A Multicenter, Controlled, Open-label Extension (OLE) Study to Assess the Long-term Safety and Efficacy of AMG 145 (Evolocumab)
Phase: PHASE2
Conditions: Hypercholesterolemia
Sponsor: Amgen

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PPD
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Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 2 of 77 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled “A Multicenter, Controlled, Open-label 
Extension (OLE) Study to Assess the Long-term Safety and Efficacy of Evolocumab 
(AMG 145)”, dated 12 November 2015, 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 1 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 Principal Investigator 
 
Date (DD Month YYYY) 
 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 3 of 77 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Multicenter, Controlled, Open-label Extension (OLE) Study to Assess the Long-term 
Safety and Efficacy of Evolocumab (AMG 145) 
Study Phase:  2 
Indication:  Hypercholesterolemia 
Primary Objective:  To characterize the safety and tolerability of long-term administration of 
AMG 145 
Secondary Objectives:  
• 
To characterize the efficacy of long-term administration of AMG 145 as assessed by low 
density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol 
(non-HDL-C), apolipoprotein B (ApoB), total cholesterol/HDL-C ratio, and 
ApoB/Apolipoprotein A-1 (ApoA1) ratio in subjects with hypercholesterolemia 
Hypotheses: The primary clinical hypothesis is that long-term exposure of AMG 145 will be safe 
and well tolerated in subjects with hypercholesterolemia.  
Primary Endpoint:  
• 
Subject incidence of adverse events  
Secondary Endpoints:  
• 
LDL-C at week 24 and week 52 
• 
Non-HDL-C at week 24 and week 52 
• 
ApoB at week 24 and week 52 
• 
Total cholesterol/HDL-C ratio at week 24 and week 52 
• 
ApoB/ApoA1 ratio at week 24 and week 52 
Study Design:  This is a multicenter, controlled, open-label extension study designed to assess 
the long-term safety and efficacy of AMG 145.  Subjects that complete a qualifying protocol will 
be randomized 2:1 to two treatment groups: Monthly AMG 145 (420mg QM) + standard of care 
(SOC) or SOC alone for the first year of the study.  During the first 12 weeks of the study (blinded 
post-randomization stabilization period), LDL-C will remain blinded and subjects must remain on 
the background lipid lowering therapy from the parent study.  After 12 weeks, LDL-C will be 
unblinded and subjects may receive additional lipid-lowering therapy based on local standards of 
care.  Subjects in the SOC only arm will not receive AMG 145 or a placebo injection for the first 
year of the study.  Randomization should occur at the end of the parent study’s end of study 
(EOS) visit or within 3 days after the parent study’s EOS visit and will be stratified by the 
treatment arm the subject was randomized to in the parent study.  Investigators, site staff, 
subjects, and the study team will be blinded to on-study lipid levels until the Week 12 
(1st quarterly) visit of this study.  At the end of the first year (week 52), starting at week 56 
(week 4/year 2) all subjects will receive open-label AMG 145 for up to 4 years (or until the 
investigator’s recommendation of discontinuation, Amgen’s recommendation of discontinuation, 
the subjects’ decision to discontinue for any reason, or until an administrative decision is made to 
close the study). 
Sample Size:  The number of subjects entering this study will depend on the number of subjects 
completing their respective AMG 145 parent studies and willingness to enroll.  Approximately 
1600 subjects are expected to participate in this study.  
Summary of Subject Eligibility Criteria:  Subjects who complete a qualifying AMG 145 protocol 
and do not experience a treatment related serious adverse event that led to IP discontinuation in 
the parent study will be eligible for this study.  For a full list of eligibility criteria, please refer to 
Section 4.1 and Section 4.2. 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 4 of 77 
CONFIDENTIAL 
 
 
Amgen Investigational Product Dosage and Administration:  During the first year, for 
subjects randomized to evolocumab (AMG 145), sites will administer investigational product 
(IP = AMG 145, 420 mg) to subjects subcutaneously QM.  The total volume of AMG 145 
70 mg/ml will be 6 mL.  Doses can be split into multiple injections (eg, 3 injections at 2 mL each) 
with the condition that the full 6 mL is provided at each respective study visit.  Once available, 
AMG 145 will be administered using 3 spring-based prefilled 1.0 mL autoinjector/pens (prefilled 
AI/Pen) or a 3.5 mL Personal Injector.  All subjects will receive appropriate lipid-lowering therapy 
based on local standards of care.  Nonetheless, until laboratory results are unblinded at week 12, 
subjects must remain on the same background lipid lowering therapy from the parent study, 
unless there is a clinically compelling reason for change.  The investigator must contact the 
Amgen medical monitor to discuss such cases on an individual basis.  After unblinding at 
week 12, investigators may prescribe any concomitant medications or treatments deemed 
necessary to provide adequate supportive care (Section 6.4).  After the end of the first year, sites 
will administer investigational product to all subjects. 
Non Amgen Investigational Product Dosage and Administration:  None. 
Control Group:  The control group comprises those subjects randomized to standard of care 
alone during the first year of study participation.  Until laboratory results are unblinded at 
week 12, the control group must also remain on the same background lipid lowering therapy from 
the parent study, unless there is a clinically compelling reason for change.  The investigator must 
contact the Amgen medical monitor to discuss such cases on an individual basis.  After 
unblinding at week 12, investigators may prescribe any concomitant medications or treatments 
deemed necessary to provide adequate supportive care (Section 6.4).  After 1 year of 
participation, these subjects will receive open-label AMG 145 and will no longer be part of the 
control group. 
Procedures:  Prior to enrolling in this study, subjects will need to undergo end of study (EOS) 
procedures for their qualifying parent study.  In addition, subjects will need to meet 
inclusion/exclusion criteria requirements.  Before randomization subjects will need to sign a new 
study informed consent form.  Subject numbers will be the same as those in their parent 
protocols.  Randomization will be stratified by the treatment arm the subject was randomized to in 
their parent study. 
During the first year, subjects randomized to AMG 145 + SOC will need to visit the site every 
4 weeks.  During these visits vital signs will be obtained and adverse events (AEs), adverse 
device effects (ADEs), serious adverse events (SAEs), and concomitant medications will be 
recorded.  Subjects randomized to SOC only, will not visit the site every 4 weeks (except at 
specified visits); rather the site will call these subjects at the scheduled visits to review 
concomitant medication changes, AEs, ADEs, and SAEs. During quarterly (every 12 weeks) 
visits, central laboratory tests will be performed for all subjects.  For a full list of study procedures, 
including the timing of each procedure, please refer to Section 7.1 and Appendix A. 
Statistical Considerations   
General Considerations 
Statistical analyses in this open-label extension study will be descriptive in nature. 
Analysis may be performed periodically throughout the study after parent studies are closed and 
individual subjects are unblinded to their lipid values. 
For all endpoints, results will be summarized by the treatment group to which subjects are 
randomized in this study, unless otherwise specified.  Subjects will be further categorized 
according to whether they were randomized to AMG 145 or not in their parent study.  For the 
randomized period, this combined treatment group will have 4 levels (parent study treatment 
group/year 1 treatment group): “AMG 145/AMG 145 + SOC”; “AMG 145/SOC only”; “Not 
AMG 145/AMG 145+SOC”, and “Not AMG 145/SOC only”.  For the final analysis (end of the 
5 years), this combined treatment group will also have 4 levels (parent study treatment 
group/year 1 treatment group/year 2-5 open-label AMG 145): “AMG 145/AMG 145 + 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 5 of 77 
CONFIDENTIAL 
 
 
SOC/AMG 145”; “AMG 145/ SOC only/AMG 145”; “Not AMG 145/AMG 145 + SOC/AMG 145”, 
and “Not AMG 145/SOC only/AMG 145”. 
Unless otherwise specified, the baseline value is defined as the subject’s baseline value from the 
parent study.   
The full analysis set (FAS) will include all subjects randomized in this study.  All analyses of the 
randomized controlled period of the study will be performed using the FAS.  Analyses of the 
period after the randomized controlled period may be limited to those receiving investigational 
product.  There will be no imputation for missing data.  
Deaths and major cardiovascular events from this and other studies with evolocumab will be 
adjudicated by an independent Clinical Events Committee (CEC) to facilitate aggregated 
analyses across the program.  Subject incidence of adjudicated events will be summarized for 
each treatment group. 
Analyses of Primary Endpoint 
AEs will be coded using the latest version of MedDRA.  Subject incidence of adverse events, 
serious adverse events, and adverse events leading to withdrawal from IP will be tabulated by 
system organ class and preferred term.  
Analyses of Secondary Endpoints 
Secondary endpoints will be summarized at each scheduled visit by both randomized treatment 
group in this study and the combined treatment group (4 levels).  For the 1-year interim analysis, 
point estimates of group means and their 95% confidence intervals will be presented. 
Differences in group means for the secondary endpoints will be estimated at each scheduled visit 
between 
• 
the AMG 145 + SOC group and the SOC only group in this study, regardless of the treatment 
arm the subject was randomized to in their parent study 
• 
the AMG 145 + SOC group and the SOC only group in this study, by whether the subject was 
randomized to AMG 145 or not in their parent study  
Other Safety Analyses 
Measurements of laboratory parameters and vital signs will be summarized at each scheduled 
visit.  Lab shift tables will be provided.  The incidence and percentages of subjects who develop 
anti-AMG 145 antibodies (binding and neutralizing) at any time will be tabulated. 
Safety Monitoring 
Amgen Global Patient Safety will perform ongoing monitoring and assessment of safety data to 
determine potential impact on study subject safety and protocol conduct.   
For a full description of statistical analysis methods, refer to Section 10. 
Sponsor:  Amgen 

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Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 7 of 77 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
AE 
Adverse event 
ADE 
Adverse Device Effect 
AHA 
American Heart Association 
ALP 
Alkaline phosphatase 
ALT (SGPT) 
Alanine aminotransferase (serum glutamic-pyruvic transaminase) 
AMG 145 
Evolocumab 
ApoA1 
Apolipoprotein A-1 
ApoB 
Apolipoprotein B 
ACTH 
Adrenocorticotropic hormone 
AST (SGOT) 
Aspartate aminotransferase (serum glutamic-oxaloacetic 
transaminase) 
AUC 
Area under the curve 
BP 
Blood pressure 
CAD 
Coronary artery disease 
CBC 
Complete blood count 
CEC 
Clinical Events Committee 
CK 
Creatine kinase 
CHD 
Coronary heart disease 
Cmax 
Mean maximum measured concentration 
CRP 
C-reactive protein 
CVD 
Cardiovascular disease 
CTCAE 
NCI Common Terminology Criteria for AEs 
Day 1 
Defined as the first day that protocol-specified investigational 
product is administered to the subject.  Day 1 for subjects 
randomized to SOC will occur upon randomization 
DILI 
Drug-induced liver injury 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
End of treatment 
Defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject 
EOS 
End-of-study for individual subject 
EU 
European Union 
FAS 
Full analysis set 
FH 
Familial hypercholesterolemia 
FSH 
Follicle-stimulating hormone 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 8 of 77 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
GCP 
Good Clinical Practice 
HDL-C 
High density lipoprotein cholesterol 
HepG2 cells 
Human hepatocellular carcinoma cell line 
HR 
Heart Rate 
hsCRP 
High sensitivity CRP 
IBG 
Independent Biostatistical Group 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC/IRB 
Independent Ethics Committee / Institutional Review Board 
IFU 
Instructions for use 
IP 
Investigational product 
IPIM 
Investigational Product Instruction Manual 
IVRS 
Interactive Voice Response System 
IV 
Intravenous 
LDL-C 
Low-density lipoprotein cholesterol 
LDLR 
LDL receptor 
LH 
Luteinizing hormone 
LLN 
Lower limit of normal 
 
LLOQ 
Lower limit of quantification 
LOF 
Loss of function 
Lp(a) 
Lipoprotein(a) 
LSP  
Lactation Surveillance Program 
MedDRA 
Medical dictionary for regulatory activities 
NASH 
Nonalcoholic steatohepatitis 
NCEP 
National Cholesterol Education Program 
NCEP ATP II 
NCEP Adult Treatment Panel II (see References) 
NCI 
National Cancer Institute 
OLE 
Open-Label Extension 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PKPD 
Pharmacokinetic / pharmacodynamic 
Q4W 
Every 4 weeks, (AMG 145 Background Section) 
QM 
QM is defined as every 4 weeks with a window of ± 7 days for each 
visit 
SAE 
Serious adverse event 
SC 
Subcutaneous 
SOC 
Standard of care 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 9 of 77 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
Source Data 
Information from an original record or a certified copy of the original 
record containing patient information for use in clinical research.  
The information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained 
in source documents (original records or certified copies). (ICH 
Guideline (E6)).  Examples of source data include Subject ID, 
Randomization ID, and Stratification Value. 
TBL 
Total bilirubin 
Tmax 
Time to maximum concentration 
TNF 
Tumor necrosis factor 
ULN 
Upper limit of normal 
VLDL-C 
Very low-density lipoprotein cholesterol 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 10 of 77 
CONFIDENTIAL 
 
 
Table of Contents 
 
Page 
Protocol Synopsis ............................................................................................................ 3 
Study Design and Treatment Schema ............................................................................. 6 
Study Glossary ................................................................................................................ 7 
1. 
OBJECTIVES ....................................................................................................... 14 
1.1 
Primary ..................................................................................................... 14 
1.2 
Secondary ................................................................................................. 14 
1.3 
Exploratory ................................................................................................ 14 
2. 
BACKGROUND AND RATIONALE ...................................................................... 14 
2.1 
Cardiovascular Disease ............................................................................ 14 
2.2 
AMG 145 Background ............................................................................... 16 
2.2.1 
First-in-Human (FIH) Study 20080397 ....................................... 17 
2.2.2 
Multiple-dose Phase 1b Study 20080398 .................................. 18 
2.2.3 
Phase 2, 12-week, Lipid-lowering Parent Studies 
Included in Aggregate Interim Analysis for Dose 
Selection ................................................................................... 19 
2.2.3.1 
Phase 2 Aggregate Interim Analysis 
Results .................................................................... 20 
2.2.3.2 
Phase 2 Aggregate Interim Analysis 
Efficacy Results ....................................................... 22 
2.2.3.3 
Phase 2 Interim Efficacy Analysis Results 
for the Randomized, Controlled, 
Open-label Extension .............................................. 25 
2.2.3.4 
Phase 2 Aggregate Interim Analysis 
Safety Results ......................................................... 25 
2.3 
Rationale ................................................................................................... 29 
2.4 
Clinical Hypotheses ................................................................................... 30 
3. 
EXPERIMENTAL PLAN ........................................................................................ 30 
3.1 
Study Design ............................................................................................. 30 
3.2 
Number of Centers .................................................................................... 30 
3.3 
Number of Subjects ................................................................................... 30 
3.3.1 
Study Duration for Participants .................................................. 30 
3.3.2 
End of Study .............................................................................. 30 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 31 
4.1 
Inclusion Criteria ....................................................................................... 31 
4.2 
Exclusion Criteria ...................................................................................... 31 
5. 
SUBJECT ENROLLMENT .................................................................................... 32 
5.1 
Randomization .......................................................................................... 32 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 11 of 77 
CONFIDENTIAL 
 
 
6. 
TREATMENT PROCEDURES .............................................................................. 33 
6.1 
AMG 145 ................................................................................................... 33 
6.1.1 
Dosage, Administration, and Schedule ...................................... 34 
6.1.2 
Dosage Adjustments ................................................................. 35 
6.1.3 
Criteria for Withholding of Investigational Product ..................... 36 
6.1.3.1 
Elevation of Creatine Kinase (CK) ........................... 36 
6.1.3.2 
Elevation of Liver Function Tests............................. 37 
6.1.3.3 
Criteria for Rechallenge After Withholding 
or Discontinuation of IP (AMG 145), Statin 
and Other Applicable Lipid Background 
Therapy ................................................................... 38 
6.2 
Medical Devices ........................................................................................ 39 
6.3 
Product Complaints, Including Device Complaints .................................... 39 
6.4 
Concomitant Therapy, Physical Exercise, and Diet ................................... 40 
6.5 
Excluded Treatments During Study Period ................................................ 40 
7. 
STUDY PROCEDURES ....................................................................................... 41 
7.1 
General Study Procedures ........................................................................ 41 
7.1.1 
Enrollment (EOS Parent/Day 1 OLE) ......................................... 41 
7.1.1.1 
Week 4 (± 7 Days)................................................... 42 
7.1.1.2 
Interval Visits (Every 4 Weeks ± 7 Days) ................. 42 
7.1.1.3 
Quarterly Visits (Every 12 Weeks 
± 7 Days) ................................................................. 43 
7.1.1.4 
Week 52 - End of Year 1 Visit (± 7 Days) ................ 43 
7.1.1.5 
Week 4/Year 2 (4 Weeks ± 7 Days) ........................ 43 
7.1.1.6 
Quarterly Visits (Every 12 Weeks ± 
7 Days).................................................................... 43 
7.1.1.7 
End of Study/Early Term OLE Visit .......................... 44 
7.1.2 
Standardization of Study Procedures ........................................ 44 
7.1.2.1 
Measurement of Vital Signs ..................................... 44 
7.1.2.2 
Blood Sample Use .................................................. 45 
7.1.2.3 
Lipid Measurements ................................................ 45 
7.1.2.4 
Laboratory Assessments ......................................... 45 
7.2 
Antibody Testing Procedures .................................................................... 47 
7.3 
Pharmacokinetic Sampling ........................................................................ 47 
7.3.1 
All Subjects ............................................................................... 47 
7.3.2 
Steroid Substudy ....................................................................... 48 
7.4 
Biomarkers Development Studies ............................................................. 48 
7.4.1 
Biomarker Sample Collection .................................................... 48 
7.4.2 
Sample Storage and Destruction ............................................... 48 
8. 
REMOVAL AND REPLACEMENT OF SUBJECTS ............................................... 49 
8.1 
Removal of Subjects ................................................................................. 49 
8.2 
Replacement of Subjects .......................................................................... 50 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 12 of 77 
CONFIDENTIAL 
 
