Clinical trial NCT02662569
Conditions: Diabetes, Hyperlipidemia, Mixed Dyslipidemia
Sponsor: Amgen
Start date: 2016-04-14; Completion date: 2017-12-06
Enrollment: 986 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study was to evaluate the effect of 12 weeks of subcutaneous evolocumab (AMG 145) in combination with statin therapy (atorvastatin) on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in diabetic adults with hyperlipidemia or mixed dyslipidemia.

Detailed description:

Arms: arm 1: Participants received placebo subcutaneous injection once every 2 weeks (Q2W) and 20 mg atorvastatin orally once a day for up to 12 weeks. arm 2: Participants received placebo subcutaneous injection once a month (QM) and 20 mg atorvastatin orally once a day for up to 12 weeks. arm 3: Participants received 140 mg evolocumab by subcutaneous injection once every 2 weeks and 20 mg atorvastatin orally once a day for up to 12 weeks. arm 4: Participants received 420 mg evolocumab by subcutaneous injection once a month and 20 mg atorvastatin orally once a day for up to 12 weeks.
Interventions: intervention 1: Evolocumab intervention 2: Atorvastatin intervention 3: Placebo
Intervention descriptions: intervention 1: Administered by subcutaneous injection intervention 2: Administered orally once a day intervention 3: Placebo to evolocumab administered by subcutaneous injection

Protocol documents:
Prot_000.pdf: 
Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 1 of 90 
CONFIDENTIAL 
Title:  A Double-blind, Randomized, Placebo-controlled, Multicenter Study to 
Evaluate Safety and Efficacy of Evolocumab (AMG 145) in Combination With 
Statin Therapy in Diabetic Subjects With Hyperlipidemia or Mixed Dyslipidemia 
Evolocumab (AMG 145) 
Amgen Protocol Number Evolocumab 20120119 
EudraCT number 2013-000723-14 
Clinical Study Sponsor: 
Amgen Inc 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Phone: +1-805-447-1000 
Key Sponsor Contact(s): 
One Amgen Center Drive MS 27-2-C 
Thousand Oaks, CA 91320, USA 
Phone:
Fax:  
Email: 
Date: 
22 February 2013 
Amendment 1 Date: 
10 December 2013 
Superseding Amendment 1 Date: 
07 February 2014 
Amendment 2 Date: 
(applies to subjects in China only) 
29 July 2015 
Amendment 3 Date: 
11 November 2015 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN, Canadian sites, 
1-866-50-AMGEN, all other countries call the local toll-free number, if provided, or call 
+1-800-772-6436; Amgen’s general number in the US (1-805-447-1000).  
PPD
PPD
PPD
PPD
NCT Number: 02662569
This NCT number has been applied to the document
for purposes of posting on clinicaltrials.gov


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 2 of 90 
CONFIDENTIAL 
Investigator’s Agreement 
I have read the attached protocol entitled “A Double-blind, Randomized, 
Placebo-Controlled, Multicenter Study to Evaluate Safety and Efficacy of Evolocumab 
(AMG 145) in Combination With Statin Therapy in Diabetic Subjects With Hyperlipidemia 
or Mixed Dyslipidemia”, dated 11 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 subinvestigators (including, if applicable, their spouses [or legal partners] and
dependent children)
at the start of the study and for up to one year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc.  
Signature 
Name of Investigator 
Date (DD Month YYYY) 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 3 of 90 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Double-blind, Randomized, Placebo-Controlled, Multicenter Study to Evaluate Safety 
and Efficacy of Evolocumab (AMG 145) in Combination With Statin Therapy in Diabetic Subjects 
With Hyperlipidemia or Mixed Dyslipidemia 
Study Phase:  3 
Indication:  Hyperlipidemia or mixed dyslipidemia 
Primary Objective:  To evaluate the effect of 12 weeks of subcutaneous (SC) evolocumab every 
2 weeks (Q2W) and monthly (QM), in combination with oral (PO) atorvastatin daily (QD), 
compared with placebo Q2W and QM, in combination with PO atorvastatin QD, on percent 
change from baseline in low-density lipoprotein cholesterol (LDL-C) in diabetic subjects with 
hyperlipidemia or mixed dyslipidemia.  
Secondary Objective(s): 
• 
to evaluate the safety and tolerability of SC evolocumab Q2W and QM in combination with 
atorvastatin QD, compared with placebo Q2W and QM, in combination with atorvastatin QD, 
in diabetic subjects with hyperlipidemia or mixed dyslipidemia 
• 
to assess the effects of 12 weeks of SC evolocumab Q2W and QM in combination with 
atorvastatin QD, compared with placebo Q2W and QM, in combination with atorvastatin QD, 
on change from baseline in LDL-C, and percent change from baseline in non-high-density 
lipoprotein cholesterol (non-HDL-C), apolipoprotein B100 (ApoB100), total cholesterol, total 
cholesterol/HDL-C ratio, ApoB100/Apolipoprotein A-1 (ApoA1) ratio, lipoprotein(a) [Lp(a)], 
triglycerides, very low-density lipoprotein cholesterol (VLDL-C), and HDL-C in diabetic 
subjects with hyperlipidemia or mixed dyslipidemia 
• 
to assess the effects of 12 weeks of SC evolocumab Q2W and QM in combination with 
atorvastatin QD, compared with placebo Q2W and QM, in combination with atorvastatin QD, 
on percent of subjects attaining LDL-C < 70 mg/dL (1.8 mmol/L) in diabetic subjects with 
hyperlipidemia or mixed dyslipidemia 
Hypotheses:  The primary hypothesis is that both dosing regimens of SC evolocumab (140 mg 
Q2W and 420 mg QM) in combination with atorvastatin QD will be well tolerated and will result in 
greater reduction of LDL-C, defined as mean percent change from baseline at weeks 10 and 
12 and percent change from baseline at week 12, compared with placebo (Q2W and QM), in 
combination with atorvastatin QD in diabetic subjects with hyperlipidemia or mixed dyslipidemia. 
Co-primary Efficacy Endpoints:   
• 
mean percent change from baseline in LDL-C at weeks 10 and 12 
• 
percent change from baseline in LDL-C at week 12 
Co-Secondary Efficacy Endpoints: 
Co-secondary efficacy endpoints are (1) the mean of weeks 10 and 12 and (2) week 12 for: 
Tier 1 
• 
change from baseline in LDL-C  
• 
percent change from baseline in non-HDL-C  
• 
percent change from baseline in ApoB100 
• 
percent change from baseline in the total cholesterol 
• 
percent change from baseline in the total cholesterol/HDL-C ratio 
• 
percent change from baseline in ApoB100/ApoA1 ratio 
• 
achievement of target LDL-C < 70 mg/dL (1.8 mmol/L) 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 4 of 90 
CONFIDENTIAL 
Tier 2 
•
percent change from baseline in Lp(a)
•
percent change from baseline in triglycerides
•
percent change from baseline in HDL-C
•
percent change from baseline in VLDL-C
Safety Endpoints 
•
subject incidence of treatment emergent adverse events
•
safety laboratory values and vital signs at each scheduled assessment
•
Electrocardiogram (ECG) parameters (such as RR, PR, QRS, QT and QTc intervals) at each
scheduled assessment
•
incidence of anti-evolocumab antibody (binding and neutralizing) formation
Study Design:  This is a phase 3, multicenter, double-blind, randomized, stratified, 
placebo-controlled study of evolocumab for diabetic subjects with hyperlipidemia or mixed 
dyslipidemia.  Subjects will undergo screening procedures, including laboratory assessments and 
a screening placebo injection, and will enter a lipid stabilization period where they will receive 
20 mg atorvastatin daily (QD).  Upon ≥ 4 weeks lipid stabilization, subjects will be randomized 
2:2:1:1 into the following treatment arms:  
•
Evolocumab SC 140 mg Q2W and atorvastatin PO 20 mg QD,
•
Evolocumab SC 420 mg QM and atorvastatin PO 20 mg QD,
•
placebo SC Q2W and atorvastatin PO 20 mg QD, or
•
placebo SC QM and atorvastatin PO 20 mg QD.
The sample size for each of the evolocumab dosing regimens, in combination with atorvastatin, 
will be approximately 300 subjects.  The sample size for each of the placebo dosing regimens, in 
combination with atorvastatin, will be approximately 150 subjects.  Randomization will be 
stratified by entry statin therapy (no statin use vs non-intensive statin use vs intensive statin use 
[see Appendix D of the protocol]) and by the site’s geographic region.  Treatment and follow-up 
period will be 12 weeks with an additional phone call or other subject contact at week 14 for 
subjects receiving IP Q2W. 
Evolocumab and placebo SC will be administered at the study site or appropriate non-investigator 
site settings, eg, at the subject’s home, per protocol Section 6 and Section 7 by spring-based 
prefilled autoinjector/pen (prefilled AI/Pen) for subjects receiving IP Q2W and by 3.5 mL Personal 
Injector for subjects receiving IP QM.  The dose frequencies of Q2W and QM will not be blinded 
but the identity of IP (evolocumab and matching SC placebo) will be blinded.  Post-IP treatment 
central laboratory results of the lipid panel, ApoA1, ApoB100, ApoB48, free fatty acids, 
chylomicrons, lipoprotein(a), PCSK9, insulin, proinsulin, C-peptide, glucagon, IL-6, adiponectin, 
vitamin E, PK, and high sensitivity C-reactive protein (hsCRP) will be blinded until unblinding of 
the clinical database and will not be reported to the investigator post-screening.  Investigators 
should not perform non-protocol testing of these analytes during a subject’s study participation 
and until at least 12 weeks after last IP administration, or the subject’s end of study, whichever is 
later. 
The study includes collection of biomarker samples and, where approved by the institutional 
review board and/or independent ethics committee (IRB/IEC) and applicable regulatory and other 
authorities, subjects will be invited to consent to pharmacogenetics analyses.  All subjects will 
complete a mixed meal tolerance test (MMTT) at the day 1 and week 12 study visits with 
1 postprandial blood collection 2 hours after the meal and up to approximately 240 subjects will 
participate in a MMTT Extended Timepoints Substudy with 2 additional postprandial blood draws 
at 1  and 3 hours after the meal.  End of study (EOS) for subjects on QM IP is at the week 12 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 5 of 90 
CONFIDENTIAL 
visit.  EOS for subjects on Q2W IP is by contact (eg, phone call) from the site at week 14 for any 
potential adverse events (AEs), adverse device effects (ADEs), and serious AEs (SAEs).  
Subjects will be encouraged to complete all planned visits regardless of their adherence to IP 
administration.  Accumulating safety and other data will be reviewed by an independent external 
Data Monitoring Committee (DMC).  Concentration values are provided in mmol/L for investigator 
convenience.  Conventional concentrations (mg/mL) will be used for the protocol, including for 
eligibility determination. 
Sample Size:  Approximately 900 subjects will be randomized. 
Summary of Subject Eligibility Criteria:  Males and females age ≥ 18 to ≤ 80 years with type 2 
diabetes (≥ 6 months) and with hyperlipidemia or mixed dyslipidemia are eligible for this study.  
For enrollment, LDL-C in subjects receiving statin therapy (any statin) at the time of entering 
screening must be ≥ 100 mg/dL (2.6 mmol/L), and in subjects not receiving statin therapy 
≥ 130 mg/dL (3.4 mmol/L) by central laboratory at screening.  Fasting triglycerides must be 
≤ 400 mg/dL (4.5 mmol/L) by central laboratory at screening. 
Major exclusion criteria include, but are not limited to:  receiving lipid-lowering therapy by 20 mg 
atorvastatin QD alone for 16 weeks is medically contraindicated or inappropriate based on 
opinion of investigator; heart failure of New York Heart Association (NYHA) class III or IV or last 
known left ventricular ejection fraction < 30%; type 1 diabetes or poorly controlled type 2 
diabetes; systolic blood pressure (SBP) > 160 mmHg or diastolic BP (DBP) > 100 mmHg; 
previously received evolocumab or any other investigational therapy to inhibit proprotein 
convertase subtilisin/kexin type 9 (PCSK9); unwillingness or inability to discontinue until end of 
study the following: red yeast rice, niacin (> 200 mg/day), > 1000 mg/day omega-3 fatty acids, 
and all prescription lipid-regulating drugs except study-provided atorvastatin; any of the following 
drugs in the last 2 months: systemic cyclosporine, systemic steroids, vitamin A derivatives and 
retinol derivatives for the treatment of dermatologic conditions (eg, Accutane), or a 
cholesterylester transfer protein (CETP) inhibitor in the last 12 months.  Female subjects cannot 
be pregnant, breast feeding, planning to become pregnant, or planning to breastfeed and 
premenopausal females must have to be willing to use (an) acceptable method(s) of effective 
birth control during treatment with investigational product (evolocumab or placebo) and for an 
additional 15 weeks after the end of treatment with investigational product (evolocumab or 
placebo).   
For a full list of eligibility criteria, please refer to Section 4.1.1 and Section 4.1.2. 
Investigational Product 
Amgen Investigational Product Dosage and Administration:  Evolocumab and placebo SC 
will be administered using a spring-based prefilled AI/Pen or by 3.5 mL Personal Injector.  Each 
prefilled AI/Pen will contain 1.0 mL deliverable volume; each Personal Injector will contain 3.5 mL 
deliverable volume. 
Evolocumab will be administered at 1 of 2 regimens: 
Evolocumab 140 mg SC Q2W by prefilled AI/Pen or 
Evolocumab 420 mg SC QM by 3.5 mL Personal Injector 
Placebo will be administered at 1 of 2 regimens: 
Placebo SC Q2W by prefilled AI/Pen or 
Placebo SC QM by 3.5 mL Personal Injector. 
Non-Amgen Non-investigational Product Dosage and Administration:  Atorvastatin 20 mg 
will be provided by Amgen. 
Procedures:  Subjects who have signed informed consent will undergo screening procedures 
including laboratory assessments and a 1-time administration of placebo by AI/Pen and will enter 
a lipid stabilization period where they will receive 20 mg atorvastatin daily (QD).  Subjects should 
maintain their diet, any allowed therapy, and exercise regimen throughout screening and study 
participation.  Eligible subjects will be scheduled to return to the study site after ≥ 4 weeks of lipid 
stabilization to initiate IP administration and other day 1 procedures.  For randomization, the site 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 6 of 90 
CONFIDENTIAL 
will contact the interactive voice response system or interactive web response system 
(IVRS/IWRS).  Day 1 is defined as the day of first administration of IP and should occur as close 
as possible or on the day of randomization but not later than 5 days after randomization.  
Subsequent mandatory study visits are at weeks 2, 8, 10, and 12 (EOS for QM subjects).  In 
addition, subjects receiving IP Q2W will be contacted (eg, by phone call) by the study site at 
week 14 (EOS for Q2W subjects) to obtain AE, ADE, and SAE information, if applicable.  For 
subjects randomized to receive IP Q2W, IP will be administered by AI/Pen at the study site on 
day 1, and weeks 2, 8, and 10.  For subjects randomized to receive IP QM, IP will be 
administered by 3.5 mL Personal Injector at the study site on day 1, and week 8.  For other 
administrations of IP by AI/Pen or 3.5 mL Personal Injector, respectively, subjects will have the 
option of self-administration, defined as SC administration of IP by the subject, designee or a 
qualified health care professional in a non-investigator site setting (eg, at home).  The subject 
(or designee, if not a qualified healthcare professional) must have demonstrated competency at 
administration of SC injections before self-administration is permitted: the first self-administered 
dose by the subject (or designee, if not a healthcare professional) must be administered at the 
site under the supervision of a healthcare provider.  Final administration of IP (evolocumab or 
placebo) is at week 8 for QM treatment and week 10 for Q2W treatment.  Subjects who 
discontinue IP for any reason will be asked to continue to return for all other study procedures 
and measurements until the end of the study. 
Vital signs, AEs/ADEs/SAEs, concomitant therapy, evaluation of fasting lipids, dietary instruction, 
physical exam, measuring waist circumference, body height and weight, 12-lead ECGs, other 
laboratory assessments, including assessment for anti-evolocumab antibodies, biomarker sample 
collection, serum pregnancy testing (females of childbearing potential), MMTT, urinalysis, and 
steroid analyte testing will be carried out per the Schedule of Assessment (Table 1) of the 
protocol.  If the subject consented to pharmacogenetics analyses, deoxyribonucleic acid (DNA) 
will be extracted from some of the blood samples.  IP administration by SC injection, if applicable, 
will be done after other procedures have been completed.   
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments (Table 1).   
Statistical Considerations: 
General Considerations 
Efficacy and safety analyses will be performed on the full analysis set (FAS), which includes all 
randomized subjects who have received at least 1 dose of IP.  Analyses will be performed 
separately by dose frequency (Q2W and QM) unless specified otherwise.  Methods of adjusting 
for multiplicity due to testing the superiority of evolocumab in combination with atorvastatin to 
placebo in combination with atorvastatin for both the co-primary and co-secondary efficacy 
endpoints within each dose frequency are provided in Section 10.5.  Subject incidence of 
exploratory endpoint events will be summarized for each treatment group. 
Analyses of Co-Primary Efficacy Endpoints 
To assess the co-primary efficacy endpoints of the mean percent change from baseline at weeks 
10 and 12 and percent change from baseline at week 12 in LDL-C, a repeated measures linear 
effects model will be used in each dose frequency to compare the efficacy of evolocumab in 
combination with atorvastatin and placebo in combination with atorvastatin.  The repeated 
measures model will include terms for treatment group, stratification factors, scheduled visit and 
the interaction of treatment with scheduled visit.  Missing values will not be imputed when the 
repeated measures linear effects model is used.  
Analyses of Co-Secondary Efficacy Endpoints 
The statistical model for the co-secondary efficacy endpoints will be similar to the co-primary 
efficacy endpoints. However, the co-secondary efficacy endpoints of LDL-C target achievement 
will be analyzed using the Cochran-Mantel-Haenszel (CMH) test adjusted by the stratification 
factors. 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 7 of 90 
CONFIDENTIAL 
Safety Analyses 
AEs will be coded using the current version of MedDRA.  Subject incidence of 
treatment-emergent adverse events, serious adverse events, and adverse events leading to 
discontinuation of IP will be tabulated by system organ class and preferred term by randomized 
treatment group.   
Measurements of laboratory parameters, ECGs, and vital signs will be summarized over time. 
Lab shift tables will be provided.  The incidence and percentages of subjects who develop 
anti-evolocumab antibodies (binding and neutralizing) at any time will be tabulated.  
Safety Monitoring 
An independent DMC will formally review the accumulating data from this and other completed 
and ongoing studies with evolocumab to ensure there is no avoidable increased risk for harm to 
subjects.  Analyses for the DMC will be provided by a group which is external to Amgen. 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen 
Data Element Standards 
Version / Date:  
Version 2.0 / 12 October 2012 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 8 of 90 
CONFIDENTIAL 
Study Design and Treatment Schema 
*Only subjects receiving IP Q2W
**Phone call for AEs/ADEs/SAEs for  
  subjects receiving SC IP 
  administration Q2W  


