dosing regimens over 
placebo. 
The power calculation is derived using SAS Enterprise Guide version 6.1. 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20150172 
Date:  06 June 2016 
Page 60 of 78 
CONFIDENTIAL 
 
 
10.3 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
Blinded individuals will not have access to unblinded information until the study is 
formally unblinded.  Unblinding and potentially unblinding information should not be 
distributed to the study team, investigators or subjects prior to the study being formally 
unblinded (eg, the formal unblinding may occur at the final analysis rather than during 
the primary analysis) except as specified (eg, Section 5.2 and Section 9.2.2.2). 
Amgen staff members who are involved in randomization, biological sample 
management, performing PK, and anti-evolocumab assay analysis will have treatment 
assignment information, but will not have access to subject level data from the clinical 
trial database. 
10.4 
Planned Analyses 
10.4.1 
Primary Analysis 
The primary analysis will be performed when all subjects have either completed all 
scheduled study visits or have early terminated from the study.  At that time, the 
database will be cleaned, processed and locked; the study will also be unblinded.  
10.5 
Planned Methods of Analysis  
10.5.1 
General Considerations 
Efficacy and safety analyses will be performed on the FAS.  Unless specified otherwise, 
the FAS will be the default analysis set in this study and data will be summarized by 
randomized treatment group.  Analyses will be performed separately by each dose 
frequency (Q2W and QM) unless specified otherwise.  The superiority of evolocumab to 
placebo will be assessed for all efficacy endpoints. 
Subject disposition, demographics, baseline characteristics, and exposure to 
investigational product 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. 
Missing data will not be imputed for safety endpoints.  
Multiplicity Adjustment Method 
The analyses of Q2W and QM will be performed as 2 independent experiments.  In 
order to preserve the familywise error rate at 0.05 within each independent experiment 
(Q2W and QM), methods of adjusting for multiplicity due to multiple endpoints 
Approved 
 
 

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

Product:  Evolocumab 
Protocol Number:  20150172 
Date:  06 June 2016 
Page 62 of 78 
CONFIDENTIAL 
 
 
10.5.2 
Co-Primary Efficacy Endpoints 
10.5.2.1 
Primary Analysis 
To assess the co-primary endpoints of the mean percent change from baseline in LDL-C 
at weeks 10 and 12 and the percent change in LDL-C from baseline at week 12, a 
repeated measures linear effects model will be used on the FAS in each dose frequency 
to compare the efficacy of evolocumab with placebo.  The repeated measures model will 
include terms for treatment group, stratification factor, scheduled visit and the interaction 
of treatment with scheduled visit.  Multiplicity adjustment procedures are defined in 
Section 10.5.1. 
10.5.2.2 
Subgroup Analysis 
If applicable, subgroup analyses on the co-primary efficacy endpoints will be conducted 
using the stratification factor and baseline covariates. 
10.5.3 
Secondary Efficacy Endpoint(s) 
The statistical model and testing of the tier 1 secondary efficacy endpoints will be similar 
to the primary analysis of the co-primary endpoints.  The secondary efficacy endpoints of 
LDL-C response (achievement of LDL-C < 70 mg/dL and achievement of > 50% LDL-C 
reduction from baseline) will be analyzed using the Cochran-Mantel Haenszel (CMH) 
test adjusted by the stratification factor. 
Analyses of the tier 2 secondary efficacy endpoints will use the same analysis model 
as the tier 1 endpoints, and testing will use a union-intersection test. 
Multiplicity adjustment procedures are defined in Section 10.5.1. 
10.5.4 
Safety Endpoints 
10.5.4.1 
Treatment Emergent Adverse Events 
The current Medical Dictionary for Regulatory Activities (MedDRA) version at the time of 
the data lock will be used to code all adverse events to a system organ class and a 
preferred term. 
Subject incidence of all treatment emergent adverse events will be tabulated by system 
organ class and preferred term.  Tables of fatal adverse events, serious adverse events, 
adverse events leading to withdrawal from investigational product, device-related 
adverse events, and significant treatment-emergent adverse events will also be 
provided.  Subject incidence of disease-related events and fatal disease-related events 
will be tabulated by system organ class and preferred term. 
Approved 
 
 

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Protocol Number:  20150172 
Date:  06 June 2016 
Page 63 of 78 
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10.5.4.2 
Laboratory Parameters 
Selected safety laboratory parameters will be summarized using descriptive statistics. 
10.5.4.3 
Vital Signs 
Vital signs will be summarized for each treatment group using descriptive statistics at 
each scheduled assessment. 
10.5.4.4 
Concomitant Medications 
Concomitant Medications of interest will be summarized for each treatment group 
10.5.4.5 
Anti-evolocumab antibody  
The incidence and percentages of subjects who develop anti-evolocumab antibody 
(binding and neutralizing) formation at any time will be tabulated. 
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 Trial Manager to the investigator.  The written 
informed consent document is to be prepared in the language(s) of the potential patient 
population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject 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(s) is/are 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.  
Approved 
 
 

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The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the ICF  is to be signed and personally dated by the subject 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 CRF demographics page, in addition to the unique subject identification 
number, include the age at time of enrollment.   
Approved 
 
 

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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 informed consent forms) are 
to be kept in confidence by the investigator, except as described below. 
In compliance with governmental/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, 
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>> 
Approved 
 
 