 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 50 
9.1 
Adverse Events .......................................................................................... 50 
9.1.1 
Definition of Adverse Events ...................................................... 50 
9.1.2 
Reporting Procedures for Adverse Events That do not 
Meet Serious Criteria .................................................................. 51 
9.2 
Serious Adverse Events ............................................................................. 53 
9.2.1 
Definition of Serious Adverse Events ......................................... 53 
9.2.2 
Reporting Procedures for Serious Adverse Events .................... 53 
9.3 
Pregnancy and Lactation Reporting ........................................................... 55 
10. 
STATISTICAL CONSIDERATIONS ....................................................................... 56 
10.1 
Study Endpoints, Subsets, and Covariates ................................................ 56 
10.1.1 
Primary Endpoint ........................................................................ 56 
10.1.2 
Secondary Endpoints ................................................................. 56 
10.1.3 
Exploratory Endpoints ................................................................ 56 
10.1.4 
Safety Endpoints ........................................................................ 57 
10.1.5 
Pharmacokinetics Endpoints ...................................................... 57 
10.1.6 
Analysis Set ................................................................................ 57 
10.1.7 
Baseline Covariates .................................................................... 57 
10.2 
Sample Size Considerations ...................................................................... 57 
10.3 
Interim Analysis and Early Stopping Guidelines ......................................... 58 
10.4 
Planned Methods of Analysis ..................................................................... 58 
10.4.1 
General Approach/Considerations ............................................. 58 
10.4.2 
Analysis of Key Study Endpoints ................................................ 59 
10.4.2.1 
Primary Endpoint Analyses ...................................... 59 
10.4.2.2 
Secondary Endpoint Analyses ................................. 59 
10.4.2.3 
Exploratory Endpoint Analyses ................................ 60 
10.4.2.4 
Safety Endpoint Analyses ........................................ 60 
10.4.2.5 
Pharmacokinetics Endpoint Analyses ...................... 61 
11. 
REGULATORY OBLIGATIONS ............................................................................. 61 
11.1 
Informed Consent ....................................................................................... 61 
11.2 
Independent Ethics Committee/Institutional Review Board 
(IEC/IRB) .................................................................................................... 62 
11.3 
Subject Confidentiality ................................................................................ 62 
11.4 
Investigator Signatory Obligations .............................................................. 63 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................... 63 
12.1 
Protocol Amendments and Study Termination ........................................... 63 
12.2 
Study Documentation and Archive ............................................................. 63 
12.3 
Study Monitoring and Data Collection ........................................................ 64 
12.4 
Investigator Responsibilities for Data Collection ........................................ 65 
12.5 
Language.................................................................................................... 65 
12.6 
Publication Policy ....................................................................................... 66 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 13 of 77 
CONFIDENTIAL 
 
 
12.7 
Compensation ........................................................................................... 66 
13. 
REFERENCES ..................................................................................................... 67 
14. 
APPENDICES ...................................................................................................... 69 
List of Tables 
Table 1.  Summary of Study Design of Four Parent Studies and Extension 
Study
 
 ...................................................................................................... 20
Table 2.  Integrated Interim Analysis of Treatment Difference (Estimate and 
95% CI) from Baseline Relative to Placebo at Week 12 in 
Select Lipid Parameters-Study 20101154, 20101155, 
20090158, 20090159 - (Integrated Interim Full Analysis Set)
 
 .................. 24
Table 3.  Overall Summary of Treatment Emergent Adverse Events by 
Investigational Product -Studies 20101154 20101155 
20090158 20090159 (Integrated Interim Observed Analysis 
Set)
 
 ......................................................................................................... 26
Table 4.  Summary of Treatment Emergent Adverse Events Occurring in 
>= 2% Subjects in AMG 145 Groups (Combined) and Greater 
Than Placebo by Preferred Term in Descending Order of 
Frequency and by Investigational Product Studies 20101154, 
20101155, 20090158, and 20090159 (Integrated Interim 
Observed Analysis Set)
 
 .......................................................................... 27
Table 5.  Analyte Listing
 
 ................................................................................................ 46
List of Figures 
Figure 1.  Aggregate Interim Analysis Percent Change from Baseline in 
Calculated LDL-C Over Time for Q2W and Q4W 
Administration of AMG 145 or Placebo
 
 ................................................... 22
Figure 2.  Aggregate Interim Analysis Percent Change from Baseline in 
Calculated LDL-C in Subjects Transitioning from AMG 145 
(Q2W or Q4W) or Placebo to AMG 145 and Standard of Care 
or Standard of Care Alone
 
 ...................................................................... 25
Figure 3.  Incidence of Liver Function Tests Greater than 3- or 5-fold ULN by 
Investigational Product Studies 20101154, 20101155, 
20090158, and 20090159 (Integrated Interim Observed 
Analysis Set)
 
 .......................................................................................... 28
Figure 4.  Incidence of Creatine Kinase > 5- or 10-fold ULN by Investigational 
Product Studies 20101154, 20101155, 20090158, and 
20090159 (Integrated Interim Observed Analysis Set)
 
 ............................ 29
List of Appendices 
Appendix A.  Schedule of Assessments
 
 ........................................................................ 70
Appendix B.  Additional Safety Assessment Information
 
 ................................................ 72
Appendix C.  Sample Serious Adverse Event Report (SAER) Form
 
 .............................. 74
Appendix D.  Pregnancy and Lactation Notification Worksheets
 
 .................................... 76

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 14 of 77 
CONFIDENTIAL 
 
 
1. 
OBJECTIVES 
1.1 
Primary 
To characterize the safety and tolerability of long-term administration of AMG 145 
1.2 
Secondary 
• 
To characterize the efficacy of long-term administration of AMG 145 as assessed by 
LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B 
(ApoB), total cholesterol/HDL-C ratio, and ApoB/Apolipoprotein A-1 (ApoA1) ratio in 
subjects with hypercholesterolemia 
1.3 
Exploratory   
• 
To assess the percent change in fasting plasma lipids (non-HDL-C, apolipoprotein B, 
total-cholesterol/HDL-C ratio, total cholesterol), and ApoB/ApoA1 ratio, triglycerides, 
Lp(a), and high sensitivity C-reactive protein (hsCRP)  
• 
To investigate potential biomarker development by biochemical analysis of blood 
samples 
• 
To characterize pharmacokinetics of AMG 145 and proprotein convertase 
subtilisin/kexin type 9 (PCSK9) levels 
• 
To estimate cardiovascular event rates in subjects treated with AMG 145 in 
aggregated exploratory analyses across the AMG 145 program 
2. 
BACKGROUND AND RATIONALE 
2.1 
Cardiovascular Disease  
Cardiovascular disease (CVD) remains the most important healthcare issue in the 
developed world and is rapidly becoming so in large parts of the developing world.  The 
following facts from the American Heart Association (AHA) Heart and Stroke Facts 
Update from 2011 illustrate the magnitude of the problem in the US (Roger et al, 2011). 
1. The 2005 overall death rate from CVD in the US was 278.9 per 100,000.  Nearly 
2400 Americans die of CVD each day - an average of 1 death every 37 seconds.  
More than 150,000 Americans killed by CVD in 2005 were less than 65 years of 
age.  In 2005, 32% of deaths from CVD occurred before the age of 75 years, 
which is well before the average life expectancy of 77.9 years.  Preliminary 
mortality data from 2006 show that CVD accounted for 34.2% (829,072) of all 
2,425,900 deaths in 2006, or 1 of every 2.9 deaths in the United States.  
2. Coronary heart disease (CHD) caused 1 of every 5 deaths in the United States in 
2005.  Coronary heart disease mortality was 445,687.  In 2009, an estimated 
785,000 Americans will have a new coronary attack, and about 470,000 will have 
a recurrent attack.  It is estimated that an additional 195,000 silent first 
myocardial infarctions occur each year.  About every 25 seconds, an American 
will have a coronary event, and about every minute someone will die from one. 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 15 of 77 
CONFIDENTIAL 
 
 
3. Each year, about 795,000 people experience a new or recurrent stroke.  About 
610,000 of these are first attacks, and 185,000 are recurrent attacks.  Preliminary 
data from 2006 indicate that stroke accounted for about 1 of every 18 deaths in 
the United States.  On average, every 40 seconds someone in the United States 
has a stroke.  From 1995 to 2005, the stroke death rate fell 29.7%, and the actual 
number of stroke deaths declined 13.5%.   
4. Coronary artery disease (CAD) affects almost 17 million Americans.  Of those 
7,900,000 suffer from myocardial infarction; 9,800,000 from angina pectoris; 
5,700,000 from congestive heart failure; and 6.5 million from stroke.  One in three 
individuals in the US has some form of cardiovascular disease.  The aging of the 
population will undoubtedly result in an increased incidence of coronary artery 
disease, heart failure, and stroke.  There has been an explosive increase in the 
prevalence of obesity and type 2 diabetes and their related complications 
(hypertension, hyperlipidemia, and atherosclerotic vascular disease) will also 
increase.  An alarming increase in unattended risk factors in the younger 
generations will continue to fuel the cardiovascular epidemic for years to come. 
5. Cardiovascular disease claims more lives each year than the next 5 leading 
causes of death combined.  Cardiovascular disease claimed 35.3% of all deaths 
in the United States in 2005.  Since 1900, cardiovascular disease has been the 
No. 1 killer in the United States every year but 1918.  
In Europe, the situation is similar to the data reported for the United States.  Coronary 
heart disease by itself remains the single most common cause of deaths in the 
European Union (EU) although the 2008 European cardiovascular disease statistics 
shows a reduction in the crude number of CHD deaths when compared with the 2005 
edition (Allender et al, 2008).  This reflects a general trend in Western, Northern and 
Southern European countries, where CHD mortality rates are falling steadily.  The 
situation in some Central and Eastern European countries is very different, with CHD 
rates rising dramatically.  This gradient is more marked for stroke mortality, where the 
crude number of deaths increased since 2005.  Over 200,000 men and nearly 
300,000 women die of stroke in the EU every year. 
Each year CVD causes over 4.3 million deaths in Europe and over 2.0 million deaths in 
the European Union (EU).  CVD causes nearly half of all deaths in Europe (48%) and in 
the EU (42%).  CVD is the main cause of death in women in all countries of Europe and 
is the main cause of death in men in all countries except France, the Netherlands and 
Spain.  CVD is the main cause of the disease burden (illness and death) in Europe 
(23% of the entire disease burden) and the second main cause of the disease burden in 
those EU countries with very low child and adult mortality (17%).  CVD mortality, 
incidence and case fatality are falling in most Northern, Southern and Western European 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 16 of 77 
CONFIDENTIAL 
 
 
Countries but either not falling as fast or rising in Central and Eastern European 
countries. 
Clearly, more effective primary and secondary CHD prevention measures are required.  
CHD prevention in the future will be the result of the ground breaking research that has 
been conducted over the past 25 years.  For example, in the 1970s, data from the 
Framingham Epidemiological Study demonstrated that increases in serum cholesterol 
levels in the general population were associated with an increased risk of death from 
CHD (Kannel et al, 1974; Kannel et al, 1979; Kannel, 1995).  In 1988, the National 
Cholesterol Education Program (NCEP) identified elevated low-density lipoprotein 
cholesterol (LDL-C) as a primary risk factor for CHD (NCEP, 1988).  In the 1993 NCEP 
Adult Treatment Panel II Report, this conclusion was further strengthened by the 
addition of aggressive dietary and drug therapy recommendations for subjects with 
known CHD (NCEP, 1993).  In 1995, Gould and associates reported meta-analysis data 
on 35 randomized clinical trials that lasted more than two years and were designed to 
reduce serum cholesterol levels (Gould et al, 1995).  They concluded that for every 
10 percentage points of cholesterol lowering, CHD mortality was reduced by 13% 
(p < 0.002) and total mortality by 10% (p < 0.03).  According to the most recently 
reported United States National Health and Nutrition Examination Survey (NHANES III), 
an estimated 5.5 million Americans with CHD should be treated with lipid-lowering 
medications under the NCEP guidelines (Sempos et al, 1993).  Presently, less than 
one-third of those CHD subjects who require lipid-lowering medications actually receive 
treatment, and only a small proportion of those who do receive treatment achieve NCEP 
target levels (Eisenberg, 1998). 
Despite the availability of several classes of very effective drugs, dyslipidemia and risk 
factor control are poorly served and there remains a large unmet medical need for new, 
effective and well tolerated therapies.  
2.2 
AMG 145 Background 
Recycling of the hepatic cell surface LDL receptor (LDLR) plays a critical role in the 
maintenance of cellular and whole body cholesterol balance by regulating plasma LDL-C 
levels.  Recently it has been shown that PCSK9 plays an important role in the recycling 
and regulation of LDLR (Horton et al, 2007; Brown and Goldstein, 2006).  PCSK9 is a 
member of the subtilisin family of serine proteases and is expressed predominantly in 
the liver, kidney, and intestine (Zaid et al, 2008).  Following secretion, it causes 
post-translational downregulation of hepatic cell surface LDLR by a mechanism that 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 17 of 77 
CONFIDENTIAL 
 
 
involves direct binding to the LDLR.  Downregulation of hepatic LDLR in turn leads to 
increased levels of circulating LDL-C.  Thus PCSK9 may represent a target for inhibition 
by novel therapeutics in the setting of dyslipidemia.  The rationale for such an approach 
is available from studies in preclinical models, and from human genetic data that provide 
strong validation for the role of PCSK9 in modulating LDL-C levels and the incidence of 
CHD in man.  These human studies have identified gain-of-function mutations in the 
PCSK9 gene that are associated with elevated serum LDL-C levels (> 300 mg/dL 
[approximately 7.8 mmol/L]) and premature CHD (Abifadel et al, 2003); and 
loss-of-function (LOF) mutations that are associated with low serum LDL-C levels 
(≤ 100 mg/dL [approximately 2.6 mmol/L]) (Cohen et al, 2005).  Strikingly, subjects with 
heterozygous LOF mutations exhibit lower serum PCSK9 levels and as much as 
88% reduction in the incidence of CHD over a 15-year period compared with noncarriers 
of the mutations (Cohen et al, 2006).  Moreover, despite complete loss of PCSK9 and 
associated very low serum LDL-C levels (< 20 mg/dL [approximately 0.5 mmol/L]), the 
2 subjects who have been identified with compound heterozygote LOF mutations appear 
healthy (Hooper et al, 2007; Zhao et al, 2006). 
AMG 145 is a fully human monoclonal immunoglobulin (Ig) G2 that binds specifically to 
human PCSK9 and prevents the interaction of PCSK9 with LDLR.  Details of the 
biochemistry, nonclinical pharmacology, nonclinical pharmacokinetics (PK), and 
nonclinical toxicology with AMG 145 are contained in the Investigator’s Brochure, 2012.  
AMG 145 binds to human, monkey, and hamster PCSK9 with high affinity (Kd < 100 pM).  
AMG 145 caused a dose-dependent inhibition of PCSK9 binding to the LDLR and of 
PCSK9-mediated reduction in low-density lipoprotein (LDL) uptake in HepG2 cells 
(human hepatocellular carcinoma cell line) in culture.  In cynomolgus monkeys and in 
hamsters, in vivo administration of AMG 145 resulted in reduced serum lipoprotein 
cholesterol levels in a dose-dependent manner.  Based on a comprehensive package of 
PK, pharmacodynamics (PD), and toxicology studies (Investigator’s Brochure, 2012), a 
program to develop AMG 145 as a treatment for dyslipidemia was initiated. 
2.2.1 
First-in-Human (FIH) Study 20080397 
The first-in-human (FIH) study of AMG 145, Study 20080397, was a randomized, 
double-blind, placebo-controlled, ascending-single-dose phase 1 study to evaluate the 
safety, tolerability, PK, pharmacodynamics (PD; as measured by LDL-C), and 
immunogenicity of AMG 145 in healthy subjects.  AMG 145 was administered at doses 
of 7, 21, 70, 210, and 420 mg SC and 21 and 420 mg IV. 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 18 of 77 
CONFIDENTIAL 
 
 
AMG 145 reduced LDL-C by an average of 55% to 60% at single doses ≥ 70 mg SC, 
with the duration of effect being dose dependent.  The LDL-C nadir was observed within 
2 weeks of dosing.  Complete suppression of PCSK9 (inability to detect unbound 
PCSK9) was observed at single doses ≥ 70 mg SC, which correlated well with the 
effects seen on circulating LDL-C.   
AMG 145 exhibited nonlinear PK after single-dose SC and IV administrations, as is 
typical with monoclonal antibodies.  Over the dose range of 7 to 420 mg; the exposure, 
measured by the mean maximum measured concentration (Cmax) and area under the 
concentration-time curve (AUC), increased in a more than dose-proportional manner.  
The apparent clearance following an SC dose reached a plateau at doses ≥ 210 mg SC 
indicating that the linear range of antibody elimination was attained.   
For mean unbound PCSK9, the single administrations of AMG 145 produced decreases 
that were also dose-related with respect to magnitude and overall duration.  Baseline 
PCSK9 values were in the range of approximately 200 to 280 ng/mL for all groups.  In 
the 210-mg dose group and in the 420-mg groups (SC or IV), mean PCSK9 decreased 
within hours after dosing to values below the lower limit of quantitation (LLOQ) 
(15 ng/mL), remained below the LLOQ until day 11, and subsequently returned to or 
toward baseline. 
Treatment-emergent adverse events were reported for 29 of the 42 subjects (69%) 
who received AMG 145 at any dose, and for 10 of the 14 subjects (71%) who received 
placebo.  No relationship was apparent between the subject incidence of adverse events 
and the dose of AMG 145, or between the subject incidence of adverse events and the 
route of administration of AMG 145 (SC versus IV). 
No adverse events were reported as serious and no subjects discontinued the study due 
to an adverse event.  There were no deaths on study. 
For further details on study 20080397, please consult the Investigator’s Brochure (2012). 
2.2.2 
Multiple-dose Phase 1b Study 20080398 
Study 20080398 was a phase 1b, randomized, double-blind, placebo-controlled, 
ascending, multiple-dose study in hypercholesterolemic subjects currently on stable 
doses of a statin.  Six doses of AMG 145 were administered at 14 or 35 mg QW; 
3 doses at 140 or 280 mg Q2W; or 2 doses at 420 mg Q4W.  Hypercholesterolemic 
subjects taking high doses of a statin received 3 doses of 140 mg SC Q2W.  The study 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 19 of 77 
CONFIDENTIAL 
 
 
also included subjects with heterozygous familial hypercholesterolemia who received 
3 doses of AMG 145 at 140 mg SC Q2W. 
AMG 145 lowered LDL-C at all doses tested.  The LDL-C nadir was dependent on the 
dose and regimen and was observed following the last dose.  Although lower doses 
(14 mg QW and 35 mg QW) led to mean reductions in LDL-C of 20% to 50%, the 
maximum mean reduction of LDL-C was 70% to 80% in the highest dose groups 
(140 mg Q2W, 280 mg Q2W, and 420 mg Q4W).  The higher dose regimens were 
associated with near complete suppression of unbound PCSK9, and the degree of 
PCSK9 suppression correlated well with the effects seen on circulating LDL-C.  Subjects 
receiving high-dose statins had a similar degree of PCSK9 suppression and LDL-C 
lowering compared with subjects on the lower doses of statins.  Subjects with 
heterozygous familial hypercholesterolemia exhibited a similar degree of PCSK9 
suppression and LDL-C reduction compared with subjects without heterozygous familial 
hypercholesterolemia.  AMG 145 exhibited nonlinear behavior following multiple doses.  
The PK profile of AMG 145 in the highest dose groups (140 mg Q2W, 280 mg Q2W, and 
420 mg Q4W) was consistent with the PK profiles of AMG 145 in the single-dose 
phase 1a study. 
Treatment-emergent adverse events were reported by 28 of 43 subjects (65%) receiving 
AMG 145 and 9 of 14 subjects (64%) receiving placebo.  No adverse events were 
reported as serious, and no subjects discontinued the study due to an adverse event.  
There were no deaths on study.  No relationship was apparent between the subject 
incidence of treatment-emergent adverse events and the dose of AMG 145 or between 
the subject incidence of treatment-related adverse events and the dose of AMG 145.  
There were no trends indicative of clinically important effects of AMG 145 on hepatic 
function tests, ECGs, or vital signs.  One subject who received 140 mg AMG 145 Q2W 
for 6 weeks with a high-dose statin tested positive for AMG 145-binding antibodies at 
day 29, but was negative for neutralizing antibodies. 
For further details on study 20080398, please consult the Investigator’s Brochure (2013).  
2.2.3 
Phase 2, 12-week, Lipid-lowering Parent Studies Included in 
Aggregate Interim Analysis for Dose Selection 
• 
Study 20101154 (N = 411) evaluating AMG 145 as monotherapy  
• 
Study 20101155 (N = 631) evaluating AMG 145 as combination therapy with 
statin (with or without ezetimibe)  
• 
Study 20090158 (N = 168) evaluating AMG 145 in subjects with heFH  
• 
Study 20090159 (N = 160) evaluating AMG 145 in statin-intolerant subjects.   