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 9 of 90 
CONFIDENTIAL 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ADE 
Adverse device effect 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT (SGPT) 
Alanine aminotransferase (serum glutamic-pyruvic transaminase) 
ApoA1 
Apolipoprotein A-1 
ApoB48 
Apolipoprotein B48 
ApoB100 
Apolipoprotein B100 
AST (SGOT) 
Aspartate aminotransferase (serum glutamic-oxaloacetic 
transaminase) 
BAS 
Bile acid sequestrants 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CABG 
Coronary artery bypass graft 
CAS 
Completer analysis set 
CBC 
Complete blood count 
CK 
Creatine kinase 
CHD 
Coronary heart disease 
CRP 
C-reactive protein 
CTCAE 
NCI Common Terminology Criteria for AEs 
CTT 
Cholesterol Treatment Trialists 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
DBP 
Diastolic blood pressure 
DHA 
Docosahexaenoic acid 
DILI 
Drug-induced liver injury 
DMC 
Data monitoring committee (Efficacy and Safety Evaluation 
Committee) 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate;  eGFR will be calculated by the 
central laboratory and provided to the investigator. 
EDC 
Electronic data capture 
End of study / Primary 
completion date 
The end of the study / primary completion date is defined as the last 
day on which a randomized subject completes the end-of-study visit 
or phone follow-up (week 12 for subjects on QM IP administration; 
week 14 for subjects on Q2W IP administration) or terminates the 
study early, whichever is later 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 10 of 90 
CONFIDENTIAL 
Abbreviation or Term 
Definition/Explanation 
End of study for individual 
subject 
Defined as the last day that protocol-specified procedures are 
conducted for an individual subject or day the subject ends study 
early.  Subjects will complete the study at week 12 (subjects on QM 
IP administration) or week 14 (subjects on Q2W IP administration).  
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 the individual subject) 
EPA 
Eicosapentaenoic acid 
FAS 
Full analysis set 
FSH 
Follicle-stimulating hormone 
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 
IFU 
Instructions for Use 
IM 
Intramuscular 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IP 
Investigational product 
IPIM 
Investigational Product Instruction Manual 
IVRS/IWRS 
Interactive Voice Response System / Interactive Web Response 
System 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
LDL-C 
Low-density lipoprotein cholesterol 
LDLR 
LDL receptor 
LH 
luteinizing hormone 
LLN 
Lower limit of normal 
LOF 
Loss of function 
Lp(a) 
Lipoprotein(a) 
MedDRA 
Medical dictionary for regulatory activities 
Monthly 
Defined as every 4 weeks with a window of ± 3 days.  For practical 
considerations, study visits are scheduled based on a weekly 
calendar with a window of +/- 3 days for each visit, thus dosing 
intervals are allowed to be up to 31 days for the QM regimen. 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 11 of 90 
CONFIDENTIAL 
Abbreviation or Term 
Definition/Explanation 
MMTT 
Mixed meal tolerance test 
NASH 
Nonalcoholic steatohepatitis 
PCI 
Percutaneous coronary intervention 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PO 
Oral administration 
QM 
QM is defined as every 4 weeks with a window of ± 3 days for each 
visit, thus dosing intervals are allowed to be up to 31 days for the 
QM regimen. 
Q2W 
Q2W is defined as every 2 weeks with a window of ± 3 days for each 
visit, thus dosing intervals are allowed to be up to 17 days for the 
Q2W regimen. 
QD 
Each day 
RBC 
Red blood cells 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 
SD 
Standard deviation 
Source Data 
Information from an original record or certified a copy of the original 
record containing patient information for use in clinical research.  
The information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained 
in source documents (original records or certified copies).  
(ICH Guideline (E6)).  Examples of source data include Subject ID, 
Randomization ID, and Stratification Value. 
Study day 1 
Defined as the first day that protocol-specified subcutaneous (SC) 
investigational product is administered to the subject 
TBL 
Total bilirubin 
TIA 
Transient ischemic attack 
TNF 
Tumor necrosis factor 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper limit of normal 
VLDL-C 
Very low-density lipoprotein cholesterol 
w/v 
Weight/volume (grams per 100 milliliter) 
WBC 
White blood cell 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 12 of 90 
CONFIDENTIAL 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................. 3 
Study Design and Treatment Schema .............................................................................. 8 
Study Glossary .................................................................................................................. 9 
1.
OBJECTIVES ......................................................................................................... 16
1.1 
Primary ....................................................................................................... 16 
1.2 
Secondary .................................................................................................. 16 
1.3 
Tertiary ....................................................................................................... 16 
1.4 
Exploratory ................................................................................................. 16 
2.
BACKGROUND AND RATIONALE ........................................................................ 17
2.1 
Cardiovascular Disease and Diabetes ....................................................... 17 
2.2 
Current Therapies for Reducing the Risk of Cardiovascular 
Disease Events ........................................................................................... 19 
2.3 
Evolocumab Background ............................................................................ 20 
2.3.1 
Mechanism of Action and Therapeutic Potential ........................ 20 
2.3.2 
Clinical Experience:  Efficacy ..................................................... 21 
2.3.3 
Clinical Experience:  Safety ........................................................ 22 
2.4 
Statin Background ...................................................................................... 23 
2.5 
Rationale .................................................................................................... 25 
2.6 
Clinical Hypotheses .................................................................................... 26 
3.
EXPERIMENTAL PLAN ......................................................................................... 26
3.1 
Study Design .............................................................................................. 26 
3.2 
Number of Sites .......................................................................................... 28 
3.3 
Number of Subjects .................................................................................... 28 
3.4 
Replacement of Subjects ............................................................................ 28 
3.5 
Estimated Study Duration ........................................................................... 28 
3.5.1 
Study Duration for Subjects ........................................................ 28 
3.5.2 
End of Study ............................................................................... 28 
4.
SUBJECT ELIGIBILITY .......................................................................................... 29
4.1 
Inclusion and Exclusion Criteria ................................................................. 29 
4.1.1 
Inclusion Criteria ......................................................................... 29 
4.1.2 
Exclusion Criteria ........................................................................ 29 
5.
SUBJECT ENROLLMENT ..................................................................................... 32
5.1 
Randomization/Treatment Assignment ...................................................... 32 
5.2 
Site Personnel Access to Individual Treatment Assignments .................... 33 
6.
TREATMENT PROCEDURES ............................................................................... 33
6.1 
Classification of Products and/or Medical Devices ..................................... 33 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 13 of 90 
CONFIDENTIAL 
6.2 
Investigational Product ............................................................................... 33 
6.2.1 
Evolocumab (Amgen Investigational Product) ............................ 33 
6.2.1.1 
Dosage, Administration, and Schedule .................... 34 
6.2.1.2 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 35 
6.2.2 
Atorvastatin (Non-Amgen Non-investigational Product) ............. 36 
6.2.2.1 
Dosage, Administration, and Schedule .................... 36 
6.2.2.2 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 36 
6.3 
Non-investigational Products ...................................................................... 36 
6.4 
Withholding of Investigational Product or Atorvastatin due to 
Elevation of Creatine Kinase (CK) .............................................................. 37 
6.5 
Hepatotoxicity Stopping and Rechallenge Rules ........................................ 37 
6.5.1 
Criteria for Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required 
Therapies due to Potential Hepatotoxicity .................................. 37 
6.5.2 
Criteria for Conditional Withholding of Amgen 
Investigational Product and Other Protocol-required 
Therapies due to Potential Hepatotoxicity .................................. 38 
6.5.3 
Criteria for Rechallenge of Amgen Investigational 
Product and Other Protocol-required Therapies After 
Potential Hepatotoxicity .............................................................. 39 
6.6 
Concomitant Therapy, Physical Exercise, and Diet .................................... 39 
6.7 
Medical Devices ......................................................................................... 39 
6.8 
Product Complaints .................................................................................... 40 
6.9 
Excluded Treatments and/or Procedures During Study Period .................. 41 
7.
STUDY PROCEDURES ......................................................................................... 41
7.1 
Schedule of Assessments .......................................................................... 41 
7.2 
General Study Procedures ......................................................................... 44 
7.2.1 
Screening, Lipid Stabilization, and Randomization .................... 46 
7.2.1.1 
Screening Placebo Injection .................................... 46 
7.2.1.2 
Screening and Lipid Stabilization ............................. 46 
7.2.1.3 
Randomization ......................................................... 48 
7.2.1.4 
Retesting .................................................................. 48 
7.2.1.5 
Rescreening ............................................................. 48 
7.2.1.6 
Screen Fail ............................................................... 48 
7.2.2 
Treatment ................................................................................... 48 
7.2.3 
Safety Follow-up Visit(s)/End of Study Visit ............................... 50 
7.3 
Antibody Testing Procedures ..................................................................... 50 
7.4 
Biomarker Development ............................................................................. 50 
7.5 
Pharmacogenetic Studies ........................................................................... 51 
7.6 
Sample Storage and Destruction ................................................................ 51 


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7.7 
Standardization of Study Procedures ......................................................... 53 
7.7.1 
Measurement of Vital Signs ........................................................ 53 
7.7.2 
Waist Circumference .................................................................. 53 
7.7.3 
Subject Compliance With Atorvastatin Dosing ........................... 53 
7.7.4 
Electrocardiograms ..................................................................... 54 
7.7.5 
Lipid Measurements ................................................................... 54 
7.7.6 
Mixed Meal Tolerance Test (All Subjects) .................................. 55 
7.7.7 
Mixed Meal Tolerance Test Extended Timepoints 
Substudy .................................................................................... 55 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 56 
8.1 
Subject’s Decision to Withdraw .................................................................. 56 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subject’s Participation Prior to Study Completion ...................................... 56 
8.3 
Reasons for Removal From Screening, Lipid Stabilization, 
Treatment, or Study .................................................................................... 57 
8.3.1 
Reasons for Removal From Screening or Lipid 
Stabilization ................................................................................ 57 
8.3.2 
Reasons for Removal From Treatment ...................................... 57 
8.3.3 
Reasons for Removal From Study ............................................. 57 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 57 
9.1 
Adverse Events .......................................................................................... 57 
9.1.1 
Definition of Adverse Events ...................................................... 57 
9.1.2 
Definition of Serious Adverse Events ......................................... 58 
9.2 
Reporting of Adverse Events ...................................................................... 59 
9.2.1 
Reporting Procedures for Adverse Events That do not 
Meet Serious Criteria .................................................................. 59 
9.2.2 
Reporting Procedures for Serious Adverse Events .................... 60 
9.3 
Pregnancy and Lactation Reporting ........................................................... 62 
10. 
STATISTICAL CONSIDERATIONS ....................................................................... 62 
10.1 
Study Endpoints, Analysis Sets, and Covariates ........................................ 62 
10.1.1 
Study Endpoints ......................................................................... 62 
10.1.1.1 
Co-primary Efficacy Endpoints ................................. 62 
10.1.1.2 
Co-secondary Efficacy Endpoints ............................ 63 
10.1.1.3 
Co-tertiary Efficacy Endpoints .................................. 63 
10.1.1.4 
Exploratory Endpoints .............................................. 63 
10.1.1.5 
Safety Endpoints ...................................................... 64 
10.1.1.6 
Pharmacokinetics Endpoints .................................... 64 
10.1.2 
Analysis Sets .............................................................................. 64 
10.1.3 
Covariates and Subgroups ......................................................... 64 
10.2 
Sample Size Considerations ...................................................................... 65 
10.3 
Access to Individual Subject Treatment Assignments by Amgen 
or Designees .............................................................................................. 66 


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10.4 
Planned Analyses ....................................................................................... 66 
10.4.1 
Data Monitoring Committee (DMC) ............................................ 66 
10.4.2 
Primary Analysis ......................................................................... 66 
10.5 
Planned Methods of Analysis ..................................................................... 67 
10.5.1 
Co-primary Efficacy Endpoints ................................................... 68 
10.5.2 
Co-secondary Efficacy Endpoints ............................................... 69 
10.5.3 
Safety Endpoints ........................................................................ 69 
11. 
REGULATORY OBLIGATIONS ............................................................................. 70 
11.1 
Informed Consent ....................................................................................... 70 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 71 
11.3 
Subject Confidentiality ................................................................................ 71 
11.4 
Investigator Signatory Obligations .............................................................. 72 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................... 72 
12.1 
Protocol Amendments and Study Termination ........................................... 72 
12.2 
Study Documentation and Archive ............................................................. 73 
12.3 
Study Monitoring and Data Collection ........................................................ 74 
12.4 
Investigator Responsibilities for Data Collection ........................................ 75 
12.5 
Language.................................................................................................... 75 
12.6 
Publication Policy ....................................................................................... 75 
12.7 
Compensation ............................................................................................ 76 
13. 
REFERENCES ....................................................................................................... 77 
14. 
APPENDICES ........................................................................................................ 82 
List of Tables 
Table 1.  Schedule of Assessments ................................................................................ 42 
Table 2.  Analyte Listing .................................................................................................. 45 
Table 3.  Standardized Mixed Meal ................................................................................. 55 
List of Appendices 
Appendix A.  Additional Safety Assessment Information ................................................ 83 
Appendix B.  Sample eSerious Adverse Event Contingency Reporting Form ................ 85 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................... 88 
Appendix D.  Lipid Modifying Background Therapy Intensity .......................................... 90 


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1. 
OBJECTIVES 
1.1 
Primary 
To evaluate the effect of 12 weeks of subcutaneous (SC) evolocumab every 2 weeks 
(Q2W) and monthly (QM), in combination with oral (PO) atorvastatin daily (QD), 
compared with placebo Q2W and QM, in combination with PO atorvastatin QD, on 
percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in diabetic 
subjects with hyperlipidemia or mixed dyslipidemia. 
1.2 
Secondary 
• 
to evaluate the safety and tolerability of SC evolocumab Q2W and QM in 
combination with atorvastatin QD, compared with placebo Q2W and QM, in 
combination with atorvastatin QD, in diabetic subjects with hyperlipidemia or mixed 
dyslipidemia 
• 
to assess the effects of 12 weeks of SC evolocumab Q2W and QM in combination 
with atorvastatin QD, compared with placebo Q2W and QM, in combination with 
atorvastatin QD, on change from baseline in LDL-C, and percent change from 
baseline in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein 
B100 (ApoB100), total cholesterol, total cholesterol/HDL-C ratio, 
ApoB100/Apolipoprotein A-1 (ApoA1) ratio, lipoprotein(a) [Lp(a)], triglycerides, very 
low-density lipoprotein cholesterol (VLDL-C), and HDL-C in diabetic subjects with 
hyperlipidemia or mixed dyslipidemia 
• 
to assess the effects of 12 weeks of SC evolocumab Q2W and QM in combination 
with atorvastatin QD, compared with placebo Q2W and QM, in combination with 
atorvastatin QD, on percent of subjects attaining LDL-C < 70 mg/dL (1.8 mmol/L) in 
diabetic subjects with hyperlipidemia or mixed dyslipidemia 
1.3 
Tertiary 
• 
to assess the treatment effects of 12 weeks SC evolocumab Q2W and QM in 
combination with atorvastatin QD, compared with placebo Q2W and QM, in 
combination with atorvastatin QD, on percent change from baseline of ApoA1 in 
diabetic subjects with hyperlipidemia or mixed dyslipidemia 
• 
to characterize evolocumab PK exposure 
1.4 
Exploratory 
• 
to describe the effects over time of SC evolocumab Q2W and QM in combination 
with atorvastatin QD, compared with placebo Q2W and QM, in combination with 
atorvastatin QD, on change from baseline in proprotein convertase subtilisin/kexin 
type 9 (PCSK9) levels and on change from baseline and percent change from 
baseline of LDL-C, total cholesterol, non-HDL-C, ApoB100, total cholesterol/HDL-C 
ratio, ApoB100/ApoA1 ratio, triglycerides, VLDL-C, HDL-C, ApoA1, and Lp(a), and 
categorical change from baseline in high sensitivity C-reactive protein (hsCRP) in 
diabetic subjects with hyperlipidemia or mixed dyslipidemia 
• 
to explore the effect of SC evolocumab Q2W and QM in combination with 
atorvastatin QD, compared with placebo Q2W and QM, in combination with 
atorvastatin QD, on fasting and postprandial plasma laboratory parameters of 
interest 


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• 
to investigate the relationship between novel and established biochemical 
cardiovascular and lipid biomarkers and effects of evolocumab 
• 
to investigate potential correlations of study data including the subject response to 
evolocumab with genetic variation in markers of PCSK9 signaling, low-density 
lipoprotein receptor (LDLR) turnover, cholesterol metabolism, inflammation, and 
plaque stability in subjects consenting to the optional pharmacogenetics analysis 
• 
to explore evolocumab population pharmacokinetics in diabetic subjects 
• 
to explore evolocumab exposure/response relationships in diabetic subjects 
2. 
BACKGROUND AND RATIONALE 
2.1 
Cardiovascular Disease and Diabetes 
Collectively, cardiovascular diseases (CVD) are regarded as a world-wide epidemic; and 
although CVD mortality has declined (primarily in developed countries) over the last two 
decades, it still represents the leading cause of death and disability in the world, as well 
as over 10% of the global total disease burden.  In 2008, the WHO estimated 57 million 
deaths world-wide, of which 36 million were due to non-communicable causes.  CVD 
accounted for over 17 million of these deaths, nearly 80% of which were due to heart 
attacks and strokes alone (responsible for 7.3 million and 6.2 million deaths, 
respectively). 
The facts below illustrate the magnitude of the problem in the US (Roger et al, 2011): 
 (i) In excess of one in three individuals in the US has some form of CVD. Coronary 
heart disease (CHD) affects almost 17 million Americans. Of those almost 8 million 
suffer from myocardial infarction; nearly 10 million from angina pectoris; nearly 6 million 
from heart failure; and 6 to 7 million from stroke.  The aging of the population and the 
explosive increase in the prevalence of obesity and type 2 diabetes and their related 
complications (hypertension, hyperlipidemia, and atherosclerotic vascular disease) will 
only serve to increase the prevalence of CVD. 
(ii) CVD claims more lives each year than cancer, chronic lower respiratory disease, and 
accidents combined. Over 2200 Americans die of CVD each day.  Mortality data show 
that CVD accounted for more than one in three deaths (over 800,000) in the United 
States.  Since 1900, CVD has been the number 1 killer in the United States every year, 
with the exception of 1 year only (1918). 
(iii) CHD caused approximately 1 of every 6 deaths in the United States.  CHD mortality 
was slightly more than 400,000.  It is estimated that each year 785,000 and 
470,000 Americans will have a new and recurrent acute coronary syndrome, 


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respectively.  An additional 195,000 silent first myocardial infarctions are estimated to 
occur each year. 
(iv) Approximately 795,000 people experience a new or recurrent stroke each year. 
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. 
The situation in the European Union (EU) is similar.  CHD by itself remains the single 
most common cause of deaths in the EU (Allender et al, 2008).  Each year CVD causes 
over 4.3 million deaths in Europe and over 2.0 million deaths in the EU.  CVD causes 
nearly half of all deaths in Europe (48%) and in the EU (42%). 
CVD remains a significant cause of morbidity in non-Western regions as well.  For 
example, in China, heart attacks and strokes account for the number 1 and 3 causes of 
death among men and women combined, respectively (He et al, 2005).  China now 
ranks among the top 10 countries in the world for total incidence of CVD, thus 
representing a significant and growing public health problem (Liu et al, 2007).  Similar 
trends have been noted in other Asian countries, India, and Brazil (Iso, 2011; 
Celermajer et al, 2012; Mansur et al, 2010).  These trends are thought to result from 
growing urbanization and industrialization which  has resulted in a rise in cardiovascular 
risk factors such as glucose intolerance, dyslipidemia, and hypertension 
(Ueshima et al, 2008; Khoo, 2003). Importantly, elevated blood glucose has been 
estimated to contribute to 22% of coronary heart disease deaths and 16% of stroke 
deaths (World Health Organization, 2009). 
Type 2 diabetes mellitus is a major independent risk factor for cardiovascular 
disease-coronary heart disease (CHD) and stroke – and conditions such as 
hypertension and dyslipidemia frequently coexist with diabetes (American Diabetes 
Association, 2005).  Most diabetic patients have an approximately 2-fold increased level 
of cardiovascular risk compared to nondiabetics, even when established CHD is absent. 
Patients with type 2 diabetes also have an increased prevalence of lipid abnormalities 
contributing to the increased risk of cardiovascular disease (Arca 2007).  Therefore, 
treatment guidelines recommend aggressive lipid treatment goals for patients with 
diabetes (eg, Brunzell et al, 2008; Grundy et al, 2004; Reiner et al, 2011; Chinese 
Society of Cardiology, 2011). 