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in writing of the study’s completion or early termination and send a copy of the 
notification to Amgen.   
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
12.2 
Study Documentation and Archive 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
In this study, the IVR/IWR system captures the following data points and these are 
considered source data:  protocol number, site number, subject ID, gender, date of birth, 
date informed consent was signed, treatment group assignment, screen failure reason, 
randomization date, randomization number and investigational product box ID 
assignment. 
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 should include: 
• 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list. 
• 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of 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) documentation, as 
applicable. 
Approved 
 
 

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In addition, all original source documents supporting entries in the CRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Clinical Monitor is responsible for verifying the CRFs at regular intervals throughout 
the study to verify adherence to the protocol; completeness, accuracy, and consistency 
of the data; and adherence to local regulations on the conduct of clinical research.  The 
Clinical Monitor is to have access to subject medical records and other study-related 
records needed to verify the entries on the CRFs. 
The investigator agrees to cooperate with the Clinical Monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global 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 CRFs must be maintained and 
readily available. 
• 
Updates to CRFs will be automatically documented through the software’s “audit 
trail”. 
• 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During this 
review, subject data are checked for consistency, omissions, and any apparent 
discrepancies.  In addition, the data are reviewed for adherence to the protocol and 
GCP.  To resolve any questions arising from the clinical data management review 
process, data queries are created in the EDC system database for site resolution 
and subsequently closed by the EDC system or by an Amgen reviewer. 
• 
The investigator signs only the Investigator Verification Form for this electronic data 
capture study or the investigator applies an electronic signature in the EDC system if 
Approved 
 
 

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Date:  06 June 2016 
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the study is set up to accept an electronic signature.  This signature indicates that 
investigator inspected or reviewed the data on the CRF, the data queries, and 
agrees with the content. 
Amgen (or designee) will perform Self-Evident Corrections (SEC) to obvious data errors 
in the clinical trial database.  SECs will be documented in the eCRF instructions 
available in the EDC system.  Examples of obvious data errors that may be corrected by 
Amgen (or designee) include deletion of obvious duplicate data (ie, the same results 
sent twice with the same date with different visit, [eg, week 4 and early termination]) and 
updating a specific response if the confirming datum is provided in the “other,specify” 
field (eg, for race, reason for ending study).  
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 2), the investigator can search publically available 
records [where permitted] to ascertain survival status.  This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible.   
12.5 
Language 
CRFs 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. 
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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, 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. 
• 
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. 
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13. 
REFERENCES 
Bi Y, Gao R, Patel A, et al.  Evidence-based medication use among Chinese patients 
with acute coronary syndromes at the time of hospital discharge and 1 year after 
hospitalization:  results from the Clinical Pathways for Acute Coronary Syndromes in 
China (CPACS) study.  Am Heart J.  2009;157:509-516. 
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. 
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. 
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. 
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. 
Biometrika 1988;75:800-802. 
HPS2-THRIVE Collaborative Group.  HPS2-THRIVE randomized placebo-controlled trial 
in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle 
and liver outcomes, and reasons for stopping study treatment.  Eur Heart J.  
2013;34:1279–1291 
Hu D, Li J, Li X.  Investigation of blood lipid levels and statin interventions in outpatients 
with coronary artery disease in China:  The China Cholesterol Education Program 
(CCEP).  Circ J.  2008;72:2040-2045. 
Knopp RH.  Drug treatment of lipid disorders.  N Engl J Med.  1999;341:498-511. 
Libby P.  The forgotten majority: unfinished business in cardiovascular risk reduction.  
J Am Coll Cardiol. 2005;46:1225-1228. 
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. Circ. 2002;106:3143-3421. 
Preiss D, Seshasai SRK, Welsh P, et al.  Risk of incident diabetes with intensive-dose 
compared with moderate-dose statin therapy.  JAMA.  2011;305:2556-2564. 
Silva M, Matthews ML, Jarvis C, et al.  Meta-analysis of drug induced adverse events 
associated with intensive-dose statin therapy.  Clin Thera.  2007;29:253-260. 
Wiens BL.  A fixed sequence bonferroni procedure for testing multiple endpoints. 
Pharmaceut Statist. 2003;2:211-215. 
Zhao S, Wang Y, Mu Y, et al; DYSIS-China Study Investigators.  Prevalence of 
dyslipidaemia in patients treated with lipid-lowering agents in China: results of the 
DYSlipidemia International Study (DYSIS).  Atherosclerosis.  2014;235:463-469 
Evolocumab Investigator’s Brochure.  Thousand Oaks, CA. Amgen Inc. 
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14. 
APPENDICES 
 
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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
The Common Terminology Criteria for Adverse Events (CTCAE) is available at the 
following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm] 
Drug-induced Liver Injury Reporting & Additional Assessments  
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation according to the criteria specified in Section 6.5 require 
the following: 
• 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
• 
The appropriate CRF (eg, Event CRF) that captures information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities is to be completed 
and sent to Amgen.  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in 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 > 3 x ULN or 2-fold increases above 
baseline values for subjects with elevated values before drug are to undergo a period of 
“close observation” until abnormalities return to normal or to the subject’s baseline 
levels.   
Assessments that are to be performed during this period include:  
• 
Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours  
• 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
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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 IgG, 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 
− 
Creatinine phosphokinase, haptoglobin, lactate dehydrogenase (LDH), and 
peripheral blood smear 
− 
Appropriate liver imaging if clinically indicated 
o Appropriate blood sampling for pharmacokinetic analysis if this has not 
already been collected  
o Hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist) 
o 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 the corresponding CRFs. 
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Appendix B.  Sample eSerious Event Contingency Form 
 
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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 
 
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