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 20 of 77 
CONFIDENTIAL 
 
 
2.2.3.1 
Phase 2 Aggregate Interim Analysis Results 
On 15 March 2012, a protocol-specified interim analysis was performed to facilitate 
phase 3 dose selection via an assessment of the safety, tolerability, and efficacy of 6 
AMG-145-dosing regimens from the phase 2 program.  This interim analysis included 
safety, tolerability, and efficacy data from 5 studies (Table 1). 
Table 1.  Summary of Study Design of Four Parent Studies and Extension Study 
 
20101154 
20101155 
20090158 
20090159 
20110110 
Trial Name 
MENDEL 
LAPLACE- 
TIMI 57 
RUTHERFORD 
GAUSS 
OSLER 
Sample Size 
405 
600 
150 
150 
>500 
Patient 
Population 
Subjects not 
on statins 
Subjects on 
statins + 
ezetimibe 
Subjects with 
HeFH 
Subjects 
with statin 
intolerance 
Subjects 
from 
studies 
20101154, 
20101155, 
20090158, 
20090159 
Fasting LDL-C  
≥ 100 mg/dL 
and 
< 190 mg/dL 
≥ 85 mg/dL 
(≥ 85to<100mg/dL
limited to 20%) 
≥ 100 mg/dL 
≥100 mg/dL; 
Not at 
LDL-C goal  
(NCEP ATP 
III) 
≥ 75mg/dL 
Randomization 
Ratio 
9 arms, 
equal 
allocation 
8 arms, equal 
allocation 
3 arms, equal 
allocation 
5 arms, 
equal 
allocation 
2:1 
Treatment  
Duration 
12 weeks 
12 weeks 
12 weeks 
12 weeks 
52 weeks 
Page 1 of 2 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 21 of 77 
CONFIDENTIAL 
 
 
Table 1.  Summary of Study Design of Four Parent Studies and Extension Study 
 
20101154 
20101155 
20090158 
20090159 
20110110 
Treatment 
Groups 
 
70mg Q2W 
70mg Q2W 
105mg 
Q2W 
105mg Q2W 
 
 
 
140mg 
Q2W 
140mg Q2W 
 
 
 
Placebo 
Q2W 
Placebo 
Q2W 
 
 
 
280mg 
Q4W 
280mg Q4W 
 
280mg Q4W 
 
350mg 
Q4W 
350mg Q4W 
350mg Q4W 
350mg Q4W 
 
420mg 
Q4W 
420mg Q4W 
420mg Q4W 
420mg Q4W 
420mg 
Q4W + 
SOC 
Placebo 
Q4W 
Placebo 
Q4W 
Placebo Q4W 
 
SOC only 
Ezetimibe 
QD 
 
 
Placebo 
Q4W + 
Ezetimibe 
QD 
 
 
 
 
420mg Q4W 
+ Ezetimibe 
QD 
 
Page 2 of 2 
The interim analysis included data from 1340 unique subjects enrolled and dosed in the 
4 parent phase 2 LDL-C lowering 12-week studies (20090158, 20090159, 20101154, 
and 20101155).  Of these, 1229 (92%) subjects completed at least 4 weeks on study 
(LDL-C values are week 4) and 692 (52%) subjects completed at least 12 weeks on 
study.  The primary efficacy analysis was based on the 692 subjects who had observed 
or imputed values of % change of LDL-C at week 12 while the data at week 4 was used 
to verify these findings.  Safety analyses were performed based on the entire sample of 
1340 subjects with hypercholesterolemia in the interim analysis.   
As of the snapshot dates, 606 subjects from the 4 phase 2 parent studies had rolled over 
into the long-term extension study (20110110).  The mean time on study for subjects in 
study 20110110 was 1.4 months plus an additional three months from the parent study.  
This translates into approximately 31% and 10% of subjects being on study (ie, parent 
and extension studies) for ≥ 5 and ≥ 6 months, respectively. 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 22 of 77 
CONFIDENTIAL 
 
 
In order to maintain blinding in the ongoing phase 2 studies, data presented herein were 
aggregated by dose and dosing regimen across the 4 parent studies. 
2.2.3.2 
Phase 2 Aggregate Interim Analysis Efficacy Results 
Statistically significant decreases in LDL-C from baseline at week 12 relative to placebo 
were observed for each of the 6 AMG 145 treatment groups (p values < 0.001; Figure 1).  
The reduction in LDL-C was dose dependent within each dosing frequency (Q2W and 
Q4W).  The largest LDL-C reductions at week 12 were seen at the highest dose within 
each dosing frequency (ie, 140 mg Q2W and 420 mg Q4W).  In the Q2W cohorts, 
decreases relative to placebo (treatment difference) ranged from 41% (70 mg) to 60% 
(140 mg) at week 12; reductions ranged from 44% (280 mg) to 56% (420 mg) at 
week 12 in the Q4W cohorts.  
Figure 1.  Aggregate Interim Analysis Percent Change from Baseline in Calculated 
LDL-C Over Time for Q2W and Q4W Administration of AMG 145 or Placebo  
 
Subgroup analyses performed on aggregate interim data showed a similar effect on the 
LDL-C treatment difference from baseline at week 12 across all subgroups within each 
dosing frequency, demonstrating a consistent treatment effect of AMG 145. 
Integrated analyses of mean percent change from baseline to week 12 in other lipid 
parameters are presented in Table 2.  Statistically significant decreases from baseline 
for all 6 AMG 145 treatment groups were observed for total cholesterol (p < 0.001), 
ApoB (p < 0.001), non-HDL-C (p < 0.001), VLDL-C (p < 0.03), Lp(a) (p < 0.001).  Mean 
reductions from baseline to week 12 relative to placebo in total cholesterol (range: 25% 
to 37%), ApoB (range: 33% to 51%), non-HDL-C (range: 36% to 53%) were strictly 
dose-dependent within each dosing frequency (ie, Q2W or Q4W).  Mean reductions from 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 23 of 77 
CONFIDENTIAL 
 
 
baseline to week 12 relative to placebo in VLDL-C (14% to 44%) and Lp(a) (15% to 
31%) concentrations were generally dose dependent, although a single deviation for 
each parameter was observed.  Favorable trends in the mean reductions from baseline 
to week 12 relative to placebo for triglycerides (range: 7% to 25%) were also observed.  
Statistically significant increases in HDL-C and ApoA1 were seen in all AMG 145 dose 
groups except for the 280 mg Q4W cohort, and the 70 mg Q2W and 280 mg Q4W 
cohorts, respectively.  AMG 145 treatment resulted in dose-dependent elevations in 
HDL-C (3% to 10%) and ApoA1 (2% to 5%) in all dose groups. 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 24 of 77 
CONFIDENTIAL 
 
 
Table 2.  Integrated Interim Analysis of Treatment Difference (Estimate and 95% 
CI) from Baseline Relative to Placebo at Week 12 in Select Lipid 
Parameters-Study 20101154, 20101155, 20090158, 20090159 - 
(Integrated Interim Full Analysis Set)  
 
Treatment Difference (Estimate) Relative to Placeboa, b 
 
AMG 145 Q2W vs Placebo Q2W 
 
AMG 145 Q4W vs Placebo Q4W 
 
Lipid 
parameter 
AMG 145 
70 mg 
(N = 43) 
AMG 145 
105 mg 
(N = 43) 
AMG 145 
140 mg 
(N = 42) 
 
AMG 145 
280 mg 
(N = 41) 
AMG 145 
350 mg 
(N = 41) 
AMG 145 
420 mg 
(N = 42) 
Calc LDL-C 
-40.96 
-50.53 
-59.54 
 
-44.25 
-51.14 
-55.99 
 95% CI 
(-46.82, -
35.10) 
(-56.41, -
44.65) 
(-65.45, -
53.62) 
 
(-50.26, -
38.24) 
(-56.95, -
45.33) 
(-61.84, -
50.13) 
 p-value 
<0.001 
<0.001 
<0.001 
 
<0.001 
<0.001 
<0.001 
 
 
 
 
 
 
 
 
Total Chol 
-25.27 
-30.75 
-36.80 
 
-28.12 
-32.31 
-34.78 
 95% CI 
(-29.47, -
21.06) 
(-34.97, -
26.54) 
(-41.04, -
32.55) 
 
(-32.17, -
24.06) 
(-36.23, -
28.39) 
(-38.74, -
30.83) 
 p-value 
<0.001 
<0.001 
<0.001 
 
<0.001 
<0.001 
<0.001 
 
 
 
 
 
 
 
 
ApoB 
-33.04 
-41.70 
-50.83 
 
-33.24 
-38.87 
-42.22 
 95% CI 
(-38.05, -
28.03) 
(-46.73, -
36.68) 
(-55.89, -
45.77) 
 
(-38.41, -
28.08) 
(-43.86, -
33.88) 
(-47.25, -
37.19) 
 p-value 
<0.001 
<0.001 
<0.001 
 
<0.001 
<0.001 
<0.001 
 
 
 
 
 
 
 
 
non-HDL-C 
-35.96 
-43.60 
-53.45 
 
-38.02 
-44.30 
-47.79 
 95% CI 
(-41.25, -
30.67) 
(-48.91, -
38.29) 
(-58.80, -
48.10) 
 
(-43.18, -
32.85) 
(-49.29, -
39.31) 
(-52.82, -
42.76) 
 p-value 
<0.001 
<0.001 
<0.001 
 
<0.001 
<0.001 
<0.001 
 
 
 
 
 
 
 
 
VLDL 
-27.73 
-22.53 
-43.74 
 
-14.40 
-18.03 
-22.77 
 95% CI 
(-43.71, -
11.74) 
(-38.79, -
6.27) 
(-60.06, -
27.42) 
 
(-27.39, -
1.40) 
(-30.69, -
5.37) 
(-35.57, -
9.96) 
 p-value 
<0.001 
0.007 
<0.001 
 
0.030 
0.005 
<0.001 
 
 
 
 
 
 
 
 
Lp(a) 
-15.21 
-24.12 
-30.69 
 
-21.96 
-27.58 
-27.23 
 95% CI 
(-24.18, -
6.24) 
(-33.12, -
15.12) 
(-39.85, -
21.53) 
 
(-29.59, -
14.33) 
(-34.90, -
20.26) 
(-34.69, -
19.76) 
 p-value 
<0.001 
<0.001 
<0.001 
 
<0.001 
<0.001 
<0.001 
 
 
 
 
 
 
 
 
Triglycerides 
-14.89 
-12.18 
-25.27 
 
-7.28 
-12.11 
-9.14 
 95% CI 
(-28.37, -
1.41) 
(-25.71, 
1.34) 
(-38.89, -
11.65) 
 
(-18.07, 
3.50) 
(-22.53, -
1.69) 
(-19.64, 
1.37) 
 p-value 
0.031 
0.077 
<0.001 
 
0.180 
0.023 
0.088 
 
 
 
 
 
 
 
 
HDL-C 
5.72 
7.13 
9.84 
 
2.79 
4.82 
5.52 
 95% CI 
(0.82, 
10.61) 
(2.22, 
12.04) 
(4.89, 
14.78) 
 
(-1.43, 
7.00) 
(0.74, 8.90) 
(1.41, 9.63) 
 p-value 
0.022 
0.005 
<0.001 
 
0.190 
0.021 
0.009 
 
 
 
 
 
 
 
 
ApoA1 
2.98 
4.09 
5.22 
 
2.42 
4.18 
5.28 
 95% CI 
(-1.01, 
6.96) 
(0.10, 8.09) 
(1.19, 9.24) 
 
(-0.73, 
5.56) 
(1.14, 7.22) 
(2.22, 8.34) 
 p-value 
0.140 
0.045 
0.011 
 
0.130 
0.007 
<0.001 
Source: Modified from integrated analysis Tables 14-4.14.1,  14-4.15.6, 14-4.9.1, 14-4.8.1, 14-4.18.6, 
14-4.24.6, 14-4.17.6, 14-4.16.6, and 14-4.20.6. 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 25 of 77 
CONFIDENTIAL 
 
 
2.2.3.3 
Phase 2 Interim Efficacy Analysis Results for the Randomized, 
Controlled, Open-label Extension 
Interim results of this open-label extension study show that treatment with AMG 145 was 
effective in reducing LDL-C concentrations in all subjects who had not previously 
received AMG 145, regardless of whether or not they had received other lipid lowering 
therapies (Figure 2).  Subjects who received AMG 145 in their parent study maintained 
their LDL-C reductions in the extension study at levels similar to that in the parent study.  
Furthermore, results demonstrate reversibility of the treatment effects of AMG 145.  
Subjects who had previously received AMG 145 in their parent study and who were 
randomized to standard of care in the extension study (ie, discontinued AMG 145 
therapy), saw their LDL-C concentrations rise to that of subjects who had never received 
AMG 145 (ie, standard of care alone) by week 4 in the extension. 
Figure 2.  Aggregate Interim Analysis Percent Change from Baseline in Calculated 
LDL-C in Subjects Transitioning from AMG 145 (Q2W or Q4W) or Placebo to 
AMG 145 and Standard of Care or Standard of Care Alone  
 
2.2.3.4 
Phase 2 Aggregate Interim Analysis Safety Results 
Treatment emergent adverse events were reported in 51% in the AMG 145 Q2W group, 
49% in the AMG 145 Q4W group, and 43% subjects in the combined placebo groups 
(Table 3).  The incidence of treatment emergent adverse events considered related to 
treatment by the investigator was 9% in the AMG 145 Q2W group, 10% in the AMG 145 
Q4W group, and 6% in the placebo group.  No trend in the incidence or severity 
(≥ grade 2 to 4) of treatment emergent adverse events or treatment-related adverse 
events was observed.  

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 26 of 77 
CONFIDENTIAL 
 
 
A total of 18 (1.3%) subjects experienced serious adverse events across the 4 studies.  
Serious adverse events were reported in a similar proportion of AMG 145 Q2W 
(6 [1.6%]), AMG 145 Q4W (8 [1.4%]), and placebo (4 [1.3%]) subjects.    
A total of 8 (0.6%) adverse events led to discontinuation of investigational product.  The 
incidence of adverse events leading to discontinuation was similar in the AMG 145 
(0.5%) and placebo (0.3%) treatment groups.  
One fatal adverse event was reported across the 4 studies; the event was considered 
unrelated to investigational product by the investigator. 
Table 3.  Overall Summary of Treatment Emergent Adverse Events by 
Investigational Product -Studies 20101154 20101155 20090158 20090159 
(Integrated Interim Observed Analysis Set) 
 
Placebo 
Total 
AMG 145 
Q2W 
Total 
AMG 145 
Q4W 
Total 
AMG 145 
Total 
All Study 
Groups 
 
(N=298) 
(N=372) 
(N=566) 
(N=938) 
(N=1340) 
 
 
 
 
 
 
All treatment emergent AEs, n (%) 
127 (42.6) 191 (51.3) 278 (49.1) 469 (50.0) 645 (48.1) 
Treatment-related AEs, n (%) 
19 (6.4) 
34 (9.1) 
55 (9.7) 
89 (9.5) 
118 (8.8) 
Serious adverse events, n (%) 
4 (1.3) 
6 (1.6) 
8 (1.4) 
14 (1.5) 
18 (1.3) 
Leading to discontinuation of IP, n (%) 
1 (0.3) 
2 (0.5) 
3 (0.5) 
5 (0.5) 
8 (0.6) 
Serious 
0 (0) 
1 (0.3) 
0 (0) 
1 (0.1) 
1 (0.1) 
Non-Serious 
1 (0.3) 
1 (0.3) 
3 (0.5) 
4 (0.4) 
7 (0.5) 
Source: Integrated Interim Analysis Table 14-6.1.2   
The incidence of treatment emergent adverse events that occurred in ≥ 2% of subjects in 
the combined AMG 145 treatment arms and with an incidence greater than placebo is 
summarized in Table 4.  The overall incidence of treatment emergent adverse events 
was slightly higher in the AMG 145 group (50%) than in the placebo group (43%); 
however, there was no notable increase in any particular adverse event.  The adverse 
events that occurred in ≥ 2% of subjects in the combined AMG 145 treatment arm and 
whose incidence was greater than in the placebo group were nasopharyngitis (7% 
AMG 145; 5% placebo), upper respiratory tract infection (3% AMG 145; 4% placebo), 
back pain (3% AMG 145; 2% placebo), myalgia (2% AMG 145; 1% placebo), and cough 
(2% each).  All other adverse events occurred in < 2% of subjects overall. 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 27 of 77 
CONFIDENTIAL 
 