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A direct correlation between dyslipidemia and cardiovascular-related deaths has been 
demonstrated across several global regions (Menotti et al, 2008; Imano et al, 2011; 
Yang et al, 2012).  Because dyslipidemia is a major modifiable risk for the development 
of CVD, therapies for hyperlipidemia/dyslipidemia can translate into an opportunity for 
significantly reducing cardiovascular morbidity and mortality throughout different 
populations and world regions. 
2.2 
Current Therapies for Reducing the Risk of Cardiovascular Disease 
Events 
Extensive clinical trial data in both primary and secondary prevention demonstrate that 
the reduction in total cholesterol, non-high-density lipoprotein cholesterol (HDL-C), and 
most importantly, LDL-C, through pharmacological therapies, lowers the risk of CVD 
events (Kannel et al, 1974; Kannel, 1995; Kannel et al, 1979). To decrease the burden 
of CVD, over 50 million patients in the United States, Europe, and Asia are currently 
treated with dyslipidemia therapies (World Health Organization, 2011). 
Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are currently the 
treatment of choice for hypercholesterolemia (Chinese Society of Cardiology, 2011; 
Teramoto et al, 2007; Grundy et al, 2004; Reiner et al, 2011). As in other regions of the 
world, in Asian countries higher potency statin use has been associated with lower 
LDL-C levels and higher proportions of patients achieving their LDL-C goals 
(Kim et al, 2008).  
Emerging data indicate that more aggressive treatment of hypercholesterolemia is 
associated with even lower risk for CVD events (Baigent et al, 2010; LaRosa et al, 2005; 
Cannon et al, 2004); data derived from primary and secondary prevention studies in 
Asian populations for example are consistent with these findings (Teramoto, 2011; 
Hiro et al, 2009; Sato et al, 2008; Nakamura et al, 2006; Koizumi et al, 2002). A recent 
Cholesterol Treatment Trialists’ (CTT) Collaboration meta-analysis 
(CTT Collaboration, 2010), which included 21 randomized controlled trials of statin 
versus control involving nearly 170,000 patients, showed that for every ~ 1 mmol/L 
reduction in LDL-C, there was an approximately 20% reduction in the risk of major 
vascular events (coronary death, non-fatal myocardial infarction, coronary 
revascularization, or stroke). Importantly, this meta-analysis, which evaluated 5 trials that 
compared more versus less intensive statin therapy, did not find a LDL-C threshold; 
additional vascular risk reduction is possible in patients with low LDL-C. 


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Despite achieving their LDL-C goals, approximately two-thirds of patients on lipid 
reduction therapy still have cardiovascular events (Libby, 2005).  While it is unlikely that 
this residual risk is entirely due to LDL-C concentrations above the goal articulated in 
recent treatment guidelines (NCEP, 2002; Grundy et al, 2004), CTT Collaboration data 
suggest that novel agents that are capable of providing additional reductions in LDL-C 
above what is possible with statins may further reduce cardiovascular morbidity and 
mortality (CTT Collaboration, 2010). Furthermore, novel therapies are needed for 
individuals who are intolerant to statin therapy and cannot achieve their respective 
LDL-C goals (Bruckert et al, 2005; Franc et al, 2003). 
Non-statin treatment options are currently available to lower LDL-C but their potency is 
limited, such that LDL-C reductions occur on the order of 15% to 20%.  Considering the 
remaining cardiovascular risk despite the availability of statin therapy, and given that 
non-statin treatment options have modest efficacy (ezetimibe, bile acid sequestrants 
[BAS], plant stanols) and/or are poorly tolerated (niacin and BAS), there is an unmet 
medical need for a potent, effective non-statin agent that will get a significant proportion 
of patients to LDL-C goal and further reduce cardiovascular risk. This need is especially 
evident among individuals at high risk for future cardiovascular events, for example 
those who have already suffered from a myocardial infarction or stroke or individuals 
with diabetes. Based on the current data, evolocumab, a fully human monoclonal 
antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), may fulfill this need 
and may provide an important addition to the treatment of hyperlipidemia/dyslipidemia 
for individuals with hyperlipidemia, including individuals with concomitant diabetes. 
2.3 
Evolocumab Background 
2.3.1 
Mechanism of Action and Therapeutic Potential 
Recycling of the hepatic cell surface 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 
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 


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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). 
Evolocumab 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 evolocumab are contained in the 
AMG 145 Investigator’s Brochure.  Evolocumab binds to human, monkey, and hamster 
PCSK9 with high affinity (Kd < 100 pM).  Evolocumab caused a dose-dependent 
inhibition of PCSK9 binding to the LDLR and of PCSK9-mediated reduction in 
low-density lipoprotein (LDL) uptake in human hepatocellular carcinoma cell line 
(HepG2) cells in culture.  In cynomolgus monkeys and in hamsters, in vivo 
administration of evolocumab resulted in reduced serum lipoprotein cholesterol levels in 
a dose-dependent manner.  Based on a comprehensive package of PK, 
pharmacodynamics (PD), and toxicology studies (AMG 145 Investigator’s Brochure), 
a program to develop evolocumab as a treatment for dyslipidemia was initiated. 
2.3.2 
Clinical Experience:  Efficacy 
In a single-dose, phase 1a study (20080397), complete suppression of circulating 
PCSK9 was observed at doses ≥ 70 mg SC, which correlated well with the effects seen 
on circulating LDL-C).  Following a SC dose, PCSK9 suppression was rapid and was 
observed at the first measured time point after administration (4 hours). 
In the ascending, multiple-dose, phase 1b study (20080398), regimens of 140 mg Q2W, 
280 mg Q2W, and 420 mg Q4W were associated with near complete suppression of 
PCSK9, and the degree of PCSK9 suppression correlated well with the effects seen on 


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circulating LDL-C (see AMG 145 Investigator’s Brochure).  Following a SC dose, PCSK9 
suppression was rapid and the time course of suppression was consistent with that 
observed following a single dose (Study 20080397).  Subjects receiving evolocumab 
with high-dose statins had a similar degree of PCSK9 suppression as subjects receiving 
evolocumab with lower doses of statins.  Subjects with heterozygous familial 
hypercholesterolemia who received evolocumab exhibited a similar degree of PCSK9 
suppression as subjects without heterozygous familial hypercholesterolemia who 
received evolocumab (Dias et al, 2012). 
Findings from 4 completed phase 2 studies (20101154, 20101155, 20090158, and 
20090158) and ongoing results from phase 2 open-label extension Study 20110110 
demonstrated that evolocumab is effective in various patient populations 
(Giugliano et al, 2012; Koren et al, 2012; Sullivan et al, 2012; Raal et al, 2012).  
Treatment with evolocumab as monotherapy or in combination with statins (or other lipid 
lowering therapies) was effective in lowering serum concentrations of LDL-C, total 
cholesterol, ApoB100, VLDL-C, triglycerides, Lp(a), non-HDL-C, total cholesterol/HDL-C 
ratio, ApoB100/ApoA1 ratio, and PCSK9, and in increasing serum concentrations of 
HDL-C and ApoA1, in subjects with hyperlipidemia or mixed dyslipidemia (including 
heterozygous familial hypercholesterolemia and statin-intolerant subjects).  Of the 
6 evolocumab doses tested in phase 2, SC doses of 140 mg Q2W and 420 mg Q4W 
resulted in the greatest effects on lipid parameters and produced comparable results 
over the dosing interval. 
Sensitivity analyses and non-parametric analyses confirmed that the primary endpoint 
analysis of efficacy was robust.  Subgroup analyses of the primary efficacy endpoint of 
percent change in LDL-C from baseline to week 12 demonstrated consistent treatment 
effects across all subgroups including sex, presence or absence of diabetes, presence 
or absence of metabolic syndrome, screening LDL-C < or ≥ 130 mg/dL, baseline 
triglyceride level, age (< 65 or ≥ 65 years), intensive statin use at baseline (yes/no), and 
race. 
For further details on evolocumab efficacy results refer to the 
AMG 145 Investigator’s Brochure.  
2.3.3 
Clinical Experience:  Safety 
Adverse events reported in completed phase 2 clinical studies (20101154, 20101155, 
20090158, and 20090159) or in the open-label phase 2 study (20110110) demonstrate 


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that evolocumab has an acceptable benefit:risk profile up to the highest dose tested 
(420 mg).  Specifically: 
• 
In completed phase 2 studies, subjects treated with evolocumab had a higher overall 
incidence of treatment emergent adverse events compared with placebo (57% and 
48%, respectively); however, there was no relationship between the dose or dosing 
frequency of evolocumab and the incidence of treatment emergent adverse events.   
• 
In completed phase 2 studies, adverse events with a subject incidence of ≥ 2% in the 
evolocumab group and exceeding the placebo incidence by ≥ 1% were as follows 
(evolocumab, placebo): nasopharyngitis (8.2%, 6.6%), myalgia (2.7%, 1.0%), and 
nausea (2.7%, 1.7%). 
• 
In completed phase 2 studies, the overall incidence of serious adverse events was 
similar between the evolocumab and placebo groups (2.1% and 1.3%, respectively).  
No individual serious adverse event was reported for > 2 (0.2%) subjects treated with 
evolocumab in these studies. 
• 
There was a higher incidence of creatine kinase elevations in the evolocumab group 
compared with placebo.  These elevations were generally associated with obvious 
precipitating events in the form of strenuous physical activity.  All of these events 
were transient (1 laboratory abnormality followed by normal laboratory values), 
resolved spontaneously  (by next laboratory assessment), and did not lead to 
discontinuation of investigational product (IP). 
For further details on evolocumab safety results refer to the 
AMG 145 Investigator’s Brochure.  
Refer to the specific section of the AMG 145 Investigator’s Brochure for additional 
information related to the physical, chemical, and pharmaceutical properties and 
formulation(s). 
2.4 
Statin Background 
In this study, evolocumab in combination with 20 mg QD atorvastatin will be compared 
with placebo in combination with 20 mg QD atorvastatin.  The clinical benefits of statin 
treatment in primary prevention as well as secondary prevention have been documented 
in multiple trials (Weart and Hogan, 2011).  A recent meta-analysis confirmed a 
beneficial effect on all-cause mortality as well as combined fatal and non-fatal 
cardiovascular endpoints in primary prevention (Taylor et al, 2011). 
Several large-scale clinical trials have assessed the efficacy of atorvastatin in the 
primary and secondary prevention of cardiovascular events in patients with diabetes 
mellitus and/or metabolic syndrome (Arca, 2007). 
A study conducted specifically in patients with type 2 diabetes found atorvastatin to be 
safe and efficacious in reducing the risk of first cardiovascular disease events, including 
stroke (Colhoun et al, 2004).  The study was terminated 2 years earlier than expected 


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because the prespecified early stopping rule for efficacy had been met. Median duration 
of follow-up was 3.9 years.  Risk rate reduction for having at least one major 
cardiovascular event was 37% [95% CI -52 to -17], p=0.001).  Assessed separately, 
acute coronary heart disease events were reduced by 36% (-55 to -9), coronary 
revascularizations by 31% (-59 to 16), and rate of stroke by 48% (-69 to -11). 
Atorvastatin reduced the death rate by 27% (-48 to 1, p=0.059).  No excess of adverse 
events was noted in the atorvastatin group.  These results are similar to the results of 
the ASCOT-LLA trial (Sever et al, 2005) which included 2532 hypertensive diabetic 
patients, where atorvastatin (vs placebo) reduced the relative risk of all cardiovascular 
events and procedures by 23% (p = 0.036) and the Heart Protection Study (HPS) where 
simvastatin reduced the relative risk (vs placebo) of major cardiovascular events by 33% 
(p = 0.0003) over 5 years (Collins et al, 2003). 
In secondary prevention, substudies of the GREACE (GREek Atorvastatin and 
Coronary-heart-disease Evaluation), TNT (Treating to New Targets) and PROVE-IT 
(PRavastatin Or atorVastatin Evaluation and Infection Therapy) trials reported results for 
the approximately 15-25% of study participants who had diabetes (Athyros et al, 2003; 
Shepherd et al, 2006; Ahmed et al, 2006). In the GREACE substudy, atorvastatin 
(vs physicians' standard care) significantly reduced the relative risk of total mortality by 
52% (p = 0.049), coronary mortality by 62% (p = 0.042), coronary morbidity by 59% 
(p < 0.002) and stroke by 68% (p = 0.046). In the TNT substudy, incidence of the 
primary endpoint was significantly lower in diabetic patients treated with atorvastatin 
80 mg/day rather than 10 mg/day (13.8% vs 17.9%; relative risk 0.75; p = 0.026). In the 
PROVE-IT substudy, a significantly lower incidence of acute cardiac events was 
reported for atorvastatin versus pravastatin recipients (21.1% vs 26.6%; p = 0.03) and, 
therefore, an absolute risk reduction of 5.5% was associated with atorvastatin therapy. 
Reported adverse events arising from statin therapy are infrequent and rarely severe 
(Weart and Hogan, 2011).  Though some studies have suggested an association 
between lower LDL cholesterol levels and hemorrhagic stroke or intracranial 
hemorrhage (Iso et al, 1989; Collins et al, 2004; Amarenco et al, 2006), several 
contemporary studies utilizing high doses of potent statins as well as two large 
meta-analyses have not observed this association (Waters et al, 2006; 
CTT Collaboration, 2010; Hackam et al, 2011).  Regarding other safety profile data 
available for statins, a pooled analysis of 49 atorvastatin trials demonstrated that the 
overall safety profiles for the 10- and 80-mg/day doses are comparable, with the 


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exception of a slightly increased rate of elevations in levels of the hepatic enzymes 
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) for the higher 
dose (Newman et al, 2006).  The most common adverse effects experienced by patients 
taking statins are those associated with the musculoskeletal system, and these effects 
occur with all statins.  Symptoms are usually restricted to muscle pain, weakness and/or 
cramps.  Myalgia, which according to various definitions may include some or all of 
these relatively minor symptoms, typically affects 5% to 10% of patients receiving statins 
(Weart and Hogan, 2011). 
Refer to the regional manufacturer package insert for additional information. 
2.5 
Rationale 
It is anticipated that evolocumab may be used in diabetic individuals who cannot achieve 
their LDL-C goals despite the use of statin therapy or are intolerant to statin therapy 
(Bruckert et al, 2005; Franc et al, 2003). Therefore, it is important to understand the 
safety and efficacy of evolocumab on the background of statin therapy in diabetic 
patients. 
Because lipid levels may vary with diet and body weight it is not possible to assess the 
true effect of evolocumab on lipid parameters as well as its safety and tolerability without 
a double-blind, randomized placebo-controlled comparator arm. 
The statin background therapy chosen for this study is atorvastatin which is also used in 
other evolocumab phase 3 trials including FOURIER, a large cardiovascular (CV) 
outcomes study.  Atorvastatin has been selected because of the robust clinical 
outcomes data that supports its use as well as the fact that it has been studied in a  
dedicated Diabetes cardiovascular outcomes trial (Colhoun et al, 2004). Atorvastatin 
also has a favorable safety and tolerability profile in comparison to other statins 
(SEARCH Study Collaborative Group 2007; Olyaei et al, 2011, Cannon et al, 2004)  
Based on regional medical practices, the 20 mg dose of atorvastatin was included in this 
study.  It is a frequently used dose and renders a significant proportion of the maximal 
LDL-C reduction available with higher doses (LIPITOR [atorvastatin calcium] package 
insert). 
The percent change from baseline in LDL-C has been chosen as the primary 
assessment for this study because current guidelines focus on LDL-C as a target for 
therapy.  There is an extensive body of data from interventional studies and 
epidemiological evidence demonstrating a strong causal relationship between serum 


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LDL-C and the risk of CHD.  These data also support the relationship with other clinical 
manifestations of atherosclerosis such as cerebrovascular disease (stroke) or peripheral 
vascular disease.  These relationships are present over a broad range of LDL-C levels. 
Non-HDL cholesterol (non-HDL-C), ApoB100, total cholesterol, the ratio of 
total cholesterol/HDL-C, and the ratio of ApoB100/ApoA1 have been included as 
secondary efficacy endpoints because these markers are known and/or useful markers 
of cardiovascular risk under certain circumstances and have been identified in prior 
studies to be affected by treatment with evolocumab.  Some of these measures may be 
employed as future targets for lipid lowering therapy. 
Triglycerides and HDL-C were included because subjects with diabetes frequently have 
low HDL and/or high triglycerides and because data from Amgen’s phase 1 and phase 
2 studies (Dias et al, 2012; Giugliano et al, 2012; Koren et al, 2012; Sullivan et al, 2012; 
Raal et al, 2012) suggest lowering of triglycerides and raising of HDL-C may be effects 
of treatment with evolocumab.  In addition, triglycerides and HDL-C are independent risk 
factors for cardiovascular disease (Austin et al, 1998; Sarwar et al, 2007). 
2.6 
Clinical Hypotheses 
The primary hypothesis is that both dosing regimens of SC evolocumab (140 mg Q2W 
and 420 mg QM) in combination with atorvastatin QD will be well tolerated and will result 
in greater reduction of LDL-C, defined as mean percent change from baseline at weeks 
10 and 12 and percent change from baseline at week 12, compared with placebo (Q2W 
and QM) in combination with atorvastatin QD in diabetic subjects with hyperlipidemia or 
mixed dyslipidemia. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a phase 3, multicenter, double-blind, randomized, stratified, placebo-controlled 
study of evolocumab for diabetic subjects with hyperlipidemia or mixed dyslipidemia.  
After undergoing screening procedures, including laboratory assessments and a 
screening placebo injection, approximately 900 subjects meeting eligibility criteria and 
completing at least 4 weeks of lipid stabilization on atorvastatin 20 mg QD will be 
randomized 2:2:1:1 into the following treatment arms:  
• 
evolocumab SC 140 mg Q2W and atorvastatin PO 20 mg QD 
• 
evolocumab SC 420 mg QM and atorvastatin PO 20 mg QD 
• 
placebo SC Q2W and atorvastatin PO 20 mg QD, or  
• 
placebo SC QM and atorvastatin PO 20 mg QD. 


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The sample size for each of the evolocumab plus atorvastatin dosing regimens will be 
approximately 300 subjects.  The sample size for each of the placebo plus atorvastatin 
dosing regimens will be approximately 150 subjects. 
Randomization into the 4 treatment groups will be stratified by entry statin therapy 
(no statin use vs non-intensive statin use vs intensive statin use [see Appendix D]) and 
by the site’s geographic region.  Treatment and follow-up period will be 12 weeks with an 
additional phone call or other subject contact at week 14 for subjects receiving IP Q2W. 
Evolocumab and placebo SC will be administered at the study site or appropriate 
non-investigator site settings, eg, at the subject’s home, per protocol Section 6 and 
Section 7 by spring-based prefilled autoinjector/pen (prefilled AI/Pen) for subjects 
receiving IP Q2W and by 3.5 mL Personal Injector for subjects receiving IP QM.  The 
dose frequencies of Q2W and QM will not be blinded but the identity of IP (evolocumab 
or matching SC placebo) will be blinded.  Post-IP treatment central laboratory results of 
the lipid panel, ApoA1, ApoB100, ApoB48, free fatty acids, chylomicrons, lipoprotein(a), 
PCSK9, insulin, proinsulin, C-peptide, glucagon, IL-6, adiponectin, vitamin E, PK, and 
high sensitivity C-reactive protein (hsCRP) will be blinded until unblinding of the clinical 
database and will not be reported to the investigator post-screening.  Investigators 
should not perform non-protocol testing of these analytes during a subject’s study 
participation and until at least 12 weeks after last IP administration, or the subject’s end 
of study, whichever is later. 
The study includes collection of biomarker samples and, where approved by the 
institutional review board and/or independent ethics committee (IRB/IEC) and applicable 
regulatory and other authorities, subjects will be invited to consent to pharmacogenetics 
analyses.  All subjects will complete a mixed meal tolerance test (MMTT) at the day 1 
and week 12 study visits with 1 postprandial blood collection 2 hours after the meal and 
up to approximately 240 subjects will participate in a MMTT Extended Timepoints 
Substudy with 2 additional postprandial blood draws at 1 and 3 hours after the meal.  
End of study (EOS) for subjects on QM IP is at the week 12 visit.  EOS for subjects on 
Q2W IP is by contact (eg, phone call) from the site at week 14 for any potential adverse 
events (AEs), adverse device effects (ADEs), and serious AEs (SAEs).  Subjects will 
be encouraged to complete all planned visits regardless of their adherence to IP 
administration.  Accumulating safety and other data will be reviewed by an independent 
external Data Monitoring Committee (DMC).  Where analyte concentrations are provided 


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in mmol/L, it is for investigator convenience.  Conventional concentrations (mg/mL) will 
be used for the protocol, including for eligibility determination. 
The overall study design is described by a study schema at the end of the protocol 
synopsis section. 
The study endpoints are defined in Section 10.1.1. 
3.2 
Number of Sites 
This study will include approximately 100 sites in North America, Europe, Asia, and may 
include sites in Australia, Latin America, Middle East, and/or in Africa.  Additional sites 
may be added if necessary to achieve the enrollment goal within the planned time. 
Sites that do not randomize subjects within 3 months of being open for enrollment may 
be closed. 
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”. 
There will be approximately 900 subjects randomized in this study.  Justification for the 
sample size can be found in Section 10.2 Sample Size Considerations. 
3.4 
Replacement of Subjects 
There will be no replacement for randomized subjects.  Enrollment will continue until the 
target number of subjects (Section 3.3) have been randomized to IP, regardless of the 
number of subjects starting lipid stabilization on atorvastatin. 
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
After signing the informed consent, subjects should be randomized within 8 weeks.  
Including the screening, study treatment, and follow-up, the maximal total duration of 
study participation for a subject on QM IP schedule will be 20 weeks or approximately 
5 months.  For a subject on Q2W IP schedule, maximal study duration will be 22 weeks 
or approximately 5 ½ months, including the contact by the site at week 14 to obtain 
potential AE, ADE, and SAE information. 
3.5.2 
End of Study 
The end of the study (primary completion) is defined as the last day on which a 
randomized subject completes the end-of-study visit or phone follow-up (week 12 for 
subjects on QM IP administration; week 14 for subjects on Q2W IP administration) or 
terminates the study early, whichever is later. 