 
Table 4.  Summary of Treatment Emergent Adverse Events Occurring in >= 2% 
Subjects in AMG 145 Groups (Combined) and Greater Than Placebo by Preferred 
Term in Descending Order of Frequency and by Investigational Product 
Studies 20101154, 20101155, 20090158, and 20090159 (Integrated Interim 
Observed Analysis Set) 
PREFERRED TERM 
Placebo 
Total 
(N = 298) 
n (%) 
AMG 145 
Q2W 
(N = 372) 
n (%) 
AMG 145 
Q4W 
(N = 566) 
n (%) 
AMG 145 
Total 
(N = 938) 
n (%) 
All Study 
Groups 
(N = 1340) 
n (%) 
  
 
 
 
 
 
Subjects with Treatment 
Emergent Adverse Events 
127  
(42.6) 
191  
(51.3) 
278  
(49.1) 
469  
(50.0) 
645  (48.1)
 
 
 
 
 
 
NASOPHARYNGITIS 
16  (5.4) 
26  (7.0) 
41  (7.2) 
67  (7.1) 
88  (6.6) 
UPPER RESPIRATORY TRACT 
INFECTION 
11  (3.7) 
14  (3.8) 
16  (2.8) 
30  (3.2) 
47  (3.5) 
BACK PAIN 
7  (2.3) 
8  (2.2) 
17  (3.0) 
25  (2.7) 
33  (2.5) 
MYALGIA 
2  (0.7) 
9  (2.4) 
13  (2.3) 
22  (2.3) 
29  (2.2) 
COUGH 
6  (2.0) 
7  (1.9) 
13  (2.3) 
20  (2.1) 
28  (2.1) 
NAUSEA 
3  (1.0) 
5  (1.3) 
16  (2.8) 
21  (2.2) 
24  (1.8) 
Source: Modified from Integrated Interim Analysis Table 14-6.13.2 
Elevated liver function tests (AST, ALT, total bilirubin) were uncommon in the 4 parent 
phase 2 studies and had a similar incidence rate across treatment groups (Figure 3).  A 
total of 4 subjects had post-baseline liver function tests > 3 x ULN with an incidence of 
0.3% for placebo (n = 1), 1.3% for ezetimibe (n =1), 0.8% for AMG 145 70 mg Q2W 
(n = 1), 0% for AMG 145 105 mg Q2W and 140 mg Q2W, 0% for AMG 145 280 mg 
Q4W, 0.5% for AMG 145 350 mg Q4W (n = 1), and 0% for AMG 145 420 mg Q4W.  One 
subject who received placebo and no subjects who received AMG 145 had liver function 
tests > 5 x ULN.   
In addition to these 4 subjects, 3 additional subjects had elevated liver function tests.  
One of these subjects (AMG 145 350 mg Q4W) had elevated ALT at baseline 
(> 3 x ULN, but < 5 x ULN) that returned to < 3 x ULN by the next assessment.  The 
other 2 subjects (1 AMG 145 105 mg Q2W and 1 AMG 145 420 mg Q4W) had 
elevations in bilirubin > 2 x ULN in the absence of liver enzyme abnormalities during the 
study; these subjects were diagnosed as probable Gilbert’s Syndrome and not included 
in the summary of elevated LFTs due to the lack of clinical relevance.  There were no 
serious adverse events reported in subjects who experienced LFT elevations. 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 28 of 77 
CONFIDENTIAL 
 
 
Figure 3.  Incidence of Liver Function Tests Greater than 3- or 5-fold ULN by 
Investigational Product Studies 20101154, 20101155, 20090158, and 20090159 
(Integrated Interim Observed Analysis Set) 
 
Post-baseline elevations in creatine kinase in the 4 parent studies were uncommon and 
transient (Figure 4).  A total of 14 subjects had post-baseline creatine kinase > 5 x ULN 
with an incidence of 0.7% for placebo (n = 2), 0% for ezetimibe, 2.4% for AMG 145 
70 mg Q2W (n = 3), 1.6% for AMG 145 105 mg Q2W (n = 2), 0.8% for AMG 145 140 mg 
Q2W (n = 1), 0% for AMG 145 280 mg Q4W, 1.0% for AMG 145 350 mg Q4W (n = 2), 
and  1.7% for AMG 145 420 mg Q4W (n = 4).  Four of 967 (0.4%) AMG 145-treated 
subjects and no placebo subjects in these studies experienced post-baseline CK 
elevations > 10 x ULN.  Two additional subjects (1 in AMG 145 105 mg Q2W and 1 in 
AMG 420 mg Q4W) had baseline creatine kinase elevations > 5 x ULN.  There was no 
relationship between the dose of AMG 145 and the incidence of CK elevations.  In 
almost all cases, elevations in CK were associated with obvious precipitating events in 
the form of unaccustomed exercise; in all subjects, except 1 (additional data unknown), 
creatine kinase returned to < 5 x ULN by the next visit.   In general, elevations of CK did 
not lead to discontinuation.  Two of the 14 subjects with elevated post-baseline creatine 
kinase discontinued investigational product; 1 subject (AMG 145 350 mg Q4W) 
discontinued after experiencing a temporally-associated grade 2 adverse event of 
myositis, and 1 subject (AMG 145 140 mg Q2W) discontinued after an unrelated car 
accident.  No serious-related adverse events occurred in subjects with creatine kinase 
elevations. 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 29 of 77 
CONFIDENTIAL 
 
 
Figure 4.  Incidence of Creatine Kinase > 5- or 10-fold ULN 
by Investigational Product Studies 20101154, 20101155, 20090158, and 20090159 
(Integrated Interim Observed Analysis Set) 
 
Analyses of treatment emergent adverse events were carried out for the subgroups of 
subjects whose lowest post-dose LDL-C concentration was ≤ 40 mg/dL (N=519) and for 
subjects whose lowest post-dose LDL-C concentration was > 40 mg/dL (N=770).  The 
overall incidence of treatment emergent adverse events in these 2 subgroups was 
similar (52% and 47%, respectively).  Similar analysis was carried out for subjects 
whose lowest post-dose LDL-C concentration was ≤ 25 mg/dL (N=290) and for subjects 
whose lowest post-dose LDL-C concentration was > 25 mg/dL (N=999).  The overall 
incidence of treatment-emergent adverse events was similar for the 2 subgroups (52% 
and 48%, respectively).  It should be noted that no placebo subjects had a post-dose 
LDL-C concentration ≤ 25 mg/dL, so comparisons could not be made. 
Samples from 1146 subjects from the 4 parent studies were tested in the immunoassay 
for anti-AMG 145 binding antibodies.  One AMG 145-treated subject and 1 placebo 
subject tested positive for anti-AMG 145 binding antibodies out of 478 AMG 145 treated 
subjects and 198 placebo treated subjects who had at least one post baseline result.  
Both subjects tested negative for neutralizing antibodies.  This represents a 0.2% and 
0.5% incidence of binding antibody development for the AMG 145 and placebo groups, 
respectively.  
2.3 
Rationale 
This study is being conducted to gather information on the long-term safety and efficacy 
of AMG 145.  Many of the subjects in the parent Phase 2 studies are in a high unmet 
Dose
% of Subjects
Placebo
Ezetimibe
70
105
140
280
350
420
Total 145
0
1
2
3
4
5
% of Subjects with CK > 5 ULN
Dose
% of Subjects
Placebo
Ezetimibe
70
105
140
280
350
420
Total 145
0
1
2
3
4
5
% of Subjects with CK > 10 ULN

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 30 of 77 
CONFIDENTIAL 
 
 
medical need group such as heterozygous familial hypercholesterolemia, or statin 
intolerance, or have failed to reach goal with available therapies.  For these populations, 
participation in this open-label extension will provide close medical supervision via 
healthcare professionals while on current standard of care therapies and an opportunity 
to receive an additional therapeutic option for LDL-C lowering.  
2.4 
Clinical Hypotheses 
The primary clinical hypothesis is that long-term exposure of AMG 145 will be safe and 
well tolerated in subjects with hypercholesterolemia. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a multicenter, controlled, open-label extension study to assess the long-term 
safety and efficacy of AMG 145.  
The overall study design is described by a study schema at the end of the protocol 
synopsis section. 
The study endpoints are defined in Section 10.1. 
3.2 
Number of Centers 
It is anticipated that approximately 240 centers will participate in the study.  The number 
of sites may vary depending on the number of subjects from the parent study. 
3.3 
Number of Subjects 
The number of subjects entering this study will depend on the number of subjects 
completing their respective AMG 145 parent studies and willingness to enroll.  The 
number of subjects expected to participate in this study is approximately 1600. 
3.3.1 
Study Duration for Participants 
Subjects will be enrolled into the study after completion of a qualifying AMG 145 study.  
During this study subjects will visit the site multiple times.  During the first year, visits will 
occur every 4 weeks for all subjects.  Quarterly visits will be data-rich and interval visits 
(every 4 weeks) will be data-sparse.  During the first year those randomized to SOC-only 
will have their interval visits conducted via phone after week 4.  Nonetheless SOC only 
subjects will still need to visit the site for their quarterly visits.  After the first year, 
quarterly visits will continue up to Week 260 (approximately 5 years).  
3.3.2 
End of Study 
The study will complete when the last subject has completed assessments for 
Week 260 (approximately year 5) or until the investigator’s recommendation of 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 31 of 77 
CONFIDENTIAL 
 
 
discontinuation, Amgen’s recommendation of discontinuation, the subjects’ decision to 
discontinue for any reason, or until an administrative decision is made to close the study. 
4. 
SUBJECT ELIGIBILITY 
The study population will consist of male and female subjects who have completed a 
qualifying AMG 145 protocol.  Subjects who complete any future qualifying AMG 145 
studies may be allowed to enroll if they meet the inclusion/exclusion criteria and the 
sponsor agrees to open the study to additional subjects.  
4.1 
Inclusion Criteria 
Subjects will be eligible for the study if they: 
1. Complete a qualifying AMG 145 parent study protocol. 
4.2 
Exclusion Criteria 
Subjects will be ineligible for the study if they fulfill any of the following criteria:  
1. Female subject is not willing to use at least one highly effective method of 
birth control during treatment and for an additional 15 weeks after the end of 
treatment unless subject is sterilized or postmenopausal;  
o Menopause is defined as 12 months of spontaneous and continuous 
amenorrhea in a female ≥ 55 years old or 12 months of spontaneous 
and continuous amenorrhea with a follicle-stimulating hormone level > 
40 IU/L (or according to the definition of "postmenopausal range" for 
the laboratory involved) in a female < 55 years old unless the subject 
has undergone bilateral oophorectomy. 
o Highly effective methods of birth control include abstinence, birth 
control pills, shots, implants, or patches, intrauterine devices (IUDs), 
sexual activity with a male partner who has had a vasectomy, condom 
or occlusive cap (diaphragm or cervical/vault caps) used with 
spermicide. 
2. Subject is pregnant or breast feeding, or might become pregnant during 
treatment and/ or within 15 weeks after the end of treatment 
3. Unreliability as a study participant based on the investigator's (or designee’s) 
knowledge of the subject (eg, inability or unwillingness to adhere to the 
protocol) 
4. Experienced a treatment-related serious adverse event that led to IP 
discontinuation in the parent study 
5. Disorder that would interfere with understanding and giving informed consent 
or compliance with protocol requirements  
6. Have an unstable medical condition, in the judgment of the investigator  
7. Subject’s medical condition requires lipid measurement and/or adjustment of 
background lipid-regulating therapy during the first 12 weeks of study 
participation 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 32 of 77 
CONFIDENTIAL 
 
 
8. Known sensitivity to any of the products to be administered during dosing 
9. Currently enrolled in another investigational device or drug study (excluding 
AMG 145 parent study), or less than 30 days since ending another 
investigational device or drug study(s),or receiving other investigational 
agent(s) 
5. 
SUBJECT ENROLLMENT 
Before subjects may be entered into the study, Amgen requires a copy of the site’s 
written independent ethics committee and/or institutional review board (IEC/IRB) 
approval of the protocol, informed consent form (ICF), and all other subject information 
and/or recruitment material, if applicable (see Section 11.2).  All subjects must 
personally sign and date the informed consent form before commencement of study 
specific procedures.  A subject is considered enrolled once they have completed their 
end of study visit in the parent protocol and have been randomized.  
All subjects who enter the study will keep the same subject identification number from 
the parent study.    
5.1 
Randomization 
During the first year subjects will be randomized to one of two treatment arms.  After 
completion of the first year, all subjects will be given open-label AMG 145.  Assignment 
to the 2 treatment arms will be based on a computer-generated randomization schedule 
prepared by Amgen before the start of the study. 
The following are the treatment arms: 
• 
AMG 145, 420 mg, 6 mL QM SC + SOC 
• 
SOC only  
Randomization to these arms will be 2 (AMG 145 + SOC): 1 (SOC only).   
Randomization will be stratified by the treatment arm a subject was randomized to in the 
parent study, which has the following 3 levels: 
• 
Randomized to AMG 145 Q2W 
• 
Randomized to AMG 145 QM 
• 
Not randomized to AMG 145   
A subject may only receive one randomization number for this OLE study and each 
randomization number will only be assigned to 1 subject.  Once eligibility into the study 
has been confirmed, a site representative will make the randomization call to the 
Interactive Voice Response System (IVRS) to assign a new OLE randomization number 

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Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 35 of 77 
CONFIDENTIAL 
 
 
should self-administer IP during visits to the investigator site under supervision of site 
personnel.  The date, time, and volume of AMG 145 will be recorded on the individual 
subject’s eCRF. 
IP will be administered either at 6 mL via vials and syringes via study site staff or 
depending on device availability preferably by subjects (while under direct observation) 
at sites; at 3ml via 3 prefilled autoinjectors/pens or at 3.5 ml via 1 personal injector.  The 
6 mL dose can be split (eg, 3 injections at 2 mL each) and administered into different 
injection sites.  The SC injections should be administered in a consecutive fashion with 
all injections completed within 30 minutes.  For further details regarding the injection 
procedures, the IPIM should be consulted.  
After completion of IP administration at each dosing visit up to year 2, subjects should be 
kept for observation for at least 30 minutes before being discharged.  The observation 
period is optional after the Week 4 visit in year 2 visit, if in the opinion of the investigator, 
the subject has not manifested an allergy or hypersensitivity to the IP to date.  
The effects of overdose of AMG 145 are not known.  All overdose occurrences must be 
documented, and corresponding AEs recorded on the appropriate electronic case report 
form (eCRF) page and in source documents. 
The dosing schedule is described by a schema in the protocol synopsis. 
6.1.2 
Dosage Adjustments 
Dose adjustments during the study (including discontinuation of IP) are discouraged, but 
will be permitted for subjects that experience intolerable adverse events.  If an 
investigator wants to make a dose adjustment they must contact the medical monitor 
prior to doing so.  All dose adjustments must be clearly documented and recorded on the 
appropriate eCRF page and in the source documents. 
Administration of IP should occur within the visit window for each scheduled visit.  IP 
must never be administered within less than 7 days of a previous dose.  
Subjects who are Late for a Scheduled Dose of Investigational Product 
Subjects that completely miss a scheduled visit or IP administration will continue in the 
study and receive scheduled study drug at the next scheduled visit.  However, this must 
be clearly documented both in the source documents and the case report forms. 
Subjects who Miss a Scheduled Dose of Investigational Product Completely 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 36 of 77 
CONFIDENTIAL 
 
 
6.1.3 
Criteria for Withholding of Investigational Product 
Reports from the central laboratory after each clinic visit must be reviewed as soon as 
possible after receipt and before the next administration of IP (AMG 145).  If any of the 
criteria below are met for withholding IP, statin, or other applicable background lipid 
therapy, the subject must be instructed to stop the applicable treatment and an 
additional visit must be scheduled for the required laboratory evaluations.  If a subject is 
experiencing elevations of laboratory values and is receiving other lipid therapies that 
may result in such elevations, eg, ezetimibe, fenofibrate, or niacin, the additional 
therapies should also be evaluated for a potential role in these elevations and 
considered for discontinuation.  Fenofibrate, ezetimibe, or niacin can result in elevation 
of CK or liver function tests.  If a subject experiences elevations in triglycerides 
> 500 mg/dL (5.65 mmol/L) and is concomitantly receiving a bile acid binding resin, the 
bile acid binding resin should be evaluated for discontinuation   
6.1.3.1 
Elevation of Creatine Kinase (CK) 
If CK is > 5x ULN, CK must be retested before IP is administered.  In addition, 
investigators will ask study subjects to promptly report muscle pain, soreness, cramps, 
or weakness especially if accompanied by malaise or fever.  If such symptoms occur 
and no scheduled study laboratory assessments are performed, the subject’s CK levels 
should be measured by unscheduled assessment.  If CK is > 5x ULN, the subject must 
be instructed as soon as possible to discontinue statin, other applicable lipid background 
therapy, and/or Amgen IP (AMG 145).  CK must be retested before statin, other lipid 
background therapy, and/or IP (AMG 145) administration can be continued.  A sample 
for urinalysis must be collected and sent to the central laboratory if CK is elevated 
> 10x ULN on retest as per table below. 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 37 of 77 
CONFIDENTIAL 
 
 
The following rules apply for scheduled laboratory assessments and for unscheduled CK 
measurements: 
CK at scheduled 
or unscheduled 
visit 
CK on retest 
Investigational Product and/or Statin and/or 
other lipid lowering therapies Administration 
> 5x ULN 
> 10x ULN 
Discontinue both statin, other lipid lowering 
therapies, and IPa.  Collect urine sample for 
urinalysis.  Contact Amgen Medical Monitor. 
> 5x to ≤ 10x ULN 
Discontinue statin, other lipid lowering 
therapies, and retest CK before administration.  
Consider continuing IP if alternative explanation. 
≤ 5x ULN 
Consider continuing statin, other lipid lowering 
therapies and IP 
a CK elevations >10x ULN that have been confirmed to be secondary to myocardial infarction do not require 
discontinuation of statin, other lipid lowering therapy or IP 
6.1.3.2 
Elevation of Liver Function Tests 
Subjects with abnormal hepatic laboratory values (eg, alkaline phosphatase [ALP], AST, 
ALT, total bilirubin [TBL], or international normalized ratio [INR] or signs/symptoms of 
hepatitis may meet the criteria for withholding of IP, statin, and other applicable lipid 
background therapy.  If the subject experiences an ALT or AST > 3X ULN, then they 
must be followed as detailed under section on close observation in Appendix B. 
IP, statin and other applicable lipid background therapy must be discontinued and the 
subject should be followed according to the recommendations in Appendix B (Additional 
Safety Assessment Information) for possible drug-induced liver injury (DILI), if ALL of the 
criteria below are met:  
• 
TBL > 2x upper limit of normal (ULN) or INR > 1.5 
AND  
• 
AST or ALT > 3x ULN  
AND  
• 
no other cause for the combination of laboratory abnormalities is immediately 
apparent; important potential causes for abnormal AST/ALT or TBL values include, 
but are not limited to: 
− 
Obstructive gall bladder or bile duct disease 
− 
Viral or alcoholic hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, 
cytomegalovirus, Herpes Simplex Virus, Varicella, etc) 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 38 of 77 
CONFIDENTIAL 
 
 
− 
Progression of malignancy involving the liver (note that metastatic disease to the 
liver, by itself, should not be used as an explanation for significant AST/ALT 
elevations) 
− 
Hypoxic or ischemic hepatopathy or congestive hepatopathy in association with 
significant right sided heart failure 
− 
Concomitant administration of other hepatotoxins, including drugs that inhibit 
bilirubin glucuronidation (eg, indinavir, atazanavir, irinotecan) or herbal or dietary 
supplements 
− 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome); 
alpha-one antitrypsin deficiency 
− 
Autoimmune hepatitis 
− 
Nonalcoholic steatohepatitis (NASH) or other fatty liver disease 
IP, statin and other applicable lipid background therapy should also be withheld and the 
subject should be evaluated for DILI if ANY of the following criteria are met:  
• 
AST or ALT > 8x ULN at any time 
• 
AST or ALT > 5x ULN but < 8x ULN for ≥ 2 weeks 
• 
TBL > 3x ULN at any time 
• 
ALP > 8x ULN at any time 
• 
Clinical signs or symptoms that are, in the opinion of the investigator, consistent with 
hepatitis (such as right upper quadrant pain/tenderness, fever, nausea, vomiting, 
jaundice, rash or eosinophilia > 5%).  If such signs or symptoms are coupled with 
ALT or AST elevations > 3x ULN, IP should be withheld.   
If IP, statin and other applicable lipid background therapy is withheld due to any of the 
conditions above, the subject should be followed according to recommendations in 
Appendix B for possible DILI.   
6.1.3.3 
Criteria for Rechallenge After Withholding or Discontinuation of IP 
(AMG 145), Statin and Other Applicable Lipid Background Therapy 
The decision to re-challenge the subject after therapy changes due to CK elevation or 
elevation of liver function tests should be discussed and agreed upon unanimously by 
the subject, Principal Investigator, and Amgen. 
If signs or symptoms recur with rechallenge of IP, then IP should be permanently 
discontinued.  If signs or symptoms recur with rechallenge of statin background therapy, 
the statin may be substituted by another statin in consultation with the Amgen medical 
monitor, if possible, or the statin therapy may be discontinued.  If signs or symptoms 
recur with rechallenge of other applicable lipid background therapy, this therapy may be 
discontinued. 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 39 of 77 
CONFIDENTIAL 
 
 
6.2 
Medical Devices  
IP will be administered per prefilled AI/Pen and 3.5 mL Personal Injector, provided by 
Amgen (Section 6.1).  Additional details regarding the use of the AI/Pen and the 3.5 mL 
Personal Injector are provided in the IPIM and in the Instructions for Use (IFU) brochure.    
Medical supplies (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.   
6.3 
Product Complaints, Including Device Complaints 
A product complaint is defined as 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) or device(s) provisioned 
and/or repackaged/modified by Amgen Drug(s) or device(s) including 
investigational product.  
Any product complaints 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.   
Concerns or irregularities about the packaging, appearance or usage of the prefilled 
AI/Pen or personal injector or other Amgen provided, protocol-required product in this 
study are to be reported to Amgen within 24 hours of discovery or notification of the 
concern or irregularity.  Should any such concerns or irregularities occur please do not 
use the IP until Amgen confirms that it is permissible to use. 
Examples of potential product complaints that need to be reported to Amgen include, but 
are not limited to: 
• 
broken container or cracked container 
• 
misuse of the AI/pen or the 3.5 mL personal injector due to misunderstanding of 
the IFU or error on the part of the user, or other inability to appropriately use the 
product (eg, due to malfunction of the AI/Pen or 3.5 mL personal injector) 
• 
missing labels, illegible labels, incorrect labels, and/or suspect labels  
• 
change in IP appearance, for example color change or visible presence of foreign 
material 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 40 of 77 
CONFIDENTIAL 
 
 
• 
unexpected quantity or volume, for example number of tablets or amount of fluid in 
the prefilled AI/Pen or 3.5 mL personal injector cartridge 
• 
evidence of tampering or stolen material 
If possible, please have the IP or other Amgen provided protocol-required suspect 
product available for examination when making a product complaint.  Maintain IP or 
other Amgen provided protocol-required suspect product 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 
informed consent through 30 days after the last dose of IP or EOS, whichever is later, 
are reported to Amgen within 24 hours of discovery or notification of the product 
complaint.   
For more details regarding the identification and reporting of product and device 
complaints, refer to the IPIM and the IFU. 
6.4 
Concomitant Therapy, Physical Exercise, and Diet  
Prior to week 12 lipid-regulating concomitant medications cannot be altered, unless 
there is a clinically compelling reason for change.  The investigator must contact the 
Amgen medical monitor to discuss such cases on an individual basis.  After the 
post-randomization stabilization period (Week 12 visit), laboratory results 
(Section 7.1.2.3) will be unblinded and investigators may prescribe any concomitant 
medications or treatments deemed necessary to provide adequate supportive care 
except for those listed in Section 6.5.  However, during year 1, investigators must refrain 
from down-titrating background therapy (eg, discontinuation or reduction of statin 
therapy) due to unblinded LDL-C values.  After year 1, investigators may down-titrate 
background therapy if deemed necessary. 
All subjects should maintain their current regimen of diet and exercise for at least the 
first 12 weeks of the study, but should also be encouraged to continue to do so through 
the remainder of the study.  Subjects will be required to refrain from unaccustomed 
intensive exercise (eg, heavy lifting or long runs) 48 hours prior to each visit. 
6.5 
Excluded Treatments During Study Period  
The use of magnesium or aluminum hydroxide-containing antacids is not recommended 
within the period of two hours before and two hours after dosing with statins given the 
potential for interference with absorption.  

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 41 of 77 
CONFIDENTIAL 
 
 
7. 
STUDY PROCEDURES 
This will be a multicenter, controlled, open-label extension study to assess the long-term 
safety and efficacy of AMG 145.  During the first year, subjects receiving AMG 145 will 
have site visits every 4 weeks.  For SOC only subjects, after week 4 all 4-week interim 
(non-quarterly) visits will be conducted via phone and all quarterly visits will occur at the 
site.  For the purpose of this study, a month is defined as 4 weeks and a quarter is 
defined as 12 weeks.   
Written informed consent must be obtained and will be implemented before protocol 
specific procedures are carried out.  The risks and benefits of participating in the study 
will be verbally explained to each potential subject prior to entering into the study.  The 
procedures to be performed at each clinic visit are described below and are summarized 
in Appendix A.  IP should not be administered until all study procedures are completed 
at each visit. 
7.1 
General Study Procedures  
7.1.1 
Enrollment (EOS Parent/Day 1 OLE) 
Day 1 for OLE study and the end of study (EOS) visit for the parent study should occur 
on the same day.  All efforts should be made to minimize any time gaps between the 
parent study EOS and Day 1 in the OLE study.  The Day 1 OLE visit will need to occur 
within 3 days of the parent EOS or all procedures (except ECG) will need to be 
repeated.  The following procedures will be performed during the end of study visit in the 
parent study:   
• 
Medical History  
• 
Vital signs: sitting blood pressure (BP), heart rate (HR) 
• 
AEs/ADEs/SAEs 
• 
Concomitant medications  
• 
Body weight 
• 
Physical exam 
• 
12-lead electrocardiogram (ECG)  
• 
Blood draw for serum pregnancy (females of childbearing potential only) and FSH 
(for applicable subjects) 
• 
Urinalysis 
• 
Blood draw for fasting lipids (≥ 9 hour fasting sample), ApoA1, ApoB, chemistry, 
hematology, PK (AMG 145), PCSK9, coagulation, hsCRP, Lp(a), HbA1c, 
biomarkers, fasting Vitamin E, and anti-AMG 145 antibodies 
• 
Administer IP (AMG 145 QM) to AMG 145 subjects (must be after completion of vital 
signs, ECG, and blood draw procedures) 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 42 of 77 
CONFIDENTIAL 
 
 
For subjects on a Q2W schedule during the parent study, some of the above procedures 
will occur during the week 12 visit and not at week 14 (eg weight, HbA1c, hsCRP, Lp(a), 
biomarkers, etc).   
Randomization - subjects will have the risks and benefits of participating in this study 
explained to them.  Subjects that meet inclusion/exclusion criteria will need to sign a new 
OLE informed consent form, if they already have not done so, before randomization.  
During this visit subjects randomized to AMG 145 study drug (QM) will have their first 
injection administered at the site (must be after completion of vital signs, ECG, and 
blood draw procedures).  Subsequent injections with vials and syringes will also occur at 
the site.  After year 1, once the AI/Pen and 3.5 mL personal injector are available, IP 
should be self-administered at home or other appropriate non-study site 
settings/locations by subjects (or designee, which may include a qualified health care 
professional) between study visits.  For subjects randomized to AMG 145 + SOC, Day 1 
is defined as the first day that protocol-specified investigational product is administered.  
For subjects randomized to SOC only, Day 1 is defined as the day of randomization. 
7.1.1.1 
Week 4 (± 7 Days) 
The following visits are for Year 1 only: 
• 
Vital signs: sitting blood pressure (BP), heart rate (HR) 
• 
AEs/ADEs/SAEs 
• 
Concomitant medications 
• 
Blood draw for serum pregnancy   
• 
Blood draw for fasting lipids (≥ 9 hour fasting sample), ApoA1, ApoB, chemistry, 
hematology, PK (AMG 145), PCSK9, coagulation, hsCRP, Lp(a), HbA1c, and 
anti-AMG 145 antibodies 
• 
Blood draw for biomarkers  
• 
Administer IP (AMG 145 QM) to AMG 145 subjects (must be after completion of vital 
signs, and blood draw procedures) 
7.1.1.2 
Interval Visits (Every 4 Weeks ± 7 Days) 
• 
SOC visit will occur via phone  
• 
Vital signs (only for AMG 145 subjects): sitting blood pressure (BP), heart rate (HR) 
• 
AEs/ADEs/SAEs 
• 
Concomitant medications 
• 
Observe IP Administration (AMG 145 QM) unless subject elects not to self-inject 
(must be after completion of vital signs) 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 43 of 77 
CONFIDENTIAL 
 
 
7.1.1.3 
Quarterly Visits (Every 12 Weeks ± 7 Days) 
• 
Vital signs: sitting blood pressure (BP), heart rate (HR) 
• 
AEs/ADEs/SAEs 
• 
Concomitant medications 
• 
Blood draw for serum pregnancy (performed at week 24 for females of childbearing 
potential only)  
• 
Blood draw for fasting lipids (≥ 9 hour fasting sample), ApoA1, ApoB, chemistry, 
hematology, PK (AMG 145), PCSK9, coagulation, hsCRP, Lp(a), HbA1c, and 
anti-AMG 145 antibodies 
• 
Blood draw for biomarkers at week 12 only  
• 
Fasting Vitamin E  at weeks 12 and 24 only 
• 
Observe IP Administration (AMG 145 QM) unless subject elects not to self-inject  
(must be after completion of vital signs, and blood draw procedures) 
7.1.1.4 
Week 52 - End of Year 1 Visit (± 7 Days) 
• 
Vital signs: sitting blood pressure (BP), heart rate (HR) 
• 
AEs/ADEs/SAEs 
• 
Concomitant medications  
• 
Body Weight 
• 
Physical exam 
• 
Blood draw for serum pregnancy (for females of childbearing potential only)  
• 
Blood draw for fasting lipids (≥ 9 hour fasting sample), ApoA1, ApoB, chemistry, 
hematology, PK (AMG 145, PCSK9), coagulation, hsCRP, Lp(a), HbA1c, fasting 
Vitamin E, and anti-AMG 145 antibodies 
• 
Urinalysis 
• 
Observe IP Administration (AMG 145 QM) unless subject elects not to self-inject 
(must be after completion of vital signs, and blood draw procedures) 
7.1.1.5 
Week 4/Year 2 (4 Weeks ± 7 Days) 
The following visits are for Years 2 through 5: 
• 
Vital signs: sitting blood pressure (BP), heart rate (HR) 
• 
AEs/ADEs/SAEs 
• 
Concomitant medications 
• 
Observe IP Administration (AMG 145 QM) unless subject elects not to self-inject 
(must be after completion of vital signs). 
7.1.1.6 
Quarterly Visits (Every 12 Weeks ± 7 Days) 
• 
Vital signs: sitting blood pressure (BP), heart rate (HR) 
• 
AEs/ADEs/SAEs 
• 
Concomitant medications 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 44 of 77 
CONFIDENTIAL 
 
 
• 
Blood draw for serum pregnancy (performed every 6 months for females of 
childbearing potential only)  
• 
Blood draw for fasting lipids (≥ 9 hour fasting sample), ApoA1, ApoB, chemistry, 
hematology, PK (AMG 145), PCSK9, coagulation, hsCRP, Lp(a), HbA1c, and 
anti-AMG 145 antibodies (at the end of each year only) 
• 
Fasting Vitamin E at weeks 76 and 100 only 
• 
Observe IP Administration (AMG 145 QM) unless subject elects not to self-inject 
(must be after completion of vital signs, and blood draw procedures). 
7.1.1.7 
End of Study/Early Term OLE Visit 
• 
Vital signs: sitting blood pressure (BP), heart rate (HR) 
• 
AEs/ADEs/SAEs 
• 
Concomitant medications  
• 
Body weight 
• 
Physical exam 
• 
Blood draw for serum pregnancy (for females of childbearing potential only)  
• 
Blood draw for fasting lipids (≥ 9 hour fasting sample), ApoA1, ApoB, chemistry, 
hematology, PK (AMG 145), PCSK9, coagulation, hsCRP, Lp(a), HbA1c, and 
anti-AMG 145 antibodies 
• 
Urinalysis 
Completion of the study is defined as the last day that protocol-specified procedures are 
conducted for an individual subject.  At the end of the study, vital status must be 
obtained for all subjects within the limits of local law.  It is preferable that all end of study 
procedures are carried out.  Subjects who are not deceased, have not withdrawn 
consent, or are not lost to follow-up, should have at minimum an End of Study 
assessment for Vital Status (alive or deceased), Adverse Events and Potential 
Endpoints.  Sites should interrogate public databases, if necessary to obtain this 
information.  If deceased, the date and reported cause of death should be obtained. 
7.1.2 
Standardization of Study Procedures 
7.1.2.1 
Measurement of Vital Signs 
Blood pressure (BP) and heart rate (HR) should be measured at each visit.  BP should 
continue to be measured in the same arm as in the parent study unless a concomitant 
condition favors the use of a different arm.  The appropriate size cuff should be used.  
The diastolic blood pressure (DBP) will be recorded as the pressure noted when sound 
disappears (Korotkoff Phase V).  Blood pressure and heart rate measurements should 
be determined after the subject has been seated for at least 5 minutes.  The subject’s 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 45 of 77 
CONFIDENTIAL 
 
 
pulse should be measured for 30 seconds and the number should be multiplied by 2 to 
obtain heart rate.   
7.1.2.2 
Blood Sample Use 
Any blood sample collected according to the Schedule of Assessments (Appendix A) 
may be analyzed for any of the tests outlined in the protocol and for any tests necessary 
to ensure subject safety.  This includes testing to ensure analytical methods produce 
reliable and valid data throughout the course of the study.  This may also include, but is 
not limited to, investigation of unexpected results, incurred sample reanalysis, and 
analyses for method transfer and comparability. 
Amgen may do additional testing on the remaining samples (ie, residual and back-up) to 
investigate and better understand hypercholesterolemia metabolic disorders, the dose 
response and/or prediction of response to AMG 145, characterize antibody response, 
and characterize aspects of the molecule (eg, metabolites).  Results from this analysis 
will be documented and maintained, but may not be reported as part of this study.  
7.1.2.3 
Lipid Measurements 
Central laboratory results of the lipid panel, as well as ApoA1, ApoB, Lp(a), and high 
sensitivity C-reactive protein (hsCRP) will be blinded to investigators, subjects, and the 
study team until the week 12 visit is completed.  Investigators and staff involved with this 
trial and all medical staff involved in the subject’s medical care should refrain from 
obtaining lipid panels between parent EOS and week 12.  Consequently, lipid lowering 
concomitant medications may not be adjusted based upon such results, unless there is a 
clinically compelling reason for change.  The investigator must contact the Amgen 
medical monitor to discuss such cases on an individual basis.  After the week 12 visit 
occurs, central laboratory results will be available to sites and lipid lowering concomitant 
medications may be adjusted as necessary.  However, investigators must refrain from 
down-titrating standard of care therapy during the first year.  If a lipid panel is drawn prior 
to week 12, all reasonable steps must be undertaken to avoid informing the subject and 
study personnel of the results.   
7.1.2.4 
Laboratory Assessments 
All on-study laboratory samples will be processed and sent to the central laboratory.  
Amgen or designee will be responsible for PK (AMG 145), PCSK9 serum levels, 
anti-AMG 145 antibody, and biomarker development assessments and the central 
laboratory will ship the samples to Amgen or a specialty laboratory for assay (depending 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 46 of 77 
CONFIDENTIAL 
 
 
on the assessment).  PK (AMG 145), PCSK9 serum levels, anti-AMG 145 antibody, and 
biomarker will be blinded to the investigator, site and subjects. 
The central laboratory will provide a study manual that outlines handling, labeling, and 
shipping procedures for all blood samples.  The date and time of sample collection will 
be recorded in the source documents at the site. 
Table 5 below outlines the specific analytes for serum chemistry, hematology, urinalysis, 
and other testing to be conducted.  
Table 5.  Analyte Listing  
Chemistry  
Coagulation Urinalysis 
Hematology 
Sodium 
Other Labs 
Potassium 
Chloride 
Bicarbonate  
Total protein 
Albumin 
Calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin 
CK 
ALP 
LDH 
AST (SGOT) 
ALT (SGPT) 
PT/INR 
Specific gravity 
pH 
Blood 
Protein 
Glucose 
Bilirubin 
WBC 
RBC 
Epithelial cells 
Bacteria 
Casts 
Crystals 
Hemoglobin 
Hematocrit 
MCV  
MCH 
MCHC 
RDW 
Platelets 
RBC 
WBC 
Differential 
• Neutrophils 
• Bands 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes 
 