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4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening). 
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1).   
4.1 
Inclusion and Exclusion Criteria 
4.1.1 
Inclusion Criteria 
101 
Subject has provided written informed consent. 
102 
Male or female, ≥ 18 to ≤ 80 years of age at signing of informed consent. 
103 
Type 2 diabetes, defined as receiving pharmacologic treatment for type 
2 diabetes for ≥ 6 months prior to screening, with stable diabetes therapy prior to 
randomization to IP and not expected to change during the duration of study 
participation.  Stable diabetes therapy is defined as no new agents added, no 
dose change of any oral antihyperglycemic drug within 2 months, and daily 
insulin dose not changed by > 25% and > 25 units within 1 month prior to 
randomization 
104 
Lipid-lowering therapy status (eg, not receiving any therapy or receiving any 
statin, ezetimibe, bile-acid sequestering resin, stanols, probucol, omega 3 fatty 
acids or niacin) must be unchanged for ≥ 4 weeks prior to LDL-C screening. 
105 
Subjects receiving statin therapy at screening must have a fasting LDL-C at 
screening of ≥ 100 mg/dL (2.6 mmol/L) as determined by central laboratory. 
106 
Subjects not receiving statin therapy at screening must have a fasting LDL-C at 
screening of ≥ 130 mg/dL (3.4 mmol/L) as determined by central laboratory. 
107 
Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) by central laboratory at screening. 
4.1.2 
Exclusion Criteria 
201 
Receiving 20 mg atorvastatin QD monotherapy for approximately 16 weeks is 
medically contraindicated or inappropriate based on opinion of investigator. 
202 
NYHA III or IV heart failure, or last known left ventricular ejection fraction < 30%. 
203 
Uncontrolled cardiac arrhythmia defined as recurrent and highly symptomatic 
ventricular tachycardia, atrial fibrillation with rapid ventricular response, or 
supraventricular tachycardia that is not controlled by medications, in the past 
6 months prior to randomization. 
204 
Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), 
coronary artery bypass graft (CABG) or stroke within 6 months prior to 
randomization. 
205 
Planned cardiac surgery or revascularization within 6 months after 
randomization. 
206 
Type 1 diabetes or poorly controlled type 2 diabetes (HbA1c > 10.0 % at 
screening and at lipid stabilization or not on stable pharmacologic therapy for 


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type 2 diabetes.  Stable therapy is defined as no new agents added, no dose 
change of any oral antihyperglycemic drug within 2 months, and daily insulin 
dose not changed by > 25% and > 25 units within 1 month prior to randomization. 
207 
Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) 
> 160 mmHg or diastolic BP (DBP) > 100 mmHg (see Section 7.7.1 regarding 
repeat measurement). 
208 
Subject is unwilling or unable to discontinue between start of lipid stabilization 
with 20 mg/day atorvastatin and end of study (week 12 for QM and week 14 for 
Q2W subjects) the following drugs or supplements: red yeast rice, niacin 
(> 200 mg/day), > 1000 mg/day omega-3 fatty acids (eg, Docosahexaenoic acid 
[DHA] and eicosapentaenoic acid [EPA], prescription and non-prescription 
combined), and all other prescription lipid-regulating drugs (eg, fibrates and 
derivatives, ezetimibe, bile-acid sequestering resin, stanols, or probucol) except 
study-provided atorvastatin. 
209 
Subject has taken a cholesterylester transfer protein (CETP) inhibitor in the last 
12 months prior to randomization, such as: anacetrapib, dalcetrapib or 
evacetrapib. 
210 
Treatment in the last 2 months prior to screening and lipid stabilization 
assessments with any of the following drugs: systemic cyclosporine, systemic 
steroids (eg, intravenous [IV], intramuscular [IM], or oral [PO] administration), 
vitamin A derivatives and retinol derivatives for the treatment of dermatologic 
conditions (eg, Accutane); (Note: vitamin A in a multivitamin preparation is 
permitted). 
211 
Hyperthyroidism or hypothyroidism as defined by thyroid stimulating hormone 
(TSH) below the lower limit of normal (LLN) or > 1.5 times the upper limit of 
normal (ULN), respectively, at screening. 
212 
Moderate to severe renal dysfunction, defined as an estimated glomerular 
filtration rate (eGFR) < 30 mL/min/1.73m2 at screening. 
213 
Persistent active liver disease or hepatic dysfunction, defined as aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) > 2 times the ULN as 
determined by central laboratory analysis at screening or lipid stabilization 
assessments. 
214 
Creatine kinase (CK) > 3 times the ULN at screening or lipid stabilization 
assessments. 
215 
Known active infection or major hematologic, renal, metabolic, gastrointestinal or 
endocrine dysfunction (except diabetes). 
216 
Deep vein thrombosis or pulmonary embolism within 3 months prior to 
randomization. 
217 
Female subject who has either (1) not used (an) acceptable method(s) of 
effective birth control (see below) for at least 1 month prior to screening and (2) 
is not willing to inform her partner of her participation in this clinical study and to 
use such (an) acceptable method(s) of effective birth control during treatment 
with IP (evolocumab or placebo) and for an additional 15 weeks after the end of 
treatment with IP  (evolocumab or placebo), unless the female subject is 
permanently sterilized or postmenopausal (see below); 


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• 
A female is considered of childbearing potential unless permanently 
sterilized or postmenopausal with menopause 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 (FSH) 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 
• 
acceptable methods of preventing pregnancy include not having intercourse, 
(true sexual abstinence), surgical contraceptive methods - (vasectomy of the 
male partner or bilateral tubal ligation/occlusion), use of hormonal birth 
control methods (pills, shots/injections, implants, or patches), intrauterine 
devices (IUDs), or two (2) barrier methods (each partner must use one barrier 
method) and at least one of the barrier methods must include spermicide 
- males must use a condom with spermicide; females must choose either a 
diaphragm with spermicide, OR cervical cap with spermicide, OR 
contraceptive sponge with spermicide.  Note:  a male and female condom 
cannot be used together due to the risk of tearing.  
o Note:  If additional medications are given during treatment which may 
alter the contraceptive requirements (these additional medications 
may require an increase in the number of contraceptive methods 
and/or length of time that contraception is to be utilized after the last 
dose of protocol-required therapies) the investigator is to discuss 
these changes with the study subject.   
218 
Subject is pregnant or breast feeding, or planning to become pregnant or 
planning to breastfeed during treatment with IP (evolocumab or placebo) and/ or 
within 15 weeks after the end of treatment with IP (evolocumab or placebo). 
219 
Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, 
breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 
5 years prior to screening. 
220 
Subject has previously received evolocumab or any other investigational therapy 
to inhibit PCSK9. 
221 
Currently receiving treatment in another investigational device or drug study, or 
less than 30 days since ending treatment on another investigational device or 
drug study(s) or planning to receive other investigational procedures while 
participating in this study. 
222 
Subject has known sensitivity to any of the active substances or their excipients 
to be administered during dosing, eg, carboxymethylcellulose, or atorvastatin. 
223 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, or unreliability as a study participant (eg, alcohol or other drug abuse 
in the past year or psychosis), to the best of the subject’s and Investigator’s 
knowledge.  
224 
History or evidence of any other clinically significant disorder, condition or 
disease that, in the opinion of the Investigator or Amgen physician, if consulted, 


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would pose a risk to subject safety or interfere with the study evaluation, 
procedures or completion. 
5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board (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 consent form before commencement of study-specific procedures.  SAEs, 
ADEs, and study-related AEs will be collected upon signing the informed consent form. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria assessed at screening.  The investigator is to document this decision 
and date, in the subject’s medical record and in/on the enrollment eCRF. 
Each subject who enters into the screening period for the study (defined as signing the 
informed consent form) receives a unique subject identification number before any 
study-related activities/procedures are performed.  The subject identification number will 
be assigned by interactive voice response system or interactive web response system 
(IVRS/IWRS).  This number will be used to identify the subject throughout the clinical 
study and must be used on all study documentation related to that subject.  
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened. 
5.1 
Randomization/Treatment Assignment 
Assignment to the 4 treatment arms (Section 3.1) will be based on a 
computer-generated randomization schedule prepared by Amgen before the start of the 
study. 
Each subject will receive a unique randomization number.  Randomization will be 
stratified by entry statin therapy (no statin use vs non-intensive statin use vs intensive 
statin use [see Appendix D] and by the site’s geographic region. 
Once a subject has completed the end of lipid stabilization assessments and continues 
to meet all eligibility criteria, a site representative will make the randomization call to the 
IVRS/IWRS to assign a randomization number to the subject.  The randomization call to 
the IVRS/IWRS is accomplished by entering the pertinent information detailed in the 
IVRS/IWRS user manual.  A confirmation fax or email will be sent to the site to verify that 


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the correct information has been entered and to confirm the assignment of a 
randomization number.  A subject will be considered randomized into the study when a 
randomization number is assigned. 
The randomization date is to be documented in the subject’s medical record and on the 
enrollment eCRF. 
5.2 
Site Personnel Access to Individual Treatment Assignments 
A subject’s treatment assignment should only be unblinded when knowledge of the 
treatment is essential for the further management of the subject on this study.  
Unblinding at the study site for any other reason will be considered a protocol deviation.  
The investigator is strongly encouraged to contact the Clinical Study Manager before 
unblinding any subject’s treatment assignment, but must do so within 1 working day after 
the event. 
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Products and/or Medical Devices 
The Amgen investigational products used in this study include: evolocumab and 
matching placebo. 
The non-Amgen non-investigational products used in this study include: atorvastatin 
20 mg. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of evolocumab, matching placebo, and atorvastatin.  
The medical devices used in this study include: prefilled autoinjector/pen and 3.5 mL 
Personal Injector. 
6.2 
Investigational Product 
6.2.1 
Evolocumab (Amgen Investigational Product) 
Evolocumab and placebo will be manufactured and packaged by Amgen Inc. and 
distributed using Amgen clinical IP distribution procedures.  Evolocumab and placebo 
SC will be provided in 2 different injection devices: 
• 
A single use, disposable, handheld mechanical (spring-based) prefilled 
autoinjector/pen (AI/Pen) for fixed dose, subcutaneous injection of 140 mg 
evolocumab in 1.0 mL deliverable volume or an identical volume of placebo.  The 
AI/Pen is intended for Q2W administration. 
• 
A single-use, disposable, on-body electro-mechanical 3.5 mL Personal Injector 
that is co-packaged with a prefilled Crystal Zenith® (CZ) cartridge assembly for 


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fixed dose, subcutaneous injection of 420 mg evolocumab in 3.5 mL deliverable 
volume or an identical volume of placebo.  The 3.5 mL Personal Injector is 
intended for QM administration.  If the 3.5 mL Personal Injector is unavailable, 
QM dosing may be provided by 3 injections by AI/Pen. 
The prefilled AI/Pen contains a 1.0 mL deliverable volume of 140 mg/mL evolocumab in 
 mM proline,
 mM acetate,
% (weight/volume [w/v]) polysorbate 80, pH
or, 
for placebo, a 1.0 mL deliverable volume of 
% (w/v) sodium carboxymethylcellulose, 
mM proline, 
mM acetate, and 
% (w/v) polysorbate 80, pH 
. 
The prefilled Crystal Zenith® (CZ) cartridge assembly of the Personal Injector contains a 
3.5 mL deliverable volume of 120 mg/mL evolocumab in
 mM proline,
 mM 
acetate, 
% (w/v) polysorbate 80, pH 
 or, for placebo, a 3.5 mL deliverable volume 
of 
% (w/v) sodium carboxymethylcellulose, 
mM proline,
 mM acetate, and 
% (w/v) polysorbate 80, pH 
. 
Evolocumab and placebo should be stored refrigerated and protected from light 
according to the storage and expiration information provided on the label (where 
required).   
AI/Pen and 3.5 mL Personal Injector should be inspected for IP quality, expiry, and 
damage before using per the instructions provided in the IPIM.  Damaged, expired, or 
degraded product should not be used and any issues with the prefilled AI/Pen or 3.5 mL 
Personal Injector should be reported to Amgen. 
Further details are provided in Section 6.7, in the IPIM and the respective Instructions for 
Use (IFU) for the devices. 
6.2.1.1 
Dosage, Administration, and Schedule 
Subcutaneous IP (evolocumab or matching placebo) will be administered SC in 
accordance with instructions in the IPIM.  IP administration by SC injection if performed 
during a study visit must occur after vital signs, electrocardiogram (ECG), and blood 
draw procedures, if applicable.  After IP administration at the first dosing visit, subjects 
will be held for observation for at least 30 minutes before being discharged. 
IP will be administered at either 140 mg evolocumab or placebo in 
1.0 mL (administration by prefilled AI/Pen) Q2W or 420 mg evolocumab or placebo in 
3.5 mL (administration by 3.5 mL Personal Injector) QM. 
In this study, subjects have the option of self-administration, defined as SC 
administration of IP by the subject, designee or a qualified health care professional in a 
CCI
CC
I
CCI
CCI
CC
I
CCI
C
CI
CCI
CC
I
CCI
C
CI
CCI
CC
I
CCI
CC
I
CC
I
CCI
CC
I


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non-investigator site setting (eg, at home).  The subject (or designee, if not a qualified 
healthcare professional) must have demonstrated competency at administration of SC 
injections before self-administration is permitted: the first self-administered dose by the 
subject (or designee, if not a healthcare professional) must be administered at the site 
under the supervision of a healthcare provider. 
Details of preparing IP and the injection procedures are included in the IPIM provided by 
Amgen prior to the start of the study.  The dosing schedule is described by a schema in 
the protocol synopsis. 
When IP is mandated to be administered at the study site, the date and completion time 
of administration, the body location of the injection, and whether the injection was fully or 
partially administered are to be recorded on each subject’s CRF. 
When IP can be administered at a non-investigator site location, at a minimum, the dates 
the devices were dispensed and the used devices returned, and for each device whether 
it was returned fully or partially used are to be recorded on each subject’s CRF. 
6.2.1.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
There will be no dose adjustments in this study.  If, in the opinion of the investigator, 
a subject is unable to tolerate a specific dose of IP, that subject will discontinue IP but 
will continue to take atorvastatin and return for all other study procedures and 
measurements until the end of the study. 
If a subject is late for administration of IP, administration should occur as soon as 
possible.  A QM dose of IP should not be administered within less than 7 days of a 
previous dose.  If a QM subject arrives for a visit with IP administration and IP was 
administered within the prior 7 days, the dose should not be administered but all other 
study procedures should be conducted.  Administration of IP should occur as soon as 
possible but at least 7 days after the previous administration.  Not more than 2 Q2W 
doses should be administered within any 7-day period.  If a Q2W subject arrives for a 
visit with IP administration and more than 1 dose of IP was administered within the prior 
7 days, the dose should not be administered but all other study procedures should be 
completed.  Administration of IP should occur as soon as possible but at least 7 days 
after the most recent previous administration. 
Subjects who completely miss a dose of IP will continue in the study and receive the 
next dose of IP per their schedule of administration. 


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6.2.2 
Atorvastatin (Non-Amgen Non-investigational Product) 
Atorvastatin (non-Amgen non-investigational product) will be used in this study as 
background therapy.  Atorvastatin will be provided by Amgen.  Additional details 
regarding this product are provided in the Investigational Product Instruction Manual 
(IPIM). 
6.2.2.1 
Dosage, Administration, and Schedule 
Atorvastatin 20 mg will be taken orally once daily and should be taken every day at 
about the same time in accordance with instructions in the IPIM.  If taken during a study 
visit, it must be taken after vital signs, ECG, and blood draw procedures have been 
completed, if applicable. 
The start date of atorvastatin administration, the dates atorvastatin is dispensed and the 
used containers returned, and the quantity returned are to be recorded on each subject’s 
CRF. 
6.2.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
There will be no dose adjustments for atorvastatin in this study.  If, in the opinion of the 
investigator, a subject is unable to tolerate a specific dose of atorvastatin after having 
been randomized to IP, the Amgen medical monitor should be contacted.  If atorvastatin 
is discontinued, IP (evolocumab or matching placebo) should be continued unless there 
is a reason to discontinue IP as well.  In either case, the subject should return for all 
other study procedures and measurements until the end of the study. 
Subjects who miss a dose of atorvastatin will be advised to take the missed dose as 
soon as they can; subsequent doses will be taken at the usual time.  However, if the 
next scheduled dose would be due in less than 6 hours, the subject will be advised to 
omit the missed dose entirely and to take the next dose at the normal time. 
6.3 
Non-investigational Products 
All other lipid-lowering drugs that are allowed per protocol and that the subject may be 
taking, must be commercially available and are not provided or reimbursed by Amgen 
(except if required by local regulation).  The investigator will be responsible for obtaining 
supplies of these drugs.  All such therapy needs to be stable and unchanged during the 
entire time of screening and study participation. 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 37 of 90 
CONFIDENTIAL 
 
 
6.4 
Withholding of Investigational Product or Atorvastatin due to 
Elevation of Creatine Kinase (CK) 
If CK is > 5x ULN, CK must be retested before atorvastatin and IP is administered.  In 
addition, investigators will ask study subjects to promptly report muscle pain, cramps, or 
weakness especially if accompanied by malaise or fever.  If such symptoms occur, the 
subject’s CK levels should be measured and if CK is > 5x ULN, the subject should be 
instructed to discontinue atorvastatin and IP.  CK must be retested before any 
atorvastatin or IP is administered.   
The following rules apply:   
CK at prior visit 
CK on retest 
Investigational Product Administration 
> 5x ULN 
> 10x ULN 
Discontinue atorvastatin and IPa.  Contact 
Amgen Medical Monitor 
> 5x to ≤ 10x ULN 
Discontinue atorvastatin and retest CK before 
atorvastatin administration.  Consider continuing 
IP if alternative explanation  
≤ 5x ULN 
Consider continuing IP and atorvastatin 
a CK elevations >10x ULN that have been confirmed to be secondary to myocardial infarction do not require 
discontinuation of IP or atorvastatin 
If muscular symptoms are severe and cause daily discomfort, even if the CK levels are 
elevated to ≤ 5x  ULN, in consultation with the Amgen medical monitor, discontinuation 
of atorvastatin, or introduction of an alternative statin may be considered at the lowest 
dose and with close monitoring. Please note that Amgen will not be providing the 
alternative statin.  
6.5 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio [INR] and/or signs/symptoms of hepatitis 
(as described below) may meet the criteria for withholding or permanent discontinuation 
of Amgen investigational product or other protocol-required therapies as specified in the 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, 
July 2009). 
6.5.1 
Criteria for Permanent Discontinuation of Amgen Investigational 
Product and Other Protocol-required Therapies due to Potential 
Hepatotoxicity 
Atorvastatin and investigational product should be discontinued permanently and the 
subject should be followed according to the recommendations in Appendix A (Additional 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 38 of 90 
CONFIDENTIAL 
 