Fasting lipids 
• Total cholesterol 
• HDL-C 
• LDL-C 
• Triglycerides  
• VLDL-C 
• Non-HDL-C 
ApoA1 
ApoB 
ApoB/ApoA1 ratio 
Total Cholesterol/HDL-C 
ratio 
hsCRP 
Lp(a) 
Anti-AMG 145 antibodies 
AMG 145 (PK) 
 PCSK9 
HbA1c 
FSH 
Fasting Vitamin E 
Steroids 
• 
ACTH 
• 
FSH 
• 
LH 
• 
Cortisol 
• 
Testosterone 
• 
Estradiol 
Pregnancy test 
  
Because Amgen wishes to examine LDL-C responses in subjects who previously 
received AMG 145 in a parent study and are subsequently randomized to SOC-alone in 
the extension study, investigators may not adjust lipid lowering background therapy until 

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Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 48 of 77 
CONFIDENTIAL 
 
 
refer to the laboratory manual for detailed instructions on sample collection, processing, 
and shipping of PK samples. 
7.3.2 
Steroid Substudy 
Subjects in the substudy will be required to consent to additional blood samples to be 
taken or for the potential use of the biomarker samples (in some cases collected 
previously) for steroid testing at Day 1, and at weeks 12, 24, and 52.  These samples will 
be used for the following tests: ACTH, FSH, LH, cortisol, testosterone, estradiol.  The 
substudy schedule is provided in Appendix A.  
7.4 
Biomarkers Development Studies 
7.4.1 
Biomarker Sample Collection 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention.   
It is expected that further advances will occur in investigational techniques that look at 
markers of PCSK9 signaling, LDLR turnover, cholesterol metabolism, inflammation, and 
plaque stability.  It is not possible at this stage to anticipate what these advances will be; 
however, considerable benefit could accrue to future sufferers of coronary artery disease 
if these markers can be correlated with the data from the study.  It is also important to 
clarify any potential drug interactions in this population of subjects who will be on a 
number of other drugs.  For biomarker analysis, blood samples will be collected at the 
end of the parent study, week 4, and at week 12 so that analyses may be performed that 
will look at markers of PCSK9 signaling, LDL-R turnover, cholesterol metabolism, 
inflammation, and plaque stability such as certain glycosylated proteins, matrix 
metalloproteinases, markers of inflammation such as C-reactive protein, 
myeloperoxidase, bromo- and nitro-tyrosine, and tumor necrosis factor (TNF) cellular 
adhesion molecules. 
The samples collected will not be suitable for any DNA or other genetic testing and it is 
specifically stated that these specimens will not be used for this purpose. 
Refer to the laboratory manual for detailed collection and handling procedures for all 
biomarker development samples. 
7.4.2 
Sample Storage and Destruction 
The biomarker samples and any other components from the cells may be stored for up 
to 20 years from the end of the study to research scientific questions related to 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 49 of 77 
CONFIDENTIAL 
 
 
hypercholesterolemia, metabolic disorders, and/or AMG 145.  The subject retains the 
right to request that the sample material be destroyed at any time by contacting the 
principal investigator.  The sponsor will be 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 principal investigator or 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).  
Following the request from the subject, the principal investigator will provide the sponsor 
with the required study and subject numbers so that any remaining plasma and blood 
samples and any other components from the cells can be located and destroyed.  If a 
commercial product is developed from this research project, the sponsor will own the 
commercial product.  The subject will have no commercial rights to such product and will 
have 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. 
REMOVAL AND REPLACEMENT OF SUBJECTS 
8.1 
Removal of Subjects 
Subjects have the right to withdraw from the treatment, procedures, or study at any time 
and for any reason without prejudice to their future medical care by the physician or at 
the institution. 
Withdrawal of full 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 including any follow-up in person, by 
phone, through 3rd parties including relatives or friends, via discussion with other 
treating physicians, and by use of medical records; subject data up to withdrawal of full 
consent will be included in the analysis of the study.  Any subject may withdraw full 
consent to participate in the study at any time during the study.  The investigator will 
discuss with the subject appropriate procedures for withdrawal from the study.  The 
investigator should ask the subject’s consent to perform the procedures listed under the 
final study visit. 
Subjects may decline to continue receiving IP or other protocol-required therapies or 
procedures at any time during the study.  If this occurs, the investigator will discuss with 
the subject appropriate procedures for discontinuation from IP or other protocol-required 
therapies or procedures and should encourage the subject to continue with collection of 
data, including endpoints and adverse events.  These subjects, as well as those who 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 50 of 77 
CONFIDENTIAL 
 
 
have stopped receiving IP or other protocol-required therapies or procedures for other 
reasons (eg, investigator or sponsor concern) should continue the schedule of study 
observations.  If the subject is unable or unwilling to continue the schedule of 
observation, the investigators should clarify what type of follow-up the subject is 
agreeable to: in person, by phone/mail, through family/friends, in 
correspondence/communication with other physicians, and/or from review of the medical 
records.  For these subjects, the EOS procedures should be used as a guide for the 
depth of information obtained for any subject that elects to continue via follow-up. 
Should a subject (or a legally acceptable representative) request or decide to withdraw 
from the study, all efforts will be made to complete and report the observations as 
thoroughly as possible up to the date of withdrawal.  All information should be reported 
on the applicable eCRFs.   
Reasons for removal from protocol-required investigational product might include: 
• 
withdrawal of full consent 
• 
subject request to end investigational product administration 
• 
administrative decision by Amgen (other than subject request or safety concern) 
• 
decision by the primary investigator / physician 
• 
pregnancy in a female subject (report on Pregnancy Notification Worksheet; 
see Appendix D) 
• 
safety concern (eg, adverse event) 
• 
Death 
Reasons for removal from study: 
• 
decision by Amgen (sponsor) 
• 
withdrawal of full consent from study 
• 
death 
• 
lost to follow-up 
8.2 
Replacement of Subjects  
There will be no replacement of subjects.  
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Adverse Events 
9.1.1 
Definition of 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.  

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 51 of 77 
CONFIDENTIAL 
 
 
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease 
(eg, diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected, and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study or 
involves an intervention such as elective cosmetic surgery or a medical procedure while 
on study is not considered an adverse event.  
An adverse device effect (ADE) is any adverse event related to the use of a medical 
device.  Adverse device effects include adverse events resulting from insufficient or 
inadequate instructions for use, adverse events resulting from any malfunction of the 
device, or adverse events resulting from use error or from intentional misuse of the 
device. 
9.1.2 
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after randomization through the EOS 
are reported using the applicable eCRF (eg, Adverse Event Summary eCRF) except for 
potential endpoints that are submitted to the CEC for adjudication.  Potential endpoints 
must NOT be reported on the AE eCRF UNLESS notified by Amgen (or delegates).  
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 the device (prefilled AI/Pen or 3.5 mL Personal 
Injector), 
 
Assessment of relatedness to investigational product (AMG 145) or any study 
mandated activity or procedure or other protocol-required therapies, and 
 
Action taken. 
The adverse event toxicity grading scale used will be the NCI Common Terminology 
Criteria for AEs (CTCAE) grading score.  The toxicity grading scale used in this study is 
described in Appendix B. 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
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CONFIDENTIAL 
 
 
The investigator must assess whether the adverse event is possibly related to IP 
(AMG 145) and/or other protocol-required therapies.  This relationship is indicated by a 
“yes” or “no” response to the question:  Is there a reasonable possibility that the event 
may have been caused by AMG 145 and/or other protocol-required therapies?  
The investigator must assess whether the adverse event is possibly related to the 
device: Prefilled AI/Pen or 3.5 mL Personal Injector used to administer IP (AMG 145).  
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 device?  
The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity or procedure.  This relationship is indicated by a “yes” or “no” 
response to the question: “Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure”? 
The investigator is 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) should not be 
recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) should be recorded as the adverse 
event. 
The investigator’s clinical judgment will be used to determine whether a subject should 
be removed from treatment or from the study due to an adverse event.  A subject, or 
subject’s parent/legal guardian, may also voluntarily withdraw from treatment due to an 
adverse event, refer to section 8.1 for additional instructions on the procedures 
recommended for safe withdrawal from treatment or the study.  If the subject withdraws 
full consent, the subject should be encouraged to undergo, at a minimum, an 
end-of-study assessment.   
The investigator is expected to follow any reported adverse events until resolved, 
improved to baseline, or stabilized. 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 53 of 77 
CONFIDENTIAL 
 
 
9.2 
Serious Adverse Events 
9.2.1 
Definition of Serious Adverse Events 
A serious adverse event (SAE) is defined as an adverse event that meets at least 1 of 
the following serious criteria: 
 
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 
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, drug-induced liver 
injury(see Appendix B for drug-induced liver injury reporting criteria), or events that 
necessitate an emergency room visit, outpatient surgery, or urgent intervention. 
Since the criteria for the CTCAE grading scale differs from the regulatory criteria for 
serious adverse events, if adverse events correspond to grade 4 “life threatening” 
CTCAE toxicity grading scale criteria (eg, laboratory abnormality reported as grade 4 
without manifestation of life threatening status), it will be left to the investigator’s 
judgment to also report these abnormalities as serious adverse events.  For any adverse 
event that applies to this situation, comprehensive documentation of the event’s severity 
status must be recorded in the subject’s medical record. 
9.2.2 
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 informed 
consent through 30 days after the last dose of investigational product or EOS, whichever 
is later, are recorded in the subject’s medical records and are submitted to Amgen.  All 
serious adverse events, except as specified below, must be submitted to Amgen within 
24 hours following the investigator’s knowledge of the event, using the Serious Adverse 
Event Report (SAER) Form.  The endpoint column on the SAER form must also be 
populated by indicating “no” or “yes”. 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 54 of 77 
CONFIDENTIAL 
 
 
For all events submitted to the CEC that also meet serious criteria according to the 
definition above (Section 9.2.1), an SAER Form must be completed and submitted to 
Amgen Global Patient Safety within 24 hours of discovery of the potential endpoint 
event.  However, a corresponding AE eCRF will only be completed if notified by Amgen 
(or delegate).  These events include the following: 
 
Death 
 
Cardiac ischemic events (myocardial infarction, hospitalization for unstable angina, 
coronary revascularization) 
 
Hospitalization for heart failure 
 
Cerebrovascular events (transient ischemic attack, stroke) 
After the protocol-required reporting period defined above, the investigator does not 
need to actively monitor subjects for serious adverse events.  However, if the 
investigator becomes aware of a serious adverse event after this protocol-required 
reporting period, the investigator will report the event 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.  The serious adverse event 
must be submitted to Amgen within 24 hours following the investigator’s knowledge of 
the event via the applicable Serious Adverse Event Report Form.  See Appendix C for a 
sample of the Serious Adverse Event Report Form.  
The investigator must assess whether the serious adverse event is possibly related to 
IP: AMG 145.  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 IP (AMG 145)?  
The investigator must assess whether the serious adverse event is possibly related to 
the device: Prefilled AI/Pen or 3.5 mL Personal Injector used to administer IP 
(AMG 145).  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 device? 
The investigator must assess whether the serious adverse event is possibly related to 
any other study-mandated activity or procedure.  This relationship is indicated by a “yes” 
or “no” response to the question: “Is there a reasonable possibility that the event may 
have been caused by a study activity/procedure”? 
The investigator is expected to follow reported serious adverse events until resolved, 
improved to baseline, or stabilized. 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 55 of 77 
CONFIDENTIAL 
 
 
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  The investigator 
may be asked to provide additional follow-up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the applicable CRF (eg, Adverse 
Event Summary CRF).  
If a subject is permanently withdrawn from the study because of a serious adverse 
event, this information must be submitted to Amgen within 24 hours.  For all Amgen 
products expectedness will be determined based on the current Investigator’s Brochure.  
Expectedness assessments will be made for all investigational products (Amgen and 
non-Amgen) using the appropriate reference safety information per local regulatory 
reporting requirements.  Suspected unexpected serious adverse reactions reported for 
subjects receiving a non-Amgen investigational product will be expedited according to 
local requirements.  
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/ECs in 
compliance with all reporting requirements according to local regulations and good 
clinical practice (GCP).  
The investigator is to notify the appropriate IRB/EC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local procedures and statutes.   
9.3 
Pregnancy and Lactation Reporting 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking evolocumab report the pregnancy to Amgen as specified below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur after the last dose of evolocumab through an 
additional 15 weeks after the end of treatment with evolocumab.   
The pregnancy should be reported to Amgen’s Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix D).    Amgen Global Patient Safety will 
follow up with the investigator regarding additional information that may be 
requested. 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 56 of 77 
CONFIDENTIAL 
 
 
If a lactation case occurs while the female subject is taking evolocumab, report the 
lactation case to Amgen as specified below.  
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur after the last dose of evolocumab through an additional 15 
weeks after the end of treatment with evolocumab. 
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours 
of the investigator’s knowledge of the event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix D).  Amgen Global Patient Safety will follow up 
with the investigator regarding additional information that may be requested. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints, Subsets, and Covariates 
10.1.1 
Primary Endpoint 
Subject incidence of adverse events 
 
10.1.2 
Secondary Endpoints 
 
LDL-C at week 24 and week 52 
 
Non-HDL-C at week 24 and week 52 
 
ApoB at week 24 and week 52 
 
Total cholesterol/HDL-C ratio at week 24 and week 52 
 
ApoB/ApoA1 ratio at week 24 and week 52 
10.1.3 
Exploratory Endpoints 
 
Subject incidence of adjudicated events 
 
Death (all cause, cardiovascular) 
 
Cardiac ischemic events (myocardial infarction, hospitalization for unstable 
angina, coronary revascularization) 
 
Hospitalization for heart failure 
 
Cerebrovascular events (transient ischemic attack, stroke) 
 
Subject incidence of non-coronary revascularization 
 
Change and percent change from baseline at each scheduled visit in each of the 
following lipid parameters: 
 
Total cholesterol 
 
non-HDL-C 
 
LDL-C 
 
ApoB 
 
total cholesterol/HDL-C ratio 
 
ApoB/ApoA1 ratio 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 57 of 77 
CONFIDENTIAL 
 
 
 
Triglycerides 
 
HDL-C 
 
VLDL-C 
 
ApoA1 
 
Lp(a) 
 
hsCRP 
 
PCSK9 at each scheduled visit 
10.1.4 
Safety Endpoints 
 
Changes from baseline in safety laboratory values (including clinical chemistry and 
hematology) and vital signs at each scheduled visit  
 
Subject incidence of anti-AMG 145 antibodies 
10.1.5 
Pharmacokinetics Endpoints 
Serum concentration of AMG 145 at selected time points 
10.1.6 
Analysis Set 
The full analysis set (FAS) will include all subjects randomized in this study.  All analyses 
of the randomized controlled period of the study will be performed using the FAS.  
Analyses of the period after the randomized controlled period may be limited to those 
receiving investigational product.  The steroid analysis set (SAS) includes all subjects 
who participate in the steroid substudy. 
10.1.7 
Baseline Covariates 
Baseline covariates include, but are not limited to: 
 
Age 
 
Gender 
 
Ethnicity or race 
 
LDL-C  
 
PCSK9 
 
Lipid modifying background therapy (eg statin, ezetimibe) 
10.2 
Sample Size Considerations 
The number of subjects entering this study will depend on the number of subjects 
completing their respective AMG 145 parent studies and willingness to enroll.  
Approximately 2000 (1970) subjects will be randomized in the qualifying parent studies.  
Assuming 80% of these subjects enroll in this extension study, the sample size will be 
approximately 1600 (1576) subjects. 

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The exact 95% confidence intervals for a 5% incidence rate under various enrollment 
assumptions using the binomial distribution for particular adverse events are provided in 
the table below.  The estimates are derived using SAS version 9.2. 
Percent of 
Subjects Enrolling 
Total Number of 
Subjects Reporting 
Adverse Event 
Estimated Adverse Event Incidence Rate 
Incidence Rate 
95% Confidence 
Interval 
60 
59/1182 
5% 
(0.04, 0.06) 
70 
69/1379 
5% 
(0.04, 0.06) 
80 
79/1576 
5% 
(0.04, 0.06) 
90 
89/1773 
5% 
(0.04, 0.06) 
10.3 
Interim Analysis and Early Stopping Guidelines 
An administrative interim analysis, which included pharmacokinetic / pharmacodynamic 
(PKPD) modeling and was based on accumulated efficacy and safety data from this and 
other concurrently conducted studies with AMG 145, was performed by an internal 
unblinded group to guide future clinical development plans.  Members in the designated 
internal unblinded group did not have direct roles or responsibilities in conducting any 
study included in this administrative interim analysis.  There was an additional 1-year 
interim analysis to summarize the data collected in the randomized study period (up to 
week 52) after all subjects had completed the week 52 visits.  There were no plans to 
modify or discontinue this study based on the results of the interim analysis.  Also, 
additional analysis may be performed periodically throughout the study after parent 
studies are closed and individual subjects are unblinded to their lipid values. 
10.4 
Planned Methods of Analysis 
10.4.1 
General Approach/Considerations 
Statistical analyses in this open-label extension study will be descriptive in nature.  No 
statistical inference is planned.   
Subject disposition, demographics and baseline characteristics will be summarized.   
Summary statistics for continuous variables will include the number of subjects, mean, 
median, standard deviation or standard error, minimum, and maximum.  For categorical 
variables, the frequency and percentage will be given. 

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One year interim and final analyses will be based on data collected from this study.  
Descriptions of any integrated analyses with the parent studies are out of scope for this 
study.  
For all endpoints, results will be summarized by the treatment group to which subjects 
are randomized to in this study, unless otherwise specified.  Subjects will be further 
categorized according to whether they were randomized to AMG 145 or not in their 
parent study.  For the randomized period, this combined treatment group will have 
4 levels (parent study treatment group/year 1 treatment group): “AMG 145/AMG 145 
+ SOC”; “AMG 145/ SOC only”; “Not AMG 145/AMG 145 + SOC”, and “Not 
AMG 145/SOC only”.  For the final analysis (end of the 5 years), this combined 
treatment group will also have 4 levels (parent study treatment group/ year 1 treatment 
group/year 2-5 open-label AMG 145): “AMG 145/AMG 145 + SOC/AMG 145”; 
“AMG 145/ SOC only/AMG 145”; “Not AMG 145/AMG 145 + SOC/AMG 145”, and “Not 
AMG 145/SOC only/AMG 145”. 
Unless specified otherwise, the baseline value is defined as the subject’s baseline value 
from the parent study.  
There will be no imputation for missing data. 
Deaths and major cardiovascular events from this and other studies with evolocumab 
will be adjudicated by an independent Clinical Events Committee (CEC) to facilitate 
aggregated analyses across the program.   
10.4.2 
Analysis of Key Study Endpoints 
10.4.2.1 
Primary Endpoint Analyses 
Adverse events will be coded using the latest version of Medical Dictionary for 
Regulatory Activities (MedDRA).  Subject incidences of adverse events, serious adverse 
events, and adverse events leading to withdrawal from IP will be tabulated by system 
organ class and preferred term. 
Subgroup analyses on the primary endpoint will be conducted on each baseline 
covariate specified in Section 10.1.7. 
10.4.2.2 
Secondary Endpoint Analyses 
The secondary endpoints will be summarized at each scheduled visit by randomized 
treatment group in this study and also the combined treatment group (4 levels).  For the 
1-year interim analysis, point estimates of group means and their 95% confidence 
intervals will be presented.  Differences in the group means, along with the 95% 

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Protocol Number:  20110110 
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confidence intervals, of the secondary endpoints will be estimated at each scheduled 
visit between 
• 
the AMG 145 + SOC group and the SOC only group in this study, regardless of the 
treatment arm the subject was randomized to in their parent study, and 
• 
the AMG 145 + SOC group and SOC only group in this study, by whether the subject 
was randomized to AMG 145 or not in their parent study. 
A repeated measures linear model will be fit for each secondary endpoint for the 1-year 
interim analysis.  The model will include at least terms for the treatment group (AMG 145 
plus SOC, SOC only), the stratification factor, scheduled visit and the interaction of the 
treatment group with scheduled visit.  Contrasts between treatment levels will be 
provided to estimate AMG 145 treatment effects at week 24 and week 52, continuing 
long term effect or discontinuing effect after 12 weeks of AMG 145 exposure.  Details of 
these contrasts will be provided in the Statistical Analysis Plan.  
10.4.2.3 
Exploratory Endpoint Analyses 
The percent change and change from baseline in laboratory based exploratory 
endpoints at each scheduled visit will be summarized. 
Major cardiovascular events from this and other studies with evolocumab will be 
adjudicated by an independent Clinical Events Committee (CEC) to facilitate aggregated 
safety analyses across the program.  These events may include death (cardiovascular, 
cerebrovascular and non-vascular), MI, stroke, coronary revascularization, urgent 
admissions for unstable angina and urgent admission for congestive heart failure.  
Subject incidence of adjudicated adverse events will be summarized. 
Adjudicated Cardiovascular Events 
10.4.2.4 
Safety Endpoint Analyses 
Laboratory parameters will be summarized using descriptive statistics at each scheduled 
visit.  Laboratory shift tables for certain analytes will be provided using the CTCAE v.4 
toxicity criteria.  The results will be based on the maximum (ie, worst) shift from baseline 
to the end of study. 
Safety Laboratory Parameters 
Vital signs will be summarized using descriptive statistics at each scheduled visit. 
Vital Signs 

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The incidence and percentages of subjects who develop anti-AMG 145 antibodies 
(binding and neutralizing) at any time will be tabulated. 
Anti-AMG 145 antibodies 
Concomitant medications of interest will be summarized. 
Concomitant Medications 
Analytes for the steroid substudy listed in Section 
Steroid substudy 
7.3.2 will be summarized for each 
treatment group using descriptive statistics at each measurement time point. 
10.4.2.5 
Pharmacokinetics Endpoint Analyses 
Summary statistics of PK concentration will be provided. 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial generic informed consent template form is provided for the investigator to use 
to customize accordingly to his or her site’s requirements.  Updates to the template will 
be communicated by letter from the Amgen study manager to the investigator.  The 
written informed consent document should be prepared in the language(s) of the 
potential patient population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol-specific screening procedures or any investigational products are administered. 
The acquisition of informed consent should be documented in the subject’s medical 
records, and the informed consent form should be signed and personally dated by the 
subject and by the person who conducted the informed consent discussion.  The original 
signed informed consent form should be retained in accordance with institutional policy, 
and a copy of the signed consent form should be provided to the subject. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood. 

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11.2 
Independent Ethics Committee/Institutional Review Board (IEC/IRB) 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IEC/IRB for 
written approval.  A copy of the written approval of the protocol and informed consent 
form must be received by Amgen before recruitment of subjects into the study and 
shipment of Amgen investigational product. 
The investigator must submit and, where necessary, obtain approval from the IEC/IRB 
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator should notify the IEC/IRB 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 will be responsible for obtaining annual IEC/IRB approval/renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IEC/IRB continuance of approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained: 
• 
On the CRFs or other documents submitted to Amgen, subjects should be identified 
by a subject identification number only, with a complete and accurate date of birth on 
the demographics CRF.   
• 
For Serious Adverse Events reported to Amgen, subjects should be identified by 
their initials, date of birth, and a subject identification number.   
• 
Documents that are not for submission to Amgen (eg, signed informed consent 
forms) should be kept in strict confidence by the investigator. 
In compliance with Federal regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IEC/IRB 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 named representatives to have access to 
his/her study-related records, including personal information, without violating the 
confidentiality of the subject. 

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11.4 
Investigator Signatory Obligations 
Each clinical study report should be signed by the investigator or, in the case of 
multicenter studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will either be: 
• 
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 
If Amgen amends the protocol, agreement from the investigator must be obtained.  The 
IEC/IRB must be informed of all amendments and give approval.  The investigator must 
send a copy of the approval letter from the IEC/IRB to Amgen. 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
investigator reserve the right to terminate the investigator’s participation in the study 
according to the study contract.  The investigator should notify the IEC/IRB 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 (IP) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen (IP), and by what mechanism, after termination of the trial and 
before it is available commercially. 
12.2 
Study Documentation and Archive 
The investigator should maintain a list of appropriately qualified persons to whom he/she 
has delegated study responsibilities.  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. 
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 

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inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.  Elements should include: 
• 
Subject files containing completed study-related worksheets, 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 IEC/IRB 
and Amgen 
• 
If kept, proof of receipt/delivery sheet, Investigational Product Accountability Record, 
Return of Investigational Product for Destruction, Final Investigational Product 
Reconciliation Statement (if applicable), and all drug-related correspondence 
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 and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Amgen 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 
monitor should 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 monitor to ensure that any problems 
detected in the course of these monitoring visits, including delays in completing CRFs, 
are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function 
(or designees).  Inspection of site facilities (eg, pharmacy, drug 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 electronic CRFs must be 
maintained and readily available. 

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• 
Updates to electronic CRFs (eCRF) 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 will be performed on subject data received at Amgen.  During 
this review, subject data will be checked for consistency, omissions, and any 
apparent discrepancies.  In addition, the data will be reviewed for adherence to the 
protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries and/or site notifications will be created in 
the EDC system database for site resolution and closed by Amgen reviewer. 
• 
The principal investigator signs only the Investigator Verification Form for this 
electronic data capture study.  This signature will indicate that the principal 
investigator inspected or reviewed the data on the CRF, the data queries, and the 
site notifications, and agrees with the content. 
Amgen (or designee) will perform self-evident corrections to obvious data errors in the 
clinical trial database, as documented in the Study Specific Self Evident Corrections 
Plan.  Examples of obvious data errors that may be corrected by Amgen (or designee) 
include deletion of obvious duplicate data (eg, same results sent twice with the same 
date with different visit—week 4 and early termination) and clarifying “other, specify” if 
data are provided (eg, race, physical examination).  Each investigative site will be 
provided a list of the types of corrections applied to study data at the initiation of the trial 
and at study closeout.   
12.4 
Investigator Responsibilities for Data Collection 
The Investigator is responsible to comply 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 (Appendix A), 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 
eCRFs must be completed in English.  TRADENAMES (if used) for concomitant 
medications may be entered in the local language. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.  Consult the 
country-specific requirements for language requirements. 

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12.6 
Publication Policy 
To coordinate dissemination of data from this study, Amgen encourages the formation of 
a publication committee consisting of several principal 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 should be met 
for every publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors), 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.  Authors should meet conditions 1, 2, and 3. 
• 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 
• 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
• 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
• 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for corporate review.  The Clinical 
Study Agreement among the institution, principal 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.  
Depending on the type of study, and if permitted under applicable regional laws or 
regulatory guidelines, subjects may be compensated for other inconveniences not 
associated with study-related injuries (eg, travel costs). 

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13. 
REFERENCES 
Abifadel M, Varret M, Rabes J-P, et al.  Mutations in PCSK9 cause autosomal dominant 
hypercholesterolemia.  Nature Genetics.  2003;34:154-156. 
Allender S, Scarborough P, Peto V, et al.  European Cardiovascular Disease Statistics 
2008 Edition.  
Brown MS, Goldstein JL.  Biomedicine. Lowering LDL--not only how low, but how long? 
Science.  2006;311:1721-1723. 
Cohen J, Pertsemlidis A, Kotowski IK, et al.  Low LDL cholesterol in individuals of 
African descent resulting from frequent nonsense mutations in PCSK9.  Nature 
Genetics.  2005;37:161-165. 
Cohen JC, Boerwinkle E, Mosley TH, Jr, Hobbs HH.  Sequence variations in PCSK9, 
low LDL, and protection against coronary heart disease.  N Engl J Med.  
2006;354:1264-1272. 
Eisenberg, DA.  Cholesterol lowering in the management of coronary artery disease: the 
clinical implications of recent trials.  Am J Med.  1998;104(2A):2S-5S. 
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in 
Adults.  Summary of the second report of the National Cholesterol Education Program 
(NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in 
adults (Adult Treatment Panel II).  JAMA.  1993 ;269:3015-3023. 
Gould AL, Rossouw JE, Santanello NC, Heyse JF, Furberg CD.  Cholesterol reduction 
yields clinical benefit.  A new look at old data.  Circulation.  1995;91 2274-2282. 
Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR.  The C679X mutation in PCSK9 is 
present and lowers blood cholesterol in a Southern African population.  Atherosclerosis.  
2007;193:445-448. 
Horton JD, Cohen JC, Hobbs HH.  Molecular biology of PCSK9: its role in LDL 
metabolism.  Trends Biochem Sci.  2007;32:71-77. 
Kannel WB, et al.  The Framingham Study:  An epidemiological investigation of 
cardiovascular disease, Section 30.  Some characteristics related to the incidence of 
cardiovascular disease and death:  The Framingham Study.  18-year follow-up.  
Washington, D.C., Dept.  of Health, Education, and Welfare, Publication No. (NIH) 74 
599, 1974. 
Kannel WB, Castelli WP, Gordon T.  Lipoprotein cholesterol in the prediction of 
atherosclerotic disease:  New perspectives based on the Framingham Study.  Ann Int 
Med.  1979;90:85-91. 
Kannel WB.  Range of serum cholesterol values in the population developing coronary 
artery disease.  Am J Cardiol.  1995;76:69C-77C. 
Roger VL, et al.  Heart Disease and Stroke Statistics – 2011 Update.  Circulation.  
2011;123:e18-e209. 
Sempos CT, Cleeman CT, Carroll MD, et al.  Prevalence of high blood cholesterol 
among US adults.  An update based on guidelines from the second report of the 
National Cholesterol Education Program Adult Treatment Panel.  JAMA.  
1993;269:3009-3014. 
Zaid A, Roubtsova A, Essalmani R, et al.  Proprotein convertase subtilisin/kexin type 9 
(PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical 
role in mouse liver regeneration.  Hepatology.  2008;48:646-654. 

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Zhao Z, Tuakli-Wosornu Y, Lagace TA, et al.  Molecular characterization of 
loss-of-function mutations in PCSK9 and identification of a compound heterozygote.  
Am J Hum Genet.  2006;79:514-523. 

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14. 
APPENDICES  

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Appendix A.  Schedule of Assessments 
Year 1 (AMG 145 +SOC vs  SOC alone) 
Years 2-5 (AMG 145 +SOC)
Study Day / Timepoint 
EOS 
Parent 
Day 1 
OLE a 
Week 4
Interval 
Visits 
(4 Weeks)
Weeks 8, 16,
20, 28, 32, 
40, and 44
Quarterly 
Visits 
(12 weeks) 
Weeks 12,24,36
and 48
Week
52 
Week 4/ 
Yr2* 
Quarterly 
Visits  
12 weeks
EOS/ET
OLE**
General Procedures 
 
 
AMG SOC
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Vital Signs (HR, BP) 
X 
X 
X 
 
X 
X 
X 
X 
X 
AEs/ADEs/SAEs 
X 
X 
X 
X b 
X 
X 
X 
X 
X 
Concomitant 
medication 
X 
X 
X 
X b 
X 
X 
X 
X 
X 
Body Weight 
X 
 
 
 
X 
 
 
X 
Physical exam 
X 
 
 
 
X 
 
 
X 
12 Lead ECG c 
X 
 
 
 
 
 
 
 
Central Laboratory 
 
 
 
 
 
 
 
 
Fasting plasma lipids, 
ApoA1,ApoB 
Xd 
X 
 
X 
X 
 
X 
X 
PK samples (AMG 145
PCSK9) 
X 
X 
 
X 
X 
 
X 
X 
Chemistry 
X 
X 
 
X 
X 
 
X 
X 
Hematology 
X 
X 
 
X 
X 
 
X 
X 
HbA1c 
X 
X 
 
X 
X 
 
X 
X 
Coagulation 
X 
X 
 
X 
X 
 
X 
X 
hsCRP, Lp(a) 
X 
X 
 
X 
X 
 
X 
X 
Fasting Vitamin E 
X e 
 
 
X e 
X e 
 
X e 
Xe
Biomarkers (blood) 
X 
X f 
 
X f 
 
 
 
 
Anti-AMG 145 
antibodies 
X 
X 
 
X 
X 
 
Xg 
X 
Serum pregnancy 
(females of 
childbearing potential) 
and FSH 
Xh 
Xi 
 
Xi 
Xi 
 
Xi 
X 
Urinalysis 
X 
 
 
 
X 
 
 
X 
Randomization 
X 
 
 
 
 
 
 
 
Investigational 
Product 
 
 
 
 
 
 
 
 
IP administration, QM 
X 
X 
X 
 
X 
X j 
X 
X 
 
Footnotes defined on next page. 

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a D1 = day of first administration of investigational product for the open-label extension; subjects will 
undergo EOS procedures for their parent study and sign a new OLE consent before being 
randomized.-Subjects randomized to study drug (AMG 145 + SOC QM) will have their first injection.  Visit 
will need to occur within 3 days of the parent EOS or all procedures (except ECG) will need to be repeated. 
b Subjects not receiving IP every 4 weeks will receive a phone call every 4 weeks to document any changes 
in concomitant medications or new AE/SAEs. 
c ECGs for subjects randomized to Q2W in the parent study will occur at week 12  
d Day 1 - measurement will only occur during parent EOS for Q2W subjects and QM subjects that miss their 
3 day EOS window. 
eVitamin E will only be collected  at EOS Parent/Day 1 and at weeks 12, 24, 52 (year 1), 76, and 100.  
Vitamin E will remain blinded throughout the study to the investigator, site and subject.  If a subject early 
terms before week 100 a Vitamin E sample should be collected. 
fBiomarkers will be collected only  at week 4 and week 12. 
gAfter year 1 antibody samples will only be collected at the end of each year. 
hFSH = in applicable subjects for study entry only – see exclusion criteria 
i Serum pregnancy testing will occur at week 4,week 24, week 52, and every  6 months  thereafter.   
j SOC subjects will obtain their first dose of AMG 145 at week 56 
* Once the AI Pen and personal injector are available, IP should be self-administered at home or other 
locations both between and during quarterly visits after week 4/Year 2.  Subjects who prefer not to 
self-administer IP may return to the study site for administration (see section 6.1.1). 
** The EOS procedures should be used as a guide for the depth of information obtained for any subject that 
elects to continue via follow-up (see section 8). 
Additional Procedures for subjects enrolled in the steroid substudy. 
STEROID SUBSTUDY  
Test 
Day 1 
Week 12 
Week 24 
Week 52 
Substudy informed consent 
X 
 
 
 
ACTH 
X 
X 
X 
X 
FSH 
X 
X 
X 
X 
LH 
X 
X 
X 
X 
Cortisol 
X 
X 
X 
X 
Testosterone 
X 
X 
X 
X 
Estradiol 
X 
X 
X 
X 

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Appendix B.  Additional Safety Assessment Information 
Refer to the NCI Common Terminology Criteria for AEs (CTCAE) Version 4.0 for 
AE grading and information.  The CTCAE is available at the following link:  
Adverse Event Toxicity Grading Scale 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
When an AE cannot be graded by CTCAE v4.0 the following severity grade may be 
used: 
Grade 
Amgen Standard Adverse Event Severity Scoring System 
1 
MILD: Aware of sign or symptom, but easily tolerated 
2 
MODERATE: Discomfort enough to cause interference with usual activity 
3 
SEVERE: Incapacitating with inability to work or do usual activity 
4 
LIFE-THREATENING: Refers to an event in which the patient was, in the view of the 
investigator, at risk of death at the time of the event.  (This category is not to be used 
for an event that hypothetically might have caused death if it were more severe.) 
5 
FATAL 
Drug-induced Liver Injury Reporting & Additional Assessments  
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST/ALT and 
TBL elevation according to the criteria specified in Section 
Reporting 
6.1.3.2 (3x ULN for AST/ALT 
and 2x ULN for TBL) require the following: 
• 
The event should be reported to Amgen as a serious adverse event within 24 hours 
of discovery or notification of the event (ie,  before additional etiologic investigations 
have been concluded) 
• 
The appropriate eCRF (eg, adverse event eCRF) that captures information 
necessary to facilitate the evaluation of treatment-emergent liver abnormalities 
should be completed.   
Other events of hepatotoxicity and potential DILI should be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.2.1. 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 73 of 77 
CONFIDENTIAL 
 