 
Safety Assessment Information) for possible drug-induced liver injury (DILI), if ALL of the 
criteria below are met:  
• 
TBL > 2x ULN or INR > 1.5 (testing determined per Appendix A) 
AND  
• 
AST or ALT > 3x ULN  
AND  
• 
no other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT and/or 
TBL values include, but are not limited to: 
− 
hepatobiliary tract disease 
− 
viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus, cytomegalovirus, 
herpes simplex virus, varicella, toxoplasmosis, and parvovirus) 
− 
right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia.   
− 
exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants and mushrooms   
− 
heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation 
(eg, indinavir, atazanavir) 
− 
alpha-one antitrypsin deficiency 
− 
alcoholic hepatitis 
− 
autoimmune hepatitis  
− 
Wilson’s disease and hemochromatosis 
− 
nonalcoholic fatty liver disease including steatohepatitis (NASH)  
− 
Non-hepatic causes (eg, rhabdomyolysis, hemolysis) 
6.5.2 
Criteria for Conditional Withholding of Amgen Investigational 
Product and Other Protocol-required Therapies due to Potential 
Hepatotoxicity 
For subjects who do not meet the criteria for permanent discontinuation of Amgen 
investigational product outlined above and have no underlying liver disease, and 
eligibility criteria requiring normal transaminases and TBL at baseline or subjects with 
underlying liver disease and baseline abnormal transaminases, the following rules are to 
be followed for withholding of Amgen investigational product and other protocol-required 
therapies:  
• 
AST or ALT > 8x ULN at any time 
• 
AST or ALT > 5x ULN but < 8x ULN for ≥ 2 weeks (or subject unable to adhere to 
enhanced monitoring schedule) 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 39 of 90 
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• 
ALT or AST > 3x ULN with 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%) 
• 
TBL > 3x ULN at any time 
• 
ALP > 8x ULN at any time 
Both atorvastatin and investigational product should be withheld pending investigation 
into alternative causes of DILI.  If atorvastatin or investigational product is withheld, the 
subject is to be followed according to recommendations in Appendix A for possible DILI.  
Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL, is discovered and the laboratory abnormalities resolve 
to normal or baseline (Section 6.5.3).   
6.5.3 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then investigational product should be 
permanently discontinued.  Subjects who clearly meet the criteria for permanent 
discontinuation (as described in Section 6.5.1) should never be rechallenged. 
6.6 
Concomitant Therapy, Physical Exercise, and Diet 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.9. 
Concomitant therapies are to be collected from screening (informed consent date) 
through the end of study.  Therapy name, indication, dose, unit, frequency, route, start 
date and stop date will be collected. 
6.7 
Medical Devices 
IP will be provided by prefilled AI/pen for Q2W administration and by 3.5 mL Personal 
Injector for QM administration (Section 6.2.1).  The prefilled AI/pen is a modified version 
of the SureClick™ autoinjector, a device that is commercially available for the 
administration of Aranesp® or Enbrel® drug product by patients or caregivers in a 
non-healthcare environment, or by healthcare professionals in the clinic environment in 
the United States (Enbrel® only) and in Europe.  The 3.5 mL Personal Injector is a novel 
single-use, disposable injector with prefilled cartridge assembly that delivers 3.5 mL of 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 40 of 90 
CONFIDENTIAL 
 
 
evolocumab to subcutaneous tissue over a period of several minutes (less than 
10 minutes). 
Medical devices (eg, syringes, sterile needles, alcohol prep pads), that are commercially 
available are not usually provided or reimbursed by Amgen (except, for example, if 
required by local regulation).  The investigator will be responsible for obtaining supplies 
of these devices. 
6.8 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s) or device(s) after it is released for distribution to market 
or clinic by either Amgen or by distributors and partners for whom Amgen 
manufactures the material.  This includes any drug(s) or device(s) provisioned 
and/or repackaged/modified by Amgen.  Drug(s) or device(s) includes 
investigational product. 
Any product complaints associated with the prefilled AI/Pen, the 3.5 mL Personal 
Injector, or other Amgen provided, protocol-required product (ie, atorvastatin) in this 
study must be reported to Amgen.  Please do not use the device or product that is 
subject of a complaint until Amgen confirms that it is permissible to do so. 
Examples of product complaints that need to be reported to Amgen include, but are not 
limited to: 
• 
broken or cracked containers 
• 
subject or healthcare provider cannot appropriately use the product despite training 
(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 
• 
unexpected quantity or volume, for example number of tablets or amount of fluid in 
the prefilled AI/Pen or 3.5 mL Personal Injector 
• 
evidence of tampering or stolen material 
If possible, please have the device or product associated with the complaint available for 
examination when making a product complaint.  Maintain device or other Amgen 
provided protocol-required suspect product at appropriate storage conditions until further 
instructions are received from Amgen. 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 41 of 90 
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The investigator is responsible for ensuring that all product 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. 
6.9 
Excluded Treatments and/or Procedures During Study Period  
The following treatments are not permitted during the study: 
• 
prescription lipid regulating medications other than fish oil (omega-3 fatty acids) and 
study-provided atorvastatin, eg, fibrates and derivatives, ezetimibe, bile-acid 
sequestering resin, stanols, or probucol  
• 
red yeast rice 
• 
niacin > 200 mg/day 
• 
omega-3 fatty acids (eg, DHA and EPA combined) > 1000 mg/day 
• 
other drugs (besides those mentioned above) that significantly affect lipid 
metabolism (eg, systemic cyclosporine, systemic steroids [IV, IM, or PO; 
Note: hormone replacement therapy is permitted], vitamin A derivatives and retinol 
derivatives for the treatment of dermatologic conditions [eg, Accutane; Note: 
Vitamin A as part of a multivitamin preparation is permitted]). 
• 
prescribed amphetamines, or amphetamine derivatives, and weight loss 
medications.  
• 
Other investigational therapies than evolocumab 
The following treatments are not recommended because of their potential impact on 
metabolism of certain statins: 
• 
medications or foods that are known potent inhibitors of CYP3A (eg, Itraconazole, 
ketoconazole, and other antifungal azoles, macrolide antibiotics erythromycin, 
clarithromycin, and the ketolide antibiotic telithromycin, HIV or HCV protease 
inhibitors, antidepressant nefazodone and grapefruit juice in large quantities 
(> 1 quart daily [approximately 1 Liter]) should not be used during the study.   
Should there be a clinical need to prescribe one of these treatments, the investigator 
should call the Amgen Medical Monitor to discuss. 
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments 
 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 42 of 90 
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Table 1.  Schedule of Assessments 
Study Day / Week / Other Timepointa 
Screen & Lipid Stabilization 
Treatment Period 
Phone 
Screen 
Enroll 
Start 
Atorva 
End of  
Lipid  
Stabil 
D1 
Visit 
Rand. 
W2 
Visit 
W4 
W6 
W8 
Visit 
W10 
Visit 
W12 
Visit 
(QM EOS) 
W14b 
Q2W 
EOS 
General Procedures 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs (sitting BP, HR) 
X 
 
 
X 
X 
 
 
 
X 
X 
 
Review for AEs/ADEs/SAEs 
X
c 
 
X
c 
X 
X 
(X)
d 
(X)
d 
X 
X 
X 
X 
Concomitant therapy 
X 
 
X 
X 
X 
 
 
X 
X 
X 
 
Dietary instruction 
X 
 
 
X 
X 
 
 
X 
X 
 
 
Physical exam 
X 
 
 
 
 
 
 
 
 
X 
 
Body weight, waist circumference 
 
 
 
X 
 
 
 
 
 
X 
 
Body height 
X 
 
 
 
 
 
 
 
 
 
 
12 lead ECG 
X 
 
 
X 
 
 
 
 
X 
X 
 
Randomization 
 
 
 
X
e 
 
 
 
 
 
 
 
Central Laboratory
f 
 
 
 
 
 
 
 
 
 
 
 
Fasting lipids
g 
X 
 
X 
X 
X 
 
 
X 
X 
X 
 
ApoA1, ApoB100, Lp(a) 
 
 
 
X 
 
 
 
 
X 
X 
 
PK (evolocumab), PCSK9 
 
 
 
X 
X 
 
 
X 
X 
X 
 
Chemistry, including fasting glucose
g 
X 
 
X 
X 
 
 
 
X 
 
X 
 
Hematology 
X 
 
 
X 
 
 
 
X 
 
X 
 
hsCRP 
 
 
 
X 
 
 
 
 
 
X 
 
HbA1c 
X 
 
 
 
 
 
 
 
 
X 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
MMTT: Plasma glucose, insulin, proinsulin, C-peptide, free 
fatty acids, glucagon, lipids, chylomicrons, ApoB48, IL-6, 
adiponectin, vitamin E, measured after a ≥ 9 hour fast just 
prior to a standardized meal (0 minutes), and then 120 
minutes after
 h 
 
 
 
X 
 
 
 
 
 
X 
 
MMTT Extended Timepoints Substudy: Same analytes as 
for MMTT, measured at additional timepoints  (60, 180 
minutes) in subjects participating in the substudy)
 h 
 
 
 
X 
 
 
 
 
 
X 
 
Biomarkers (blood)
ji 
 
 
 
X 
 
 
 
 
 
X 
 
Anti-evolocumab antibodies 
 
 
 
X 
 
 
 
 
 
X 
 
HCV testing
j 
X 
 
 
 
 
 
 
 
 
 
 
HCV viral load
j 
 
 
 
X 
X 
 
 
X 
 
X 
 
Serum pregnancy; FSH
k 
X 
 
X 
 
 
 
 
 
 
X 
 
Urine pregnancy 
 
 
 
X 
X 
 
 
X 
 
 
 
Urinalysis, urine microalbumin 
 
 
 
X 
 
 
 
 
 
X 
 
Page 1 of 2 
Footnotes defined on last page of this table. 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 43 of 90 
CONFIDENTIAL 
 
 
Table 1.  Schedule of Assessments 
Study Day / Week / Other Timepointa 
Screen & Lipid Stabilization 
Treatment Period 
Phone 
Screen 
Enrol 
Start 
Atorva 
End of 
Lipid 
Stabil 
D1 
Visit 
Rand. 
W2 
Visit 
W4 
W6 
W8 
Visit 
W10 
Visit 
W12 
Visit 
(QM EOS) 
W14b 
Q2W 
EOS 
Steroid analytes
l 
 
 
 
X 
 
 
 
 
 
X 
 
Investigational Product 
 
 
 
 
 
 
 
 
 
 
 
Screening placebo injection 
X 
 
 
 
 
 
 
 
 
 
 
Atorvastatin dispensation
m 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
Atorvastatin tablet count
m 
X 
 
X 
X 
X 
 
 
X 
 
X 
 
AI/Pen / 3.5 mL Personal Injector Instruction 
X 
 
 
X 
X 
 
 
X 
 
 
 
AI/Pen / 3.5 mL Personal Injector dispensation 
 
 
 
 
X 
 
 
X 
 
 
 
AI/Pen / 3.5 mL Personal Injector reconciliation 
 
 
 
 
 
 
 
X 
 
 
 
Q2W IP on-site 
 
 
 
X 
X 
 
 
X 
X 
 
 
QM IP on-site 
 
 
 
X 
 
 
 
X 
 
 
 
Q2W IP on-site or in non-investigator site setting  
 
 
 
 
 
X 
X 
 
 
 
 
QM IP on-site or in non-investigator site setting 
 
 
 
 
 
X 
 
 
 
 
 
Page 2 of 2 
a D1 = day of first administration of IP; a visit window of ± 3 days applies to all other visits; atorvastatin will be taken orally every day for ≥ 4 weeks of lipid stabilization 
before randomization and then continuously until the week 12 visit; atorvastatin should be taken every day at about the same time 
b subjects on Q2W IP schedule; subject is being contacted by the site at week 14, eg, by phone call 
c only AEs possibly related to study procedures and ADEs/SAEs are collected during the screening and lipid stabilization period 
d only if a visit to the study site is performed instead of IP administration at a non-investigator site location  
e randomization should be on day 1 or as close as possible and must not be earlier than 5 days prior to day 1 
f blood samples must be taken prior to IP administration, if applicable 
g if subject is not fasting on day 1, reschedule; if subject is not fasting after day 1, do all procedures except fasting labs and IP administration, if applicable; schedule 
another visit, if possible within the visit window for fasting labs and IP administration 
h postprandial blood draw at 120 ± 10 mins after standardized mixed meal (see Section 7.7.6) for all subjects; additional postprandial blood draws at 60 ± 10 mins and 
180 ± 10 mins for subjects participating in the MMTT Extended Timepoints Substudy (see Section 7.7.7).  Other markers for metabolic status may be assessed as 
well. 
i if the subject consented to pharmacogenetics analyses, deoxyribonucleic acid (DNA) will be extracted from some of the blood samples, eg, biomarker samples 
j HCV antibodies only in subjects at high risk for, or with history of, HCV infection, or born between 1945 and 1965 (see Section 7.2.1.1) or if ALT or AST > 2x ULN at 
any time during screening; viral load only in subjects positive for HCV 
k pregnancy testing in females of childbearing potential, FSH only if applicable per Section 4.1.2, exclusion 217 
l Applies to subjects in China only:  steroid analytes include cortisol, adrenocorticotropic hormone, estradiol, testosterone, luteinizing hormone (LH), and FSH 
m timepoints of atorvastatin dispensation and tablet count may vary regionally and differ from the timepoints shown here  


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 44 of 90 
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Refer to Sections 7.2 through 7.7 and the applicable supplemental laboratory manual, 
ECG manual, and IPIM for detailed study procedures. 
Refer to the applicable supplemental central laboratory and ECG  manuals for detailed 
collection and handling procedures.   
7.2 
General Study Procedures  
This is a multi-center, randomized, double-blind, placebo-controlled trial.  The study 
consists of 2 periods: 
• 
screening period 
• 
double-blind treatment period 
For the purpose of this study, a week is defined as 7 calendar days. 
Written informed consent must be obtained and will be implemented before protocol 
specific procedures are carried out.  The risks and benefits of participating in the study 
will be verbally explained to each potential subject prior to entering into the study.  The 
procedures to be performed at each study site visit are described below and the timing 
of the procedures is provided in Table 1.  If IP is administered during a study visit, 
administration must be after completion of vital signs, ECG, and blood draw procedures, 
as applicable. 
Subjects must be fasting for ≥ 9 hours before each study visit.  For procedures if the 
subject is not fasting when presenting at the study site for a visit, please see 
Section 7.2.1.1 and Section 7.2.2 below. 
All screening and on-study laboratory samples will be processed and sent to the central 
laboratory.  Amgen or designee will be responsible for the evaluation of PK 
(evolocumab) and PCSK9 serum levels, anti-evolocumab antibody, and biomarker 
development assessments and the central laboratory will ship the samples to Amgen or 
a specialty laboratory for assay (depending on the assessment). 
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 2 below outlines the specific analytes for serum chemistry, hematology, urinalysis, 
and other testing to be conducted. 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 45 of 90 
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Table 2.  Analyte Listing 
Chemistry  
Coagulation 
Urinalysis 
Hematology 
Other Labs 
Sodium 
Potassium 
Chloride 
Bicarbonate  
Total protein 
Albumin 
Calcium 
Magnesium 
Phosphorus 
Fasting glucose 
BUN or Urea 
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin 
CK 
ALP 
LDH 
AST (SGOT) 
ALT (SGPT) 
PT/INR (per 
Appendix A) 
Specific 
gravity 
pH 
Blood 
Protein 
Glucose 
Bilirubin 
WBC 
RBC 
Epithelial cells 
Bacteria 
Casts 
Crystals 
Hemoglobin 
Hematocrit 
RBC 
RDW 
MCV  
MCH 
MCHC 
WBC 
Platelets 
Differential 
• Neutrophils 
• Bands 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes 
 
Fasting lipids 
• Total cholesterol 
• HDL-C 
• LDL-C 
• Triglycerides 
• VLDL-C 
• non-HDL-C 
ApoA1 
ApoB100 
ApoB48 
hsCRP 
Lp(a) 
Insulin 
Proinsulin 
C-peptide 
Free fatty acids 
Glucagon 
Chylomicrons 
Vitamin E 
IL-6 
Adiponectin 
Anti-evolocumab antibodies 
PCSK9 
evolocumab (PK) 
HbA1c 
Pregnancy test (females of 
childbearing potential) 
FSH (if needed per 
exclusion 217) 
TSH 
HCV antibody* 
HCV viral load** 
Steroid analytes:*** 
• Cortisol 
• Adrenocorticotropic 
hormone 
• Estradiol 
• Testosterone 
• Luteinizing hormone 
(LH) 
• FSH 
*HCV antibodies are measured before initiating treatment with IP in subjects at high risk for (see 
Section 7.2.1.1), or with history of, HCV infection, or born between 1945 and 1965, and in subjects with 
ALT or AST > 2x ULN at any time during screening.  Please note that subjects with ALT or AST > 2x ULN 
must be screen failed unless the elevation is transient as confirmed by retesting per Section 7.2.1.3.   
** Viral load will be tested at the time points indicated in Table 1 in subjects who are positive for HCV. 
***Applies to subjects in China only. 


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Some laboratory results may inadvertently unblind investigators to treatment assignment 
to evolocumab.  Central laboratory results of the lipid panel, ApoA1, ApoB, Lp(a), and 
hsCRP will not be reported to the investigator (or study personnel) post-screening.  
Investigators should not perform non-protocol testing of these analytes during a subject’s 
study participation from first administration of IP until at least 12 weeks after last IP 
administration, or the subject’s end of study, whichever is later. 
7.2.1 
Screening, Lipid Stabilization, and Randomization 
Subjects who are considered for entry into the study and have the risk and benefits of 
participating in the study explained will enter screening by signing and dating the 
informed consent form for this study.  Screening should be completed and the subject 
randomized or screen failed within 8 weeks of signing the informed consent.   
7.2.1.1 
Screening Placebo Injection 
In order to reduce the burden of unnecessary procedures on subjects who subsequently 
elect not to participate in the study or continue with study procedures, all subjects will 
undergo a placebo administration to confirm tolerance of SC administration by SC 
injection prior to enrollment.  This placebo administration can be done before or after 
screening venipuncture procedures but must be done before enrollment.  The 
administration corresponds to the IP dose volume for Q2W administration and consists 
of 1 injection of 1.0 mL placebo, using 1 AI/Pen.  This administration is following the 
same procedures as injections of IP during the treatment period.  Further details are 
provided in the IPIM. 
7.2.1.2 
Screening and Lipid Stabilization 
The following procedures are to be completed during the screening period: 
• 
confirmation that the Informed Consent Form has been signed  
• 
demographic data including sex, date of birth, age, race, and ethnicity will be 
collected in order to study their possible association with treatment effectiveness, 
subject safety, or, for example, to further study biomarker variability 
• 
medical history  
• 
vital signs (sitting BP, heart rate [HR]; see Section 7.7.1) 
• 
review for AEs/ADEs/SAEs (AEs possibly related to study procedures, ADEs and 
SAEs are collected during screening) 
• 
concomitant therapy  
• 
physical examination 
• 
body height 
• 
12-lead ECG in triplicate using centralized ECG services equipment 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 47 of 90 
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• 
blood draw for fasting lipids (≥ 9 hour fasting sample), chemistry (including fasting 
glucose), hematology, HbA1c, TSH, serum pregnancy (females of childbearing 
potential only), and FSH (only if required to ensure menopause in a female subject 
[see exclusion criterion 217]) by central laboratory (Note: eGFR will be calculated by 
the central laboratory and will be provided to the site for eligibility determination) 
• 
blood draws for hepatitis C virus (HCV) antibodies in subjects at high risk for, or with 
history of, HCV infection, or born between 1945 and 1965, or with AST or ALT 
> 2x ULN at any time during screening* 
− 
High risk subjects for this protocol are those who meet any of the following 
conditions: 
o ever injected illegal drugs 
o received clotting factors made before 1987  
o received blood or organ donation before July 1992 or were 
exposed to blood known to be infected with HCV 
o were ever on chronic hemodialysis  
o are known to be infected with HIV 
o have a known HCV-infected sexual partner  
• 
the subject will be instructed to maintain his/her current diet throughout the course of 
the study and avoid going on any strict diet or aiming to lose weight during the study 
• 
screening placebo injection as per Section 7.2.1.1; includes instruction/training on 
AI/Pen use 
• 
randomization, if eligible 
* Please note that subjects with ALT or AST > 2x ULN must be screen failed unless the 
elevation is transient as confirmed by retesting per Section 7.2.1.4. 
If a fasting sample could not be obtained at the initial screening visit and the other 
screening laboratory assessments confirm eligibility for the study, fasting lipid and 
glucose samples to determine eligibility must be obtained before changing or 
discontinuing the current lipid lowering treatment. 
Eligible subjects will be enrolled (Section 5) and will start their lipid stabilization on 20 mg 
QD atorvastatin background therapy.  If during lipid stabilization a subject is found not to 
tolerate the assigned atorvastatin background therapy, the subject should not continue 
but should early terminate the study.  In contrast, if intolerance is discovered after 
randomization to IP, the subject should continue the study until completion.  Before  
reducing or discontinuing treatment with atorvastatin, please contact the Amgen medical 
monitor.  All prohibited lipid lowering therapy (see exclusion 208 and Section 6.9) must 
be discontinued at the start of lipid stabilization. 
After ≥ 4 weeks of lipid stabilization, subjects will return to the study site for the end of 
lipid stabilization assessments.   