 
All subjects in whom IP is withheld due to potential DILI or who experience AST/ALT 
elevations >3x ULN should undergo a period of “close observation” until abnormalities 
return to normal or to the subject’s baseline levels.  Assessments that should be 
performed during this period include:  
Additional Clinical Assessments and Observation 
• 
Repeat liver chemistries within 24-48 hours (ALT, AST, ALP, TBL); in cases of TBL 
>2x ULN or AST/ALT much greater than 3x ULN, retesting should be performed 
within 24 hours  
− 
Subjects should be monitored at least twice weekly; testing frequency may 
decrease to once per week or less if laboratory abnormalities stabilize or the IP 
has been discontinued AND the subject is asymptomatic 
• 
Obtain PT/INR, fractionated bilirubin and any other potentially relevant laboratory 
evaluations of liver function or disease  
• 
Obtain complete blood count (CBC) with differential to assess for eosinophilia 
• 
Obtain appropriate blood sampling for pharmacokinetic analysis if this has not 
already been collected  
• 
Obtain a more detailed history of:  
− 
Prior and/or concurrent diseases or illness 
− 
Exposure to environmental and/or industrial chemical agents  
− 
Symptoms (if applicable) including right upper quadrant pain, hypersensitivity-
type reactions, fatigue, nausea, vomiting and fever 
− 
Prior and/or concurrent use of alcohol, recreational drugs and special diets 
− 
Concomitant medications (including non-prescription medicines & herbal and 
dietary supplements)  
• 
Initiate full viral and autoimmune hepatitis evaluation (serologies for hepatitis A,B,C, 
D, E, Epstein-Barr Virus, Herpes Simplex Virus, etc); evaluate for other potential 
causes of DILI including but not limited to: NASH, hypoxic/ischemic hepatopathy, 
and biliary tract disease  
• 
Obtain gastroenterology or hepatology consult  
• 
Perform appropriate liver imaging or biopsy if clinically indicated; strongly consider 
these tests in cases of concurrent transaminase and TBL elevation as specified in 
Section 6.1.3.2. 
• 
Follow the subject until all laboratory abnormalities return to baseline or normal.  The 
“close observation period” should continue for a minimum of 4 weeks after drug 
discontinuation. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding eCRFs. 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 74 of 77 
CONFIDENTIAL 
 
 
Appendix C.  Sample Serious Adverse Event Report (SAER) Form 
 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 75 of 77 
CONFIDENTIAL 
 
 
 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 76 of 77 
CONFIDENTIAL 
 
 
Appendix D.  Pregnancy and Lactation Notification Worksheets 
 
 
 

Product:  Evolocumab  
Protocol Number:  20110110 
Date:  12 November 2015 
Page 77 of 77 
CONFIDENTIAL 
 
 
 

Product:  Evolocumab 
Protocol Number:  20110110 
Date:  12 November 2015 
Page 1 of 14 
CONFIDENTIAL 
 
 
Amendment 7 
Protocol Title:  A Multicenter, Controlled, Open-label Extension (OLE) Study to 
Assess the Long-term Safety and Efficacy of Evolocumab (AMG 145) 
 
Amgen Protocol Number (evolocumab) 20110110 
EudraCT 2011-001915-29 
 
Date: 
24 May 2011 
Amendment 1 Date: 
15 April 2015 
Superseding Amendment 1 
Date 
26 August 2011 
Amendment 2 Date 
08 September 2011 
Amendment 3 Date 
24 April 2012 
Amendment 4 Date 
20 June 2012 
Amendment 5 Date 
26 February 2014 
Amendment 6 Date 
09 March 2015 
 
Amendment 7 Date 
12 November 2015 
Rationale: 
The protocol is being amended to: 
• 
Update Safety language 
• 
Update End of Study Language 
• 
Make minor editorial changes 

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PPD
PPD
PPD
PPD

Product:  Evolocumab 
Protocol Number:  20110110 
Date:  12 November 2015 
Page 3 of 14 
CONFIDENTIAL 
 
 
With: 
 
Date: 
24 May 2011 
Amendment 1 Date: 
15 August 2011 
Superseding Amendment 1 Date 
26 August 2011 
Amendment 2 Date 
08 September 2011 
Amendment 3 Date 
24 April 2012 
Amendment 4 Date 
20 June 2012 
Amendment 5 Date 
26 February 2014 
Amendment 6 Date 
09 March 2015 
Amendment 7 Date 
12 November 2015 
Section:  Protocol Synopsis, Study Design 
Replace: 
At the end of the first year (week 52), starting at week 56 (week 4/year 2) all subjects will 
receive open-label AMG 145 for approximately 4 years (or until the investigator’s 
recommendation of discontinuation, Amgen’s recommendation of discontinuation, the 
subjects’ decision to discontinue for any reason, or until an administrative decision is 
made to close the study). 
With: 
At the end of the first year (week 52), starting at week 56 (week 4/year 2) all subjects will 
receive open-label AMG 145 for up to 4 years (or until the investigator’s 
recommendation of discontinuation, Amgen’s recommendation of discontinuation, the 
subjects’ decision to discontinue for any reason, or until an administrative decision is 
made to close the study). 
Section:  Protocol Synopsis, During the First Year 
Add: 
During the first year, subjects randomized to AMG 145 + SOC will need to visit the site 
every 4 weeks.  During these visits vital signs will be obtained and adverse events 
(AEs), adverse device effects (ADEs), serious adverse events (SAEs), and 
concomitant medications will be recorded.  Subjects randomized to SOC only, will not 
visit the site every 4 weeks (except at specified visits); rather the site will call these 
subjects at the scheduled visits to review concomitant medication changes, AEs, ADEs, 
and SAEs. During quarterly (every 12 weeks) visits, central laboratory tests will be 

Product:  Evolocumab 
Protocol Number:  20110110 
Date:  12 November 2015 
Page 4 of 14 
CONFIDENTIAL 
 
 
performed for all subjects.  For a full list of study procedures, including the timing of each 
procedure, please refer to Section 7.1 and Appendix A. 
Section:  Study Glossary 
Add: 
ADE 
Adverse Device Effect 
NCI 
National Cancer Institute 
Section:  3.3.1 Study Duration for Participants 
Replace: 
Subjects will be enrolled into the study after completion of a qualifying AMG 145 study.  
During this study subjects will visit the site multiple times.  During the first year, visits will 
occur every 4 weeks for all subjects.  Quarterly visits will be data-rich and interval visits 
(every 4 weeks) will be data-sparse.  During the first year those randomized to SOC-only 
will have their interval visits conducted via phone after week 4.  Nonetheless SOC only 
subjects will still need to visit the site for their quarterly visits.  The study will continue for 
approximately 5 years (or until the investigator’s recommendation of discontinuation, 
Amgen’s recommendation of discontinuation, the subjects’ decision to discontinue for 
any reason, or until an administrative decision is made to close the study). 
With: 
Subjects will be enrolled into the study after completion of a qualifying AMG 145 study.  
During this study subjects will visit the site multiple times.  During the first year, visits will 
occur every 4 weeks for all subjects.  Quarterly visits will be data-rich and interval visits 
(every 4 weeks) will be data-sparse.  During the first year those randomized to SOC-only 
will have their interval visits conducted via phone after week 4.  Nonetheless SOC only 
subjects will still need to visit the site for their quarterly visits.  After the first year, 
quarterly visits will continue up to Week 260 (approximately 5 years).  
Section:  3.3.2 End of Study 
Replace: 
The study will continue for approximately 5 years (or until the investigator’s 
recommendation of discontinuation, Amgen’s recommendation of discontinuation, the 
subjects’ decision to discontinue for any reason, or until an administrative decision is 
made to close the study). 

Product:  Evolocumab 
Protocol Number:  20110110 
Date:  12 November 2015 
Page 5 of 14 
CONFIDENTIAL 
 
 
With: 
The study will complete when the last subject has completed assessments for 
Week 260 (approximately year 5) or until the investigator’s recommendation of 
discontinuation, Amgen’s recommendation of discontinuation, the subjects’ decision to 
discontinue for any reason, or until an administrative decision is made to close the study. 
Section:  6 Treatment Procedures 
Replace: 
AMG 145 will be the investigational product (IP) in this study.  During the first year 
subjects will be randomized to AMG 145 +SOC or SOC only.  After completion of the 
first year, all subjects will be given open-label AMG 145. 
An Investigational Product Instruction Manual (IPIM) containing detailed information 
regarding the storage, preparation, and administration of the investigational product will 
be provided separately.  
With: 
AMG 145 will be the investigational product (IP) in this study.  In several countries, IP 
is referred to as investigational medicinal product (IMP).  In this document, IMP 
will be referred to as IP.  During the first year subjects will be randomized to AMG 145 
+SOC or SOC only.  After completion of the first year, all subjects will be given 
open-label AMG 145. 
The investigational medical devices used in this study are the prefilled 
autoinjector/pen (AI/Pen) and the 3.5 mL Personal Injector. 
An Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of the investigational product and this document will be provided 
separately.  
Section:  6.2 Medical Devices 
Add: 
IP will be administered per prefilled AI/Pen and 3.5 mL Personal Injector, provided by 
Amgen (Section 6.1).  

Product:  Evolocumab 
Protocol Number:  20110110 
Date:  12 November 2015 
Page 6 of 14 
CONFIDENTIAL 
 
 
Section:  6.3 Product Complaints, Including Device Complaints 
Replace: 
A product complaint is defined as any written, electronic or oral communication that 
alleges deficiencies related to the identity, quality, durability, reliability, safety, 
effectiveness, or performance of a drug or device after it is released for distribution to 
market or clinic by either Amgen or by distributors and partners for whom Amgen 
manufactures the material.  
Any product complaints 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.   
Concerns or irregularities about the packaging, appearance or usage of the prefilled 
AI/Pen or personal injector or other Amgen provided, protocol-required product in this 
study are to be reported to Amgen within 24 hours of discovery or notification of the 
concern or irregularity.  Should any such concerns or irregularities occur please do not 
use the IP until Amgen confirms that it is permissible to use. 
Examples of potential product complaints that need to be reported to Amgen include, but 
are not limited to: 
• 
broken container or cracked container 
• 
misuse of the AI/pen due to misunderstanding of the IFU or error on the part of the 
user, or other inability to appropriately use the product (eg, due to malfunction of the 
AI/Pen or 3.5 mL personal injector) 
With: 
A product complaint is defined as 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) or device(s) provisioned 
and/or repackaged/modified by Amgen Drug(s) or device(s) including 
investigational product.  
Any product complaints 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.   

Product:  Evolocumab 
Protocol Number:  20110110 
Date:  12 November 2015 
Page 7 of 14 
CONFIDENTIAL 
 
 
Concerns or irregularities about the packaging, appearance or usage of the prefilled 
AI/Pen or personal injector or other Amgen provided, protocol-required product in this 
study are to be reported to Amgen within 24 hours of discovery or notification of the 
concern or irregularity.  Should any such concerns or irregularities occur please do not 
use the IP until Amgen confirms that it is permissible to use. 
Examples of potential product complaints that need to be reported to Amgen include, but 
are not limited to: 
• 
broken container or cracked container 
• 
misuse of the AI/pen or the 3.5 mL personal injector due to misunderstanding of 
the IFU or error on the part of the user, or other inability to appropriately use the 
product (eg, due to malfunction of the AI/Pen or 3.5 mL personal injector) 
Section:  7.1.1 Enrollmenet (EOS Parent/Day 1 OLE), 3rd bullet 
Add: 
• 
AEs/ADEs/SAEs 
Section:  7.1.1.1 Week 4 (± 7 Days), 2nd bullet 
Add: 
• 
AEs/ADEs/SAEs 
Section:  7.1.1.2 Interval Visits (Every 4 Weeks ± 7 Days), 3rd bullet 
Add: 
• 
AEs/ADEs/SAEs 
Section:  7.1.1.3 Quarterly Visits (Every 12 Weeks ± 7 Days), 2nd bullet 
Add: 
• 
AEs/ADEs/SAEs 
Section:  7.1.1.4 Week 52 - End of Year 1 Visit (± 7 Days), 2nd bullet 
Add: 
• 
AEs/ADEs/SAEs 
Section:  7.1.1.5 Week 4/Year 2 (4 Weeks ± 7 Days), 2nd bullet 
Add: 
• 
AEs/ADEs/SAEs 

Product:  Evolocumab 
Protocol Number:  20110110 
Date:  12 November 2015 
Page 8 of 14 
CONFIDENTIAL 
 
 
Section:  7.1.1.6 Quarterly Visits (Every 12 Weeks ± 7 Days) 
Add: 
• 
AEs/ADEs/SAEs 
Section:  7.1.1.7 End of Study/Early Term OLE Visit 
Add: 
• 
AEs/ADEs/SAEs 
Section:  7.1.2.3 Lipid Measurements 
Delete: 
Adverse event data for all subjects who experience 2 consecutive UC LDL-C values 
below 25 mg/dL during the trial will be reviewed in aggregate by an independent non-
program related Amgen safety physician to evaluate any potential safety risks.  
Section:  8.1 Removal of Subjects 
Add: 
Reasons for removal from study: 
• 
decision by Amgen (sponsor) 
• 
withdrawal of full consent from study 
• 
death 
• 
lost to follow-up 
Section:  9.1.1 Definition of Adverse Events 
Add: 
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease (eg, 
diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected, and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study or 
involves an intervention such as elective cosmetic surgery or a medical procedure while 
on study is not considered an adverse event.  

Product:  Evolocumab 
Protocol Number:  20110110 
Date:  12 November 2015 
Page 9 of 14 
CONFIDENTIAL 
 
 
Section:  9.1.2 Reporting Procedures for Adverse Events 
Add: 
9.1.2 Reporting Procedures for Adverse Events That Do Not Meet Serious 
Criteria 
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 the device (prefilled AI/Pen or 3.5 mL Personal 
Injector), 
• 
Assessment of relatedness to investigational product (AMG 145) or any study 
mandated activity or procedure or other protocol-required therapies, and 
• 
Action taken. 
Section:  9.3 Pregnancy and Lactation Reporting 
Replace: 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking protocol-required therapies report the pregnancy to Amgen as specified 
below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur after the last dose of protocol-required therapies 
through an additional 15 weeks after the end of treatment with IP (AMG 145).   
The pregnancy should be reported to Amgen’s global Pregnancy Surveillance Program 
within 24 hours of the investigator’s knowledge of the event of a pregnancy.  Report a 
pregnancy on the Pregnancy Notification Worksheet (Appendix D).  The Pregnancy 
Surveillance Program (PSP) will seek to follow the pregnant woman throughout her 
pregnancy and her baby up to 12 months after birth. 
If a lactation case occurs while the female subject is taking protocol-required therapies 
report the lactation case to Amgen as specified below.  
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur after the last dose of protocol-required therapies through an 
additional 15 weeks after the end of treatment with IP (AMG 145). 

Product:  Evolocumab 
Protocol Number:  20110110 
Date:  12 November 2015 
Page 10 of 14 
CONFIDENTIAL 
 
 
Any lactation case should be reported to Amgen’s global Lactation Surveillance Program 
(LSP) within 24 hours of the investigator’s knowledge of the event.  Report a lactation 
case on the Lactation Notification Worksheet (Appendix D). 
With: 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking evolocumab report the pregnancy to Amgen as specified below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur after the last dose of evolocumab through an 
additional 15 weeks after the end of treatment with evolocumab.   
The pregnancy should be reported to Amgen’s Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix D).  Amgen Global Patient Safety will 
follow up with the investigator regarding additional information that may be 
requested. 
If a lactation case occurs while the female subject is taking evolocumab, report the 
lactation case to Amgen as specified below.  
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur after the last dose of evolocumab through an additional 15 
weeks after the end of treatment with evolocumab. 
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours 
of the investigator’s knowledge of the event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix D).  Amgen Global Patient Safety will follow up 
with the investigator regarding additional information that may be requested. 
Section:  Appendix A, 5th row 
Add: 
AEs/ADEs/SAEs 
X 
X 
X 
X b 
X 
X 
X 
X 
X 

Product:  Evolocumab 
Protocol Number:  20110110 
Date:  12 November 2015 
Page 11 of 14 
CONFIDENTIAL 
 
 
Section:  Appendix D.  Pregnancy and Lactation Notification Worksheets 
Replace: 

Product:  Evolocumab 
Protocol Number:  20110110 
Date:  12 November 2015 
Page 12 of 14 
CONFIDENTIAL 
 
 
 

Product:  Evolocumab 
Protocol Number:  20110110 
Date:  12 November 2015 
Page 13 of 14 
CONFIDENTIAL 
 
 
With: 
 
 
 

Product:  Evolocumab 
Protocol Number:  20110110 
Date:  12 November 2015 
Page 14 of 14 
CONFIDENTIAL 
 
 
 
 

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Printed copy is not official record. 
 
Product:  AMG 145 
Protocol Number:  20110110 
Date:  26 August 2011 
Page 1 of 21 
 
 
Amendment 1 
Protocol Title:  A Multicenter, Controlled, Open-label Extension (OLE) Study to 
Assess the Long-term Safety and Efficacy of AMG 145 
 
Amgen Protocol Number AMG 145 20110110 
 
Amendment Date: 
26 August 2011 
 
Rationale: 
This document provides the rationale and detailed list of changes for superseding 
Amendment 1, dated 26 August 2011, from the original study protocol, dated 24 May 
2011.  
The purpose of the amendment is to: 
• 
Add “OSLER” study name 
• 
Add a standard of care control arm 
• 
Clarify that subjects should remain in follow-up after discontinuation of 
investigational product (IP) and update the list of possible reasons for withdrawal 
from IP 
• 
Add an exploratory objective of estimation of cardiovascular event rates 
• 
Add international units for lipid concentrations for informational purpose 
• 
Open up inclusion criteria to all qualifying AMG 145 parent protocols 
• 
Clarify measurement methods for LDL-C by a preparative ultracentrifugation and 
by calculation 
• 
Revise section 8.1 (Removal of Subjects) in accordance with current regulatory 
guidelines 
• 
Clarify that death and certain cardiovascular events that are submitted for 
adjudication are not submitted as adverse event/serious adverse event until the 
site is notified that the event was a death that is not expected in this patient 
population or an event that was adjudicated negatively (did not qualify as 
adjudicated endpoint) 
• 
Add adjudicated events as exploratory endpoints 
• 
Add a week 4 study visit 
• 
Decrease the study duration to 1 year 
• 
Add section 5.1 Randomization 
• 
Update the statistics section to reflect the control arm 
New superseding amendment changes - Sections 9.1.2 and 9.2.2 were revised to 
clarify that events reported to the Clinical Events Classification Committee (CEC) for 
adjudication as potential endpoints are not reported as serious adverse events. Such 
events are only reported as SAEs if they are found by the CEC not to meet pre-
defined criteria for a positively adjudicated endpoint.