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 48 of 90 
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7.2.1.3 
Randomization 
Subjects who continue to meet all eligibility criteria at the end of lipid stabilization will be 
randomized and will return to the study site again for day 1 procedures while continuing 
their atorvastatin background treatment.  Randomization should be on day 1 or as close 
as possible and not earlier than maximally 5 days prior. Subjects can only be 
randomized 1 time for this study. 
7.2.1.4 
Retesting 
If, in the investigator’s judgment, lab abnormalities are likely to be transient, (ie, subject 
participated in vigorous exercise and CK is elevated immediately afterwards), laboratory 
tests can be repeated.  Triglycerides, CK, and liver function and other laboratory values, 
except LDL-C, can be retested at any time during screening as long as the subject can 
be evaluated for eligibility and randomized within the allowed screening period.  LDL-C 
should not be retested due to out-of-range LDL-C concentration during screening. 
7.2.1.5 
Rescreening 
Subjects receiving statin therapy (any statin) when entering screening and with LDL-C 
< 100 mg/dL (2.6 mmol/L) at screening and subjects not receiving any statin therapy 
when entering screening and with LDL-C < 130 mg/dL (3.4 mmol/L) at screening are 
considered screen failures and cannot be rescreened for this study.  Suitable subjects 
who are ineligible at the initial screening for other reasons and have not been 
randomized can be re-consented and rescreened at a later time unless they withdraw 
from screening.  For subjects who are rescreened, data from the first screening period 
will not be used for the analysis. 
With the exception of the screening placebo injection, rescreened subjects who are 
re-consented will repeat all screening procedures.  Rescreened subjects will maintain 
the originally assigned subject identification number. 
7.2.1.6 
Screen Fail 
Subjects who fail any of the eligibility criteria during screening or rescreening and have 
not been randomized need to be screen failed in IVRS/IWRS before they can be 
re-consented and re-registered in IVRS/IWRS for rescreening. 
7.2.2 
Treatment 
Subjects who are randomized will visit the study site for treatment start.  The first 
administration of IP should be on the day, or as close as possible to the day, of 
randomization but not later than 5 calendar days after randomization.  Day 1 is defined 


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as the day of first administration of IP.  The date of first administration of IP will be 
recorded in IVRS/IWRS and will determine the schedule of subsequent study visits. 
Subjects must be fasting for ≥ 9 hours before each study visit where fasting lipid 
samples are obtained.  If the subject is not fasting for the scheduled study day 1 visit, no 
visit procedures are performed.  The subject must return as soon as possible in a fasting 
state for study day 1 visit procedures.  If the subject is not fasting as required for a visit 
after study day 1, visit procedures should be completed except for fasting laboratory 
sample collection and IP administration, if applicable.  An extra visit must be completed 
for the omitted procedures as soon as possible and, if possible, within the window for the 
respective visit. 
The following procedures will be completed during the 12 week treatment period at the 
times designated in the Schedule of Assessments (Table 1): 
• 
vital signs (sitting BP, HR; see Section 7.7.1) 
• 
review for AEs/ADEs/SAEs 
• 
review of concomitant therapy 
• 
encourage subject to maintain a stable diet 
• 
body weight and waist circumference (see Section 7.7.2) 
• 
12-lead ECG in triplicate using centralized ECG services equipment 
• 
blood draw for fasting lipids (≥ 9 hour fasting sample), ApoA1, ApoB, chemistry, 
hematology, PK, PCSK9, hsCRP, Lp(a), biomarkers, anti-evolocumab antibodies, 
and viral load in subjects positive for HCV 
• 
subjects in China only:  blood draw for steroid analytes including cortisol, 
adrenocorticotropic hormone, estradiol, testosterone, luteinizing hormone (LH), and 
FSH 
• 
mixed meal tolerance test 
• 
urine sample for urinalysis 
• 
urine pregnancy testing for females of childbearing potential 
• 
dispense and reconcile atorvastatin and instruct subject in administration 
• 
IP administration at the study site (must be after completion of vital signs, ECG, and 
blood draw procedures, if applicable) 
• 
dispense AI/Pen or 3.5 mL Personal Injector, respectively, with instructions for use at 
week 4 (all subjects) and week 6 (Q2W subjects only) 
No additional blood will be collected for the pharmacogenetics analyses.  For subjects 
who have consented to the pharmacogenetic portion of this study, DNA will be extracted 
from blood samples already collected on day 1 or another visit (see Section 7.5 
“Pharmacogenetic Studies” and Section 7.6 “Sample Storage and Destruction”). 


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If a subject withdraws from the study early, all efforts should be made to complete and 
report the observations as thoroughly as possible up to the date of withdrawal.  If 
possible, the procedures of week 12 should be completed at the time of withdrawal. 
7.2.3 
Safety Follow-up Visit(s)/End of Study Visit 
Subjects receiving IP QM will end the study with the week 12 visit.  Subjects on Q2W IP 
schedule will end the study by being contacted by the site, eg, by phone call, at week 14 
to collect any AEs, ADEs, or SAEs. 
7.3 
Antibody Testing Procedures 
Blood samples for antibody testing are to be collected per Table 1 for the measurement 
of anti-evolocumab binding antibodies.  All subjects who have received at 
least 1 administration of evolocumab will have samples assayed for binding and, if 
positive, neutralizing antibodies. Samples testing positive for binding antibodies will also 
be tested for neutralizing antibodies and may be further characterized for quantity/titer, 
isotype, affinity and presence of immune complexes. Sites will be notified of any positive  
neutralizing antibody results to evolocumab. If results are not provided, no neutralizing 
antibodies to evolocumab have been detected.  Additional blood samples may be 
obtained to rule out anti-evolocumab antibodies during the study. Subjects who test 
positive for neutralizing antibodies to evolocumab at the final scheduled study visit will 
be asked to return for additional follow-up testing. This testing should occur 
approximately every 3 months starting from when the site has been notified of the 
positive result, until: (1) neutralizing antibodies are no longer detectable or (2) the 
subject has been followed for a period of at least 1 year (± 4 weeks). More frequent 
testing (eg, every month) or testing for a longer period of time may be requested in the 
event of safety-related concerns. Follow-up testing will not be required where it is 
established that the subject did not receive evolocumab. All follow-up results, both 
positive and negative will be communicated to the sites. Subjects who test positive for 
binding, non-neutralizing antibodies and have clinical sequelae that are considered 
potentially related to an anti-evolocumab antibody response may also be asked to return 
for additional follow-up testing. 
7.4 
Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention. 


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It is expected that further advances will occur in the future 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 14.5 mL of blood will be 
collected at each of the time points indicated in Table 1 so that biomarkers related to, but 
not limited to PCSK9 signaling, LDLR turnover, cholesterol metabolism, inflammation, 
and plaque stability such as certain glycosylated proteins, matrix metalloproteinases, 
additional markers of inflammation such as myeloperoxidase, bromo and nitro-tyrosine, 
and tumor necrosis factor (TNF) cellular adhesion molecules may be studied. 
Refer to the laboratory manual for detailed collection and handling procedures for all 
biomarker development samples. 
7.5 
Pharmacogenetic Studies 
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed.  These optional pharmacogenetics analyses focus on 
inherited genetic variations such as those of the PCSK9 gene or the LDLR gene to 
evaluate their possible correlation to the disease and/or responsiveness to the therapies 
used in this study.  The goals of the optional studies include the use of genetic markers 
to help in the investigation of cardiovascular disease, hyperlipidemia and other metabolic 
disorders and/or to identify subjects who may have positive or negative response to 
evolocumab.  No additional blood will be collected for this analysis.  For subjects who 
have consented to the pharmacogenetic portion of this study, DNA will be extracted from 
blood samples already collected.  Subjects can participate in the main trial irrespective of 
whether they do or do not consent to the pharmacogenetic portion of the study. 
7.6 
Sample Storage and Destruction 
Any blood sample collected according to the Schedule of Assessments (Table 1) can be 
analyzed for any of the tests outlined in the protocol and for any tests necessary to 
minimize risks to study subjects.  This includes testing to ensure analytical methods 
produce reliable and valid data throughout the course of the study.  This can also 
include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability. 


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All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality. 
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand 
processes related to PCSK9 signaling, LDLR turnover, cholesterol metabolism, 
inflammation, and plaque stability such as certain glycosylated proteins, matrix 
metalloproteinases, additional markers of inflammation such as myeloperoxidase, bromo 
and nitro-tyrosine, and tumor necrosis factor (TNF) cellular adhesion molecules, the 
dose response and/or prediction of response to PCSK9 inhibition, eg, by evolocumab, 
characterize antibody response, and characterize aspects of the molecule 
(eg, mechanism of action/target, metabolites).  Results from this analysis are to be 
documented and maintained, but are not necessarily reported as part of this study.  
Samples can be retained for up to 20 years. 
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of pharmacogenetic, biomarker development, or other 
exploratory studies are not placed in the subject’s medical record and are not be made 
available to the subject, members of the family, the personal physician, or other third 
parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood samples and any other components from the samples can be located and 
destroyed.  Samples will be destroyed once all protocol-defined procedures are 
completed.  However, information collected from samples prior to the request for 
destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the Investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 


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discoveries, or derivative materials gained or produced from the sample.  
See Section 11.3 for subject confidentiality. 
7.7 
Standardization of Study Procedures 
7.7.1 
Measurement of Vital Signs 
Blood pressure (BP) and heart rate (HR) will be measured at each visit.  Use of an 
automated oscillometric device for BP measurement is preferred and recommended.  BP 
will initially be recorded in both of the subject’s arms unless a concomitant condition 
favors the use of a particular arm.  The arm with the higher systolic reading at screening 
will then be used for BP determinations throughout the study.  The appropriate size cuff 
should be used.  BP and HR measurements will be determined after the subject has 
been seated for at least 5 minutes.  The subject’s pulse should be measured for 
30 seconds and the number multiplied by 2 to obtain heart rate.  Before randomization, 
BP measurement can be repeated if the previous reading is outside of the eligibility 
range.  The repeat BP measure should be taken at least 2 minutes following the 
previous measure. 
7.7.2 
Waist Circumference 
Subjects should wear minimal clothing to ensure that the measuring tape is correctly 
positioned.  Subjects should stand erect with the abdomen relaxed, arms at the sides, 
feet together and with their weight equally divided over both legs.  To perform the waist 
measurement, the lowest rib margin is first located and marked with a pen.  The iliac 
crest is then palpated in the midaxillary line, and also marked.  It is recommended to 
apply an elastic tape horizontally midway between the lowest rib margin and the iliac 
crest, and tie firmly so that it stays in position around the abdomen about the level of the 
umbilicus.  The elastic tape thus defines the level of the waist circumference, which can 
then be measured by positioning the measuring tape over the elastic tape.  Subjects are 
asked to breathe normally, and to breathe out gently at the time of the measurement to 
prevent them from contracting their muscles or from holding their breath.  Measurements 
should be performed using the same procedure throughout the study.  The reading is 
taken to the nearest centimeter or ½ inch and entered in the source document. 
7.7.3 
Subject Compliance With Atorvastatin Dosing 
Once the subject has been enrolled, if compliance with atorvastatin falls below 80% or 
goes above 120% (as determined by evaluation of the number of tablets prescribed), the 
investigator (or designee) must re-instruct the subject on proper dosing of the study 
medication as well as determine the factors that resulted in poor compliance with study 


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medication.  Subject compliance will be determined by counting the number of tablets 
returned against the number of days the subject should have taken the drug.  
Compliance should be assessed at the timepoints indicated in Table 1 or as instructed 
by Amgen. 
7.7.4 
Electrocardiograms 
At each scheduled visit where ECGs are being obtained ECGs will be collected in 
triplicate approximately 1 minute apart.  Using equipment supplied to each site, all 
protocol-specified ECGs will be acquired and transmitted to the centralized ECG 
services provider.  The PI or designated physician will review acquired ECGs.  One (1) 
signed, original ECG tracing should be retained with the subject’s source documents.  At 
the request of the sponsor, the original ECG should be made available to Amgen to be 
manually read by a central reader. 
The centralized ECG services cardiologists will perform standard interpretations of all 
tracings.  A cardiologist reviewed ECG report will be provided to the study site.  
Investigators must initial and date the ECG reports upon receipt.  If the investigator’s 
interpretation of any protocol-specified or unscheduled ECG differs from that supplied by 
centralized ECG services provider, it is the responsibility of the investigator to make the 
final clinical decisions.  The investigator’s interpretation does not need to be reconciled 
with that supplied by centralized ECG services cardiologists.  Any clinical interventions 
based on these results need to be documented in the appropriate source documents 
and eCRF as applicable.  It is the responsibility of the investigator to obtain additional 
ECGs required for the clinical management of the subject, using centralized ECG 
services equipment or equipment on-site. 
Further detail about the equipment provided and its use for this study will be provided in 
an Investigator ECG Manual distributed to the sites before start of enrollment. 
7.7.5 
Lipid Measurements 
Only the screening LDL-C concentration will be reported to the site for the eligibility 
decision.  Central laboratory results of the lipid panel, as well as ApoA1, ApoB, and 
lipoprotein(a) (and PCSK9 and hsCRP) will be blinded post-treatment until unblinding of 
the clinical database. and will not be reported to the investigator post-screening.  In 
addition, investigators and staff involved with this trial and all medical staff involved in 
the subject’s medical care should refrain from obtaining lipid panels from randomization 
until at least 12 weeks after the subject’s last administration of IP or until the subject 
ends the study, whichever is later (to avoid potential unblinding).  If a lipid panel is 


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drawn, all reasonable steps must be undertaken to avoid informing the subject and study 
personnel of the results. 
7.7.6 
Mixed Meal Tolerance Test (All Subjects) 
A liquid mixed meal tolerance test (MMTT) will be performed after an overnight fast (no 
food or drinks other than water for ≥ 9 hours) at the day 1 and the week 12 study visit.  
Each MMTT should be done at approximately the same time of day throughout the study 
(± 2 hours).  The fasting venous blood samples at each of these 2 visits should be 
collected as close as possible before consuming a standardized mixed meal (see below) 
and before the subject receives any food or drink (other than water) or investigational 
product.  Subjects are then fed a standardized mixed meal, as defined in Table 3 below, 
for example Boost.  The same type standardized mixed meal should be used for day 1 
and for week 12.   
The beginning of the consumption of the liquid mixed meal is considered time “0” of the 
MMTT.  Postprandial blood samples are collected at 120 ± 10 min after consumption of 
the standardized mixed meal for assessment of the following analytes: 
• 
plasma glucose, insulin, proinsulin, C-peptide, free fatty acids, glucagon, lipids, 
chylomicrons, ApoB48, IL-6, adiponectin, vitamin E. 
Table 3.  Standardized Mixed Meal 
Content component 
Grams 
Grams % 
Calories (kcal) 
Calories % 
Protein 
15 
28 
60 
25 
Total Fat 
6 
11 
48 
20 
Carbohydrate 
33 
61 
132 
55 
Totals 
54 
100 
240 
100 
aComponent weight in standardized mixed meal used can differ but total calories should not differ by more 
than ± 10% of 240 kcal. The same type standard mixed meal should be used for day 1 and week 12. 
7.7.7 
Mixed Meal Tolerance Test Extended Timepoints Substudy 
Where offered and locally approved for the study center, subjects can be invited to 
participate in a MMTT Extended Timepoints Substudy.  Enrollment into the substudy will 
be capped at approximately 240 subjects.  The substudy consists of 2 additional 
postprandial blood draws in the MMTT on day 1 and week 12 as per Section 7.7.6.  
Postprandial blood draws for subjects participating in the substudy will be at the 
following timepoints after consumption of the standardized meal: 
• 
60 ± 10 min 
• 
120 ± 10 min 
• 
180 ± 10 min 


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The same postprandial analytes as per Section 7.7.6 will be measured at each of these 
timepoints.  
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subject’s Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects (or a legally acceptable representative) can decline to continue receiving IP 
and/or other protocol-required therapies or procedures at any time during the study but 
continue participation in the study.  If this occurs, the Investigator is to discuss with the 
subject the appropriate processes for discontinuation from IP or other protocol-required 
therapies and must discuss with the subject the options for continuation of the Schedule 
of Assessments (Table 1) and collection of data, including endpoints and adverse 
events.  The Investigator must document the change to the Schedule of Assessments 
(Table 1) and the level of follow-up that is agreed to by the subject (eg, in person, by 
telephone/mail, through family/friends, in correspondence/communication with other 
physicians, from review of the medical records).   
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publically available 
data can be included after withdrawal of consent.  The Investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.  The investigator should 
ask the subject’s consent to perform the procedures listed under the final study visit. 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subject’s Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product and/or other protocol-required therapies, protocol procedures, or the study as a 
whole at any time prior to study completion.   
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 12.1. 


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8.3 
Reasons for Removal From Screening, Lipid Stabilization, 
Treatment, or Study 
8.3.1 
Reasons for Removal From Screening or Lipid Stabilization 
Reasons for removal from screening or lipid stabilization include any of the following: 
• 
subject request  
• 
safety concern (eg, due to an adverse event, failure to follow contraception, 
pregnancy, breast feeding, and/or atorvastatin withholding requirements) 
• 
decision by sponsor (other than subject request or safety concern) 
• 
death 
• 
lost to follow-up 
8.3.2 
Reasons for Removal From Treatment  
Reasons for removal from protocol-required investigational products or procedural 
assessments include any of the following: 
• 
subject request   
• 
safety concern (eg, due to an adverse event, failure to follow contraception, 
pregnancy, breast feeding, and/or protocol requirements) 
• 
death 
• 
lost to follow-up 
• 
decision by Sponsor (other than subject request, safety concern, lost to follow-up) 
8.3.3 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
• 
decision by sponsor  
• 
withdrawal of consent from study 
• 
death 
• 
lost to follow-up 
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.  
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, 


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diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected, and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study or 
involves an intervention such as elective cosmetic surgery or a medical procedure while 
on study, is not considered an adverse event. 
An adverse device effect is any adverse event related to the use of a medical device.  
Adverse device effects include adverse events resulting from insufficient or inadequate 
instructions for use, adverse events resulting from any malfunction of the device, or 
adverse events resulting from use error or from intentional misuse of the device. 
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study. 
9.1.2 
Definition of Serious Adverse Events 
A serious adverse event 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, DILI (see Appendix A for 
drug-induced liver injury reporting criteria), or events that necessitate an emergency 
room visit, outpatient surgery, or urgent intervention. 


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9.2 
Reporting of Adverse Events 
9.2.1 
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after randomization and all adverse 
events possibly related to study procedures from signing the informed consent through 
the end of study are reported using the applicable eCRF (eg, Adverse Event Summary). 
The investigator must assign the following adverse event attributes: 
• 
adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
• 
dates of onset and resolution (if resolved), 
• 
severity 
• 
assessment of relatedness to investigational products (evolocumab or placebo 
and/or the medical device(s) AI/Pen or 3.5 mL Personal Injector), or any 
study-mandated activity or procedure, respectively, and 
• 
action taken. 
The adverse event grading scale used will be the most current version of the NCI 
Common Terminology Criteria for AEs (CTCAE) grading scale.  The grading scale used 
in this study is referenced in Appendix A.   
The investigator must assess whether the adverse event is possibly related to IP 
(evolocumab or placebo).  This relationship is indicated by a “yes” or “no” response to 
the question: Is there a reasonable possibility that the event may have been caused by 
IP?   
The investigator must assess whether the adverse event is possibly related to the 
prefilled AI/Pen or 3.5 mL Personal Injector device used to administer IP.  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 other 
study-mandated activity (eg, screening / lipid stabilization procedure or background 
therapy).  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 another study 
activity (eg, screening / lipid stabilization procedure or background therapy)?” 
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 


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findings without clinical significance (based on the investigator's judgment) are not to be 
recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. 
The Investigator is expected to follow reported adverse events until stabilization or 
reversibility.  If the severity of an adverse event worsens from the date of onset to the 
date of resolution, record a single event for each increased level of severity on the 
Adverse Event eCRF. 
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 IP or EOS, whichever is later, are 
recorded in the subject’s medical record and are submitted to Amgen.  All serious 
adverse events must be submitted to Amgen within 24 hours following the investigator’s 
knowledge of the event via the applicable eCRF.   
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.  
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
Serious Adverse Event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event (eSAE) Contingency Report Form within 24 hours of the 
investigator’s knowledge of the event.  See Appendix B for a sample of the Serious 
Adverse Event Worksheet/electronic Serious Adverse Event Contingency Report Form.  
If the first notification of a Serious Adverse Event is reported to Amgen via the eSerious 
Adverse Event (eSAE) Contingency Report Form, the data must be entered into the 
EDC system when the system is again available.   
The investigator must assess whether the serious adverse event is possibly related to IP 
(evolocumab or placebo).  This relationship is indicated by a “yes” or “no” response to 


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the question: Is there a reasonable possibility that the event may have been caused by 
IP? 
The investigator must assess whether the serious adverse event is possibly related to 
the prefilled AI/Pen or 3.5 mL Personal Injector device used to administer IP.  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 (eg, screening / lipid stabilization procedure or 
background therapy).  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 
another study activity (eg, screening / lipid stabilization procedure or background 
therapy)?” 
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility.  If the severity of a serious adverse event worsens from the date of onset 
to the date of resolution, record a single event for each increased level of severity on the 
Adverse Event eCRF.  
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 protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities.  Investigators 
will receive notification of related serious adverse events reports sent to regulatory 
authorities in accordance with local requirements. 
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 


Product:  Evolocumab 
Protocol Number:  20120119 
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in compliance with all reporting requirements according to local regulations and good 
clinical practice.  
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local 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 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 15 weeks after the end of treatment with IP. 
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C).   
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 
15 weeks after the end of treatment with IP.  
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours 
of the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C). 
10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Co-primary Efficacy Endpoints 
• 
mean percent change from baseline in LDL-C at weeks 10 and 12 
• 
percent change from baseline in LDL-C at week 12 


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10.1.1.2 
Co-secondary Efficacy Endpoints 
Co-secondary efficacy endpoints are (1) the mean of weeks 10 and 12 and (2) week 12 
for: 
Tier 1 endpoints 
• 
change from baseline in LDL-C 
• 
percent change from baseline in non-HDL-C 
• 
percent change from baseline in ApoB100 
• 
percent change from baseline in the total cholesterol 
• 
percent change from baseline in the total cholesterol/HDL-C ratio 
• 
percent change from baseline in ApoB100/ApoA1 ratio 
• 
achievement of target LDL-C < 70 mg/dL (1.8 mmol/L) 
Tier 2 endpoints 
• 
percent change from baseline in Lp(a) 
• 
percent change from baseline in triglycerides 
• 
percent change from baseline in HDL-C 
• 
percent change from baseline in VLDL-C 
10.1.1.3 
Co-tertiary Efficacy Endpoints 
• 
mean percent change from baseline at weeks 10 and 12 and percent change from 
baseline at week 12 in ApoA1  
10.1.1.4 
Exploratory Endpoints 
• 
subject incidence of non-coronary revascularization 
• 
change and percent change from baseline at each scheduled assessment in each of 
the following parameters: 
− 
LDL-C 
− 
total cholesterol 
− 
non-HDL-C 
− 
ApoB100 
− 
total cholesterol/HDL-C ratio 
− 
ApoB100/ApoA1 ratio 
− 
VLDL-C 
− 
HDL-C  
− 
ApoA1 


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− 
triglycerides 
− 
Lp(a) 
• 
hsCRP at each scheduled assessment 
• 
HbA1c at each scheduled assessment 
• 
PCSK9 change from baseline at each scheduled assessment 
• 
fasting and post-prandial laboratory parameters of interest (including MMTT 
Extended Timepoints Substudy assessments) 
10.1.1.5 
Safety Endpoints 
• 
subject incidence of treatment emergent adverse events  
• 
safety laboratory values and vital signs at each scheduled assessment  
• 
ECG parameters (such as RR, PR, QRS, QT and QTc intervals) at each scheduled 
assessment 
• 
incidence of anti-evolocumab antibody (binding and neutralizing) formation 
10.1.1.6 
Pharmacokinetics Endpoints 
• 
serum concentration of evolocumab at selected time points 
10.1.2 
Analysis Sets 
The full analysis set (FAS) includes all randomized subjects who received at least 
1 dose of IP.  This analysis set will be used in both efficacy and safety analyses.  In 
efficacy analyses, subjects will be grouped according to their randomized treatment 
group assignment.  For safety analyses, subjects will be grouped according to their 
randomized treatment group assignment with the following exception: if a subject 
receives treatment throughout the study that is different than the randomized treatment 
group assignment, then the subject will be grouped by the actual treatment group.   
The completer analysis set (CAS) includes subjects in the FAS who adhered to the 
scheduled IP regimen and have observed value for the co-primary endpoints.   
10.1.3 
Covariates and Subgroups 
Baseline covariates include, but are not limited to: 
• 
stratification factors: 
− 
statin therapy at study entry (no statin use vs non-intensive statin use vs 
intensive statin use [see Appendix D]   
− 
site’s geographic region 
• 
age: < 65 years, ≥ 65 years 
• 
sex 
• 
race 


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• 
baseline LDL-C: < median, ≥ median 
• 
family history of premature coronary heart disease: yes, no 
• 
baseline PCSK9 level: < median, ≥ median 
10.2 
Sample Size Considerations 
The sample size is 300 subjects for each of the evolocumab SC in combination with 
atorvastatin arms, and 150 subjects for each of the placebo in combination with 
atorvastatin arms.  The sample size should provide adequate power to determine the 
superiority of evolocumab in combination with atorvastatin to placebo in combination 
with atorvastatin as measured by the co-primary endpoints in both dose frequencies 
using the FAS. The primary analysis will require the tests of each co-primary endpoint to 
be significant at a level of 0.05 (Section 10.5).  From the global phase 2 studies in the 
evolocumab program, the treatment effect measured as the mean of week 10 and 
week 12 were as large or larger than week 12 and highly correlated (> 85%) with ones at 
week 12.  From the global phase 2 study 20110155, the treatment effects (on top of 
stable background statin therapy) of evolocumab compared to placebo for 140 mg Q2W 
and 420 mg QM in the mean percent change from baseline in LDL-C are -66.10 
(95% CI [-71.48,-60.72])  and -50.33 (95% CI [-56.04,-44.62]) at week 12, respectively 
and the observed evolocumab dose group means in the type 2 diabetes mellitus cohort 
were comparable to the overall population. The power calculation is derived assuming a 
treatment effect in the percent reduction of LDL-C of at least 35% at week 12 in each 
dose frequency, with a common standard deviation (SD) of 20%. It is assumed that 
approximately 15% of subjects randomized into IP will end IP early, thus attenuating the 
treatment effects. It is assumed there will be no treatment effect differences among 
treatment groups after these subjects end IP early.  After accounting for treatment 
attenuation due to early IP termination, the assumed treatment effect is a 30% reduction 
in LDL-C with a common SD of 30%. Assuming 2% of randomized subjects do not 
receive any IP, the planned sample size will provide at least 99% power in testing the 
superiority of evolocumab in combination with atorvastatin to placebo in combination 
with atorvastatin at week 12 in each dose frequency. Therefore, the sample size as 
planned will provide at least 98% (99% x 99%) power for the co-primary endpoints in 
each of the dose frequencies.  
Since the testing statistics from the Q2W and QM groups are independent, there is 
approximately a 96% (98% x 98%) chance to show the superiority of both dose 
frequencies for the co-primary endpoints. 


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Sample size assumptions, such as the missing value rate, will be monitored by the study 
team while maintaining study blind. 
The power calculation is derived using nQuery version 7.01. 
10.3 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
Blinded individuals will not have access to unblinded information until the study is 
formally unblinded.  Unblinding and potentially unblinding information should not be 
distributed to the study team, investigators or subjects prior to the study being formally 
unblinded (eg, the formal unblinding may occur at the final analysis rather than during 
the primary analysis) except as specified (eg, Section 5.2 and Section 9.2.2). 
Individual subject treatment assignments will be maintained by the IVRS/IWRS. Any 
unplanned unblinding occurring during the study period will be documented and reported 
in the final clinical study report. 
The independent DMC members and Independent Biostatistical Group (IBG) will have 
access to treatment assignments and subject level data from the clinical trial database.  
Amgen staff members who are involved in randomization, biological sample 
management, performing PK, and anti-evolocumab antibody assay analysis will have 
treatment assignment information but will not have access to subject level data from the 
clinical trial database. 
10.4 
Planned Analyses 
10.4.1 
Data Monitoring Committee (DMC) 
An external independent DMC has been established to formally review the accumulating 
data from this and other completed and ongoing studies with evolocumab to ensure 
there is no avoidable increased risk for harm to subjects.  The independent DMC is 
chaired by an external academic cardiologist who is an expert in lipids and clinical trials.  
Analyses for the DMC are provided by the Independent Biostatistical Group (IBG), which 
is external to Amgen.  Details are provided in the DMC charter.  
10.4.2 
Primary Analysis 
The primary analysis will be conducted when all subjects have either completed all the 
scheduled study visits or have early terminated from the study.  At that time, the 
database will be cleaned, processed and a snapshot will be taken; the study will also be 
unblinded.  Based on the snapshot, efficacy and safety analyses will be performed on 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
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the FAS.  Unless specified otherwise, the FAS will be the default analysis set in this 
study and data will be summarized by randomized treatment group.  
Analyses will be performed separately by each dose frequency (Q2W and QM) unless 
specified otherwise. 
10.5 
Planned Methods of Analysis  
Subject disposition, demographics, baseline characteristics, and exposure to IP will be 
summarized. 
General Considerations 
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.   
Methods of handling missing data for efficacy endpoints will be described throughout this 
section.  Missing data will not be imputed for safety endpoints. 
In order to preserve the familywise error rate at 0.05, each independent dose frequency 
(Q2W and QM) will be allocated a significance level of 0.05.  For FAS, methods of 
adjusting for multiplicity due to testing the superiority of evolocumab in combination with 
atorvastatin to placebo in combination with atorvastatin for both the co-primary and 
co-secondary efficacy endpoints for the co-primary endpoints within each dose 
frequency are described in the diagram below. 
Multiplicity Adjustment Method 


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Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 69 of 90 
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measures model will include terms for treatment group, stratification factors, scheduled 
visit and the interaction of treatment with scheduled assessment.  Missing values will not 
be imputed when the repeated measures linear effects model is used. 
The statistical significance of the treatment effect difference between evolocumab in 
combination with atorvastatin and placebo in combination with atorvastatin will be tested. 
Multiplicity adjustment procedures are defined in Section 10.5.  
Sensitivity Analysis 
To evaluate the robustness of the analysis results, sensitivity analyses will be performed 
as follows: 
• 
The primary analysis will be repeated using the CAS. 
• 
Non-parametric analyses will be performed.  
Subgroup Analysis 
If applicable, subgroup analyses on the co-primary endpoints will be conducted using the 
stratification factors and baseline covariates.   
10.5.2 
Co-secondary Efficacy Endpoints 
The statistical model and testing of the tier 1 co-secondary efficacy endpoints will be 
similar to the primary analysis of the co-primary endpoints.  The co-secondary efficacy 
endpoints of LDL-C target achievement will be analyzed using the 
Cochran-Mantel-Haenszel (CMH) test adjusted by the stratification factors. 
Analyses of the tier 2 co-secondary efficacy endpoints will use the same analysis model 
as the tier 1 endpoints, and testing will use a union-intersection test. 
Multiplicity adjustment procedure of testing evolocumab in combination with atorvastatin 
vs. placebo in combination with atorvastatin for co-secondary endpoints is defined in 
Section 10.5. 
10.5.3 
Safety Endpoints 
Adverse Events 
Adverse events will be coded using the current version of the Medical Dictionary for 
Regulatory Activities (MedDRA).  Subject incidences of treatment-emergent adverse 
events, serious adverse events and adverse events leading to discontinuation of IP will 
be tabulated by system organ class and preferred term for each treatment group. 


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Safety Laboratory Parameters 
Laboratory parameters will be summarized for each treatment group using descriptive 
statistics at each scheduled assessment.  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 EOS. 
Vital Signs 
Vital signs will be summarized for each treatment group using descriptive statistics at 
each scheduled assessment. 
Electrocardiogram 
RR, PR, QRS, QT, and QTc intervals will be summarized by treatment group at each 
scheduled assessment.  Frequency tables for maximal QTc and maximal change in QTc 
at post-dose period using the categories suggested in the ICH E14 guidelines will be 
provided by treatment group. 
Concomitant Medications 
Concomitant medications of interest will be summarized for each treatment group. 
Anti-evolocumab antibodies 
The incidence and percentages of subjects who develop anti-AMG145 antibodies 
(binding and neutralizing) at anytime will be tabulated. 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the template are to 
be communicated formally in writing from the Amgen Clinical Study Manager or 
designee to the investigator.  The written informed consent document is to be prepared 
in the language(s) of the potential patient population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol-specific screening procedures or any investigational product(s) is/are 
administered. 


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The acquisition of informed consent is to be documented in the subject’s medical 
records, and the informed consent form  is to be signed and personally dated by the 
subject and by the person who conducted the informed consent discussion.  The original 
signed informed consent form is to be retained in accordance with institutional policy, 
and a copy of the signed consent form is to be provided to the subject. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
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. 
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IRB/IEC for 
written approval.  A copy of the written approval of the protocol and 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 IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator is to notify the IRB/IEC of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures. 
The investigator is responsible for obtaining annual IRB/IEC approval or renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IRB/IEC continuance of approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen.   
• 
Subjects are to be identified by a unique subject identification number. 
• 
Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations.   
• 
On the CRF demographics page, in addition to the unique subject identification 
number, include the age at time of enrollment.   


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• 
For Serious Adverse Events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with 
local laws and regulations), and date of birth (in accordance with local laws and 
regulations). 
• 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are 
to be kept in confidence by the investigator, except as described below. 
In compliance with International Conference on Harmonization Good Clinical Practice 
(ICH GCP) Guidelines, it is required that the investigator and institution permit 
authorized representatives of the company, of the regulatory agency(s), and the IRB/IEC 
direct access to review the subject’s original medical records for verification of 
study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of 
the study.  The investigator is obligated to inform and obtain the consent of the subject to 
permit such individuals to have access to his/her study-related records, including 
personal information. 
11.4 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of 
multi-center studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
• 
a recognized expert in the therapeutic area 
• 
an Investigator who provided significant contributions to either the design or 
interpretation of the study 
• 
an Investigator contributing a high number of eligible subjects 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
If Amgen amends the protocol, agreement from the Investigator must be obtained.  The 
IRB/IEC must be informed of all amendments and give approval.  The investigator must 
send a copy of the approval letter from the IRB/IEC to Amgen. 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
Investigator reserve the right to terminate the Investigator’s participation in the study 
according to the study contract.  The investigator is to notify the IRB/IEC in writing of the 
study’s completion or early termination and send a copy of the notification to Amgen.   
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  


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However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
12.2 
Study Documentation and Archive 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
In this study, the IVRS/IWRS system captures the following data points and these are 
considered source data:  protocol number, site number, subject ID, gender, date of birth, 
date informed consent was signed, treatment group assignment, screen failure reason, 
randomization date, randomization number and IP box ID assignment. 
eCRF entries may be considered source data if the CRF is the site of the original 
recording (ie, there is no other written or electronic record of data). 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.  Elements should include: 
• 
Subject files containing completed CRF, informed consent forms, and subject 
identification list 
• 
Study files containing the protocol with all amendments, 
AMG 145 Investigator’s Brochure, copies of prestudy documentation, and all 
correspondence to and from the IRB and Amgen 
• 
If kept, proof of receipt, Investigational Product Accountability Record, Return of 
Investigational Product for Destruction, Final Investigational Product Reconciliation 
Statement (if applicable), and all drug-related correspondence 
• 
Non-investigational product(s) and or medical device documentation, as applicable. 
In addition, all original source documents supporting entries in the eCRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 


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


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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 for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 1), the investigator can search publically available 
records [where permitted]) to ascertain survival status.  This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible.   
12.5 
Language 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.   
12.6 
Publication Policy 
To coordinate dissemination of data from this study, Amgen encourages the formation of 
a publication committee consisting of several investigators and appropriate Amgen staff, 
the governance and responsibilities of which are set forth in a Publication Charter.  The 
committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff as appropriate as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 


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Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors), which states (August 2013 
revision): 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published; (4) agreement to be accountable for all aspects of the work 
in ensuring that questions related to the accuracy or integrity of any part of the work 
are appropriately investigated and resolved.  Authors should meet conditions 1, 2, 3, 
and 4. 
• 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 
• 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
• 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
• 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
12.7 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 


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13. 
REFERENCES 
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Amgen. AMG 145 Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc. 
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Brown MS, Goldstein JL.  Biomedicine.  Lowering LDL--not only how low, but how long? 
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Bruckert E, Hayem G, Dejager S, Yau C, B´egaud B. Mild to Moderate Muscular 
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Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with 
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Cannon CP, Braunwald E, McCabe CH, et al.  Intensive versus moderate lipid lowering 
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Celermajer DS, Chow CK, Marijon E, Anstey NM, Woo KS.  Cardiovascular disease in 
the developing world: prevalences, patterns, and the potential of early disease detection.  
J Am Coll Cardiol. 2012;60:1207-1216. 
Chinese Society of Cardiology of Chinese Medical Association, Editorial Board of 
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Cholesterol Treatment Trialists' (CTT) Collaboration, Baigent C, Blackwell L, et al.  
Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of 
data from 170,000 participants in 26 randomised trials.  Lancet.  2010;376:1670-1681. 


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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. 
Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular 
disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes 
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2004;364:685-696. 
Collins R, Armitage J, Parish S, Sleigh P, Peto R; Heart Protection Study Collaborative 
Group.  MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 
5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 
2003;361:2005-2016. 
Collins R, Armitage J, Parish S, Sleight P, Peto R; Heart Protection Study Collaborative 
Group.  Effects of cholesterol-lowering with simvastatin on stroke and other major 
vascular events in 20536 people with cerebrovascular disease or other high-risk 
conditions.  Lancet.  2004;363:757-767. 
Dias CS, Shaywitz AJ, Wasserman SM, at al. Effects of AMG 145 on low-density 
lipoprotein cholesterol levels: results from 2 randomized, double-blind, 
placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and 
hypercholesterolemic subjects on statins. J Am Coll Cardiol. 2012;60:1888-1898. 
Franc S, Dejager S, Bruckert E, Chauvenet M, Giral P, Turpin G. A comprehensive 
description of muscle symptoms associated with lipid-lowering drugs. Cardiovasc Drugs 
Ther. 2003;17:459-465. 
Giugliano RP, Desai NR, Kohli P, et al. Efficacy, safety, and tolerability of a monoclonal 
antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in 
patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, 
placebo-controlled, dose-ranging, phase 2 study. Lancet. 2012;380:2007-2017.  
Grundy SM, Cleeman JI, Merz CN, et al.  Implications of recent clinical trials for the 
National Cholesterol Education Program Adult Treatment Panel III Guidelines.  
Circulation.  2004;110:227-239. 
Hackam DG, Woodward M, Newby LK, et al.  Statins and intracerebral hemorrhage: 
collaborative systematic review and meta-analysis.  Circulation.  2011;124:2233-2242. 
He J, Gu D, Wu X, et al. Major causes of death among men and women in China. N 
Engl J Med. 2005;353:1124-34. 
Hiro T, Kimura T, Morimoto T, et al.  Effect of intensive statin therapy on regression of 
coronary atherosclerosis in patients with acute coronary syndrome: a multicenter 
randomized trial evaluated by volumetric intravascular ultrasound using pitavastatin 
versus atorvastatin (JAPAN-ACS [Japan assessment of pitavastatin and atorvastatin in 
acute coronary syndrome] study).  J Am Coll Cardiol.  2009;54:293-302. 
Hochberg Y.  A sharper Bonferroni procedure for multiple tests of significance.  
Biometrika 1988;75:800-802. 
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.  


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Horton JD, Cohen JC, Hobbs HH.  Molecular biology of PCSK9: its role in LDL 
metabolism.  Trends Biochem Sci.  2007;32:71-77. 
Imano H, Noda H, Kitamura A, et al.  Low-density lipoprotein cholesterol and risk of 
coronary heart disease among Japanese men and women: the Circulatory Risk in 
Communities Study (CIRCS).  Prev Med.  2011;52:381-386. 
Iso H.  Lifestyle and cardiovascular disease in Japan.  J Atheroscler Thromb.  
2011;18:83-88. 
Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD.  Serum cholesterol levels and 
six-year mortality from stroke in 350,977 men screened for the multiple risk factor 
intervention trial.  N Engl J Med.  1989;320:904-910. 
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. 
Khoo KL, Tan H, Liew YM, Janus DE. Lipid and coronary heart disease in Asia. 
Atherosclerosis. 2003;169:1–10. 
Kim HS, Wu Y, Lin SJ, et al. Current status of cholesterol goal attainment after statin 
therapy among patients with hypercholesterolemia in Asian countries and region: the 
Return on Expenditure Achieved for Lipid Therapy in Asia (REALITY-Asia) study. 
Curr Med Res Opin. 2008;24:1951-1963.  
Koizumi J, Shimizu M, Miyamoto S, Origasa H, Mabuchi H.  Effect of 
pravastatin-induced LDL-cholesterol reduction on coronary heart disease and 
cerebrovascular disease in Japanese: Hokuriku lipid coronary heart disease 
study-pravastatin atherosclerosis trial (Holicos-PAT).  J Atheroscler Thromb.  
2002;9:251-259. 
Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerability of a monoclonal 
antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with 
hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, 
phase 2 study. Lancet. 2012;380:1995-2006.  
LaRosa JC, Grundy SM, Waters DD, et al.  Intensive lipid lowering with atorvastatin in 
patients with stable coronary disease.  N Engl J Med.  2005;352:1425-1435. 
Libby P.  The forgotten majority: unfinished business in cardiovascular risk reduction.  
J Am Coll Cardiol.  2005;46:1225-1228. 
LIPITOR® [package insert]. New York, NY: Pfizer Inc; 2012. 
http://labeling.pfizer.com/ShowLabeling.aspx?id=587. Accessed January 30, 2013. 
Liu L. Cardiovascular diseases in China. Biochem. Cell Biol. 2007;85:157-163. 
Mansur Ade P, Favarato D, Avakian SD, Ramires JA.  Trends in ischemic heart disease 
and stroke death ratios in Brazilian women and men.  Clinics (Sao Paulo). 
2010;65:1143-1147. 


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Menotti A, Lanti M, Kromhout D, et al. Homogeneity in the relationship of serum 
cholesterol to coronary deaths across different cultures: 40-year follow-up of the Seven 
Countries Study. Eur J Cardiovasc Prev Rehabil. 2008;15:719-725. 
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, 
and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third 
Report of the National Cholesterol Education Program (NCEP) Expert Panel on 
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult 
Treatment Panel III) final report. Circulation. 2002;106:3143-3421. 
Nakamura H, Arakawa K, Itakura H et al.  Primary prevention of cardiovascular disease 
with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial.  
Lancet.  2006;368:1155-1163. 
Newman C, Tsai J, Szarek M, Luo D, Gibson E.  Comparative safety of atorvastatin 
80 mg versus 10 mg derived from analysis of 49 completed trials in 14,236 patients.  
Am J Cardiol.  2006;97:61-67. 
Olyaei A, Greer E, Delos Santos R, Rueda J. The Efficacy and Safety of the 
3-Hydroxy-3- methylglutaryl-CoA Reductase Inhibitors in Chronic Kidney Disease, 
Dialysis, and Transplant Patients. Clin J Am Soc Nephrol.2011;6: 664–678. 
Raal F, Scott R, Somaratne R, et al. Low-density lipoprotein cholesterol-lowering effects 
of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 
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Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial 
Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation. 
2012;126:2408-2417.  
Reiner Z, Catapano AL, De Backer G, et al. ESC/EAS Guidelines for the management of 
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J. 2011;32:1769-1818 
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update: a report from the American Heart Association. Circulation. 2011;123:e18-e209. 
Sarwar N, Danesh J, Eiriksdottir G, et al.  Triglycerides and the risk of coronary heart 
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Sever PS, Poulter NR, Dahlöf B, et al. Reduction in cardiovascular events with 
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Sullivan D, Olsson AG, Scott R, et al. Effect of a monoclonal antibody to PCSK9 on 
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14. 
APPENDICES 


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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
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: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications\ctc.htm. 
Drug-induced Liver Injury Reporting & Additional Assessments  
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation according to the criteria specified in Section 6.4 require 
the following: 
• 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
• 
The appropriate CRF (eg, Adverse Event CRF) that captures information necessary 
to facilitate the evaluation of treatment-emergent liver abnormalities is to be 
completed and sent to the Amgen.  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.2.2. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Sections 6.5.1 and 6.5.2 or who experience AST or ALT elevations >3 x ULN are to 
undergo a period of “close observation” until abnormalities return to normal or to the 
subject’s baseline levels.  Assessments that are to be performed during this period 
include:  
• 
Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours  
• 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 


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Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic 
• 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL: 
− 
Obtain complete blood count (CBC) with differential to assess for eosinophilia 
− 
Obtain serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti 
Smooth Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to 
assess for autoimmune hepatitis 
− 
Obtain serum acetaminophen (paracetamol) levels 
− 
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 use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
− 
Obtain viral serologies 
− 
Obtain CPK, haptoglobin, Lactate dehydrogenase (LDH), and peripheral blood 
smear 
− 
Perform appropriate liver imaging if clinically indicated 
• 
Obtain appropriate blood sampling for pharmacokinetic analysis if this has not 
already been collected  
• 
Obtain hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist) 
• 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal.  The “close observation period” is to 
continue for a minimum of 4 weeks after discontinuation of all investigational 
product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding CRFs. 


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Appendix B.  Sample eSerious Adverse Event Contingency Reporting Form 
 


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Appendix C.  Pregnancy and Lactation Notification Worksheets 
  


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Appendix D.  Lipid Modifying Background Therapy Intensity 
(Group A) Intensive statin usage  
Subject has at least one of the following recorded for 
the last 4 weeks prior to screening: 
• 
atorvastatin ≥ 40 mg QD 
• 
rosuvastatin ≥ 20 mg QD 
• 
simvastatin ≥ 80 mg QD (note that 
simvastatin 80 mg QD is not approved in 
some countries, eg, the United States) 
• 
any statin1 QD plus ezetimibe 
(Group B) Non-intensive statin usage  
Subject has been taking any dose of a statin at least 
weekly for the last 4 weeks prior to screening and is 
not included in Group A  
(Group C) No statin 
Subject is not included in Group A or Group B 
Note:  Statin includes atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, 
and simvastatin. 


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Amendment 3 
Protocol Title:  A Double-blind, Randomized, Placebo-controlled, Multicenter 
Study to Evaluate Safety and Efficacy of Evolocumab (AMG 145) in Combination 
With Statin Therapy in Diabetic Subjects With Hyperlipidemia or Mixed 
Dyslipidemia 
 
Amgen Protocol Number Evolocumab 20120119 
EudraCT number 2013-000723-14 
 
Original Protocol Date: 
22 February 2013 
Amendment 1 Date: 
10 December 2013 
Superseding Amendment 1 Date: 
07 February 2014 
Amendment 2 Date: 
(applies to subjects in China only) 
29 July 2015 
Amendment 3 Date: 
11 November 2015 
Rationale: 
This protocol is being amended to remove potential endpoint (PEP) adjudication by the 
clinical events committee (CEC) and add/update safety language and adverse device 
effect reporting.   


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Description of Changes: 
Section:  Global  
Change:  Version dates updated throughout document from 29 July 2015 to 
11 November 2015. 
Section:  Global 
Change:  Typographic, grammatical, and formatting errors were corrected throughout 
the protocol. 
Section:  Title Page, Key Sponsor Contact(s) 
Replace: 
, MD 
One Amgen Center Drive  
Thousand Oaks, CA 91320, USA 
Phone:
Fax:  
Email: 
 
With: 
 
One Amgen Center Drive MS 27-2-C 
Thousand Oaks, CA 91320, USA 
Phone:
Fax:  
Email: 
 
Section:  Title Page 
Add: 
Amendment 3 Date: 
11 November 2015 
Section:  Synopsis, Study Design, 4th paragraph 
Replace: 
EOS for subjects on Q2W IP is by contact (eg, phone call) from the site at week 14 for 
any potential adverse events (AEs) or serious AEs (SAEs).  Subjects will be encouraged 
to complete all planned visits regardless of their adherence to IP administration.  Deaths 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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and specific cardiovascular (CV) events will be adjudicated by an independent external 
Clinical Events Committee (CEC) and accumulating safety and other data will be 
reviewed by an independent external Data Monitoring Committee (DMC). 
With: 
EOS for subjects on Q2W IP is by contact (eg, phone call) from the site at week 14 for 
any potential adverse events (AEs), adverse device effects (ADEs), and serious AEs 
(SAEs).  Subjects will be encouraged to complete all planned visits regardless of their 
adherence to IP administration.  Accumulating safety and other data will be reviewed by 
an independent external Data Monitoring Committee (DMC). 
Section:  Synopsis, Study Design, Summary of Subject Eligibility Criteria, 2nd paragraph 
Add: 
Female subjects cannot be pregnant, breast feeding, planning to become pregnant, or 
planning to breastfeed and premenopausal females must have to be willing to use (an) 
acceptable method(s) of effective birth control during treatment with investigational 
product (evolocumab or placebo) and for an additional 15 weeks after the end of 
treatment with investigational product (evolocumab or placebo). 
Section:  Synopsis, Study Design, Procedures, 1st paragraph 
Add: 
In addition, subjects receiving IP Q2W will be contacted (eg, by phone call) by the study 
site at week 14 (EOS for Q2W subjects) to obtain AE, ADE and SAE information, if 
applicable. 
Section:  Synopsis, Study Design, Procedures, 2nd paragraph 
Add: 
Vital signs, AEs/ADEs/SAEs, concomitant therapy, evaluation of fasting lipids, dietary 
instruction, physical exam, measuring waist circumference, body height and weight, 
12-lead ECGs, other laboratory assessments, including assessment for anti evolocumab 
antibodies, biomarker sample collection, serum pregnancy testing (females of 
childbearing potential), MMTT, urinalysis, and steroid analyte testing will be carried out 
per the Schedule of Assessment (Table 1) of the protocol.   


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 4 of 14 
CONFIDENTIAL 
 
 
 
Section:  Synopsis, Study Design, Statistical Considerations, General Considerations 
Delete: 
Methods of adjusting for multiplicity due to testing the superiority of evolocumab in 
combination with atorvastatin to placebo in combination with atorvastatin for both the 
co-primary and co-secondary efficacy endpoints within each dose frequency are 
provided in Section 10.5.  Events of death, myocardial infarction (MI), hospitalization for 
unstable angina, coronary revascularization, stroke, transient ischemic attack (TIA), and 
hospitalization for heart failure will be adjudicated by an independent CEC.   
Section:  Study Design, Study Design and Treatment Schema 
Add: 
  
 
Section:  Study Glossary 
Add: 
ADE 
Adverse device effect 
Section:  Study Glossary 
Delete: 
CEC 
Clinical events committee 
Section:  1.4, Exploratory 
Delete: 
• 
to estimate cardiovascular event rates in subjects treated with evolocumab, including 
aggregated exploratory analyses across the evolocumab program 
Section:  3.1, Study Design, 5th paragraph 
Replace: 
EOS for subjects on Q2W IP is by contact (eg, phone call) from the site at week 14 for 
any potential adverse events (AEs) or serious AEs (SAEs).  Subjects will be encouraged 
to complete all planned visits regardless of their adherence to IP administration.  Deaths 
and specific cardiovascular (CV) events will be adjudicated by an independent external 
*Only subjects receiving IP Q2W 
**Phone call for AEs/ADEs/SAEs for   
  subjects receiving SC IP  
  administration Q2W  


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 5 of 14 
CONFIDENTIAL 
 
 
 
Clinical Events Committee (CEC) and accumulating safety and other data will be 
reviewed by an independent external Data Monitoring Committee (DMC).   
With: 
EOS for subjects on Q2W IP is by contact (eg, phone call) from the site at week 14 for 
any potential adverse events (AEs), adverse device effects (ADEs), and serious AEs 
(SAEs).  Subjects will be encouraged to complete all planned visits regardless of their 
adherence to IP administration.  Accumulating safety and other data will be reviewed by 
an independent external Data Monitoring Committee (DMC). 
Section:  3.5.1, Study Duration for Subjects 
Add: 
For a subject on Q2W IP schedule, maximal study duration will be 22 weeks or 
approximately 5 ½ months, including the contact by the site at week 14 to obtain 
potential AE, ADE, and SAE information. 
Section:  4.1.2, Exclusion Criteria  
Replace: 
217 
Female subject who has either (1) not used (an) acceptable method(s) of birth 
control (see below) for at least 1 month prior to screening or (2) is not willing to 
inform her partner of her participation in this clinical study and to use such (an) 
acceptable method(s) during treatment with IP (evolocumab or placebo) and for 
an additional 15 weeks after the end of treatment with IP  (evolocumab or 
placebo), unless the female subject is sterilized or postmenopausal (see below); 
• 
A female is considered of childbearing potential unless sterilized or 
postmenopausal with 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 (FSH) 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 
With: 
217 
Female subject who has either (1) not used (an) acceptable method(s) of 
effective birth control (see below) for at least 1 month prior to screening and (2) 
is not willing to inform her partner of her participation in this clinical study and to 
use such (an) acceptable method(s) of effective birth control during treatment 
with IP (evolocumab or placebo) and for an additional 15 weeks after the end of 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 6 of 14 
CONFIDENTIAL 
 
 
 
treatment with IP  (evolocumab or placebo), unless the female subject is 
permanently sterilized or postmenopausal (see below); 
• 
A female is considered of childbearing potential unless permanently 
sterilized or postmenopausal with menopause 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 (FSH) 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 
Section:  4.1.2, Exclusion Criteria, 217 
Replace: 
• 
acceptable methods of preventing pregnancy include not having intercourse, 
(sexual abstinence), surgical contraceptive methods - (vasectomy of the male 
partner or bilateral tubal ligation/occlusion), use of hormonal birth control 
methods (pills, shots/injections, implants, or patches), intrauterine devices 
(IUDs), or two
With: 
 (2) barrier methods (each partner must use one barrier 
method) with spermicide - males must use a condom with spermicide; 
females must choose either a diaphragm with spermicide, OR cervical cap 
with spermicide, OR contraceptive sponge with spermicide.  
• 
acceptable methods of preventing pregnancy include not having intercourse, 
(true sexual abstinence), surgical contraceptive methods - (vasectomy of the 
male partner or bilateral tubal ligation/occlusion), use of hormonal birth 
control methods (pills, shots/injections, implants, or patches), intrauterine 
devices (IUDs), or two
Section:  5, Subject Enrollment 
 (2) barrier methods (each partner must use one barrier 
method) and at least one of the barrier methods must include spermicide 
- males must use a condom with spermicide; females must choose either a 
diaphragm with spermicide, OR cervical cap with spermicide, OR 
contraceptive sponge with spermicide.  Note:  a male and female condom 
cannot be used together due to the risk of tearing.  
Add: 
SAEs, ADEs, and study-related AEs will be collected upon signing the informed consent 
form. 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 7 of 14 
CONFIDENTIAL 
 
 
 
Section:  6.1, Classification of Products and/or Medical Devices, 3rd paragraph 
Add: 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of evolocumab, matching placebo, and atorvastatin.  
Section:  6.8, Product Complaints, 1st paragraph 
Replace: 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of any investigational or non-investigational product or device. 
With: 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s) or device(s) after it is released for distribution to market 
or clinic by either Amgen or by distributors and partners for whom Amgen 
manufactures the material.  This includes any drug(s) or device(s) provisioned 
and/or repackaged/modified by Amgen.  Drug(s) or device(s) includes 
investigational product. 
Section:  Table 1.  Schedule of Assessments 
Replace: 
Review for AEs/SAEs/CV events Xc  
Xc 
X 
X 
(X)d (X)d X 
X 
X 
X 
With: 
Review for AEs/ADEs/SAEs 
Xc  
Xc 
X 
X 
(X)d (X)d X 
X 
X 
X 
Section:  Table 1. Schedule of Assessments, footnotes 
Add: 
c only AEs possibly related to study procedures and ADEs/SAEs are collected during the screening and lipid 
stabilization period 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 8 of 14 
CONFIDENTIAL 
 
 
 
Section:  7.2.1.2, Screening and Lipid Stabilization, bullet point 
Replace: 
• 
review for AEs/SAEs (AEs possibly related to study procedures and SAEs are 
collected during screening) 
With: 
• 
review for AEs/ADEs/SAEs (AEs possibly related to study procedures and ADEs 
and SAEs are collected during screening) 
Section:  7.2.2, Treatment, 3rd paragraph, bullet point 
Replace: 
• 
review for AEs/SAEs/CV events 
With: 
• 
review for AEs/ADEs/SAEs 
Section:  7.2.3, Safety Follow-up Visit(s)/End of Study Visit 
Replace: 
Subjects receiving IP QM will end the study with the week 12 visit.  Subjects on Q2W IP 
schedule will end the study by being contacted by the site, eg, by phone call, at week 14 
to collect any AEs, SAEs, or CV events. 
With: 
Subjects receiving IP QM will end the study with the week 12 visit.  Subjects on Q2W IP 
schedule will end the study by being contacted by the site, eg, by phone call, at week 14 
to collect any AEs, ADEs, or SAEs. 
Section:  9.1.1, Definition of Adverse Events, 2nd paragraph 
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 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 9 of 14 
CONFIDENTIAL 
 
 
 
involves an intervention such as elective cosmetic surgery or a medical procedure while 
on study, is not considered an adverse event. 
Section:  9.2.1, Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria, 2nd paragraph, bullet point 
Replace: 
• 
assessment of relatedness to investigational products or the AI/Pen or 
3.5 mL Personal Injector), respectively, and 
With 
• 
assessment of relatedness to investigational products (evolocumab or placebo 
and/or the medical device(s) AI/Pen or 3.5 mL Personal Injector), or any 
study-mandated activity or procedure, respectively, and 
Section:  9.2.1, Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria, 5th paragraph 
Add: 
The investigator must assess whether the adverse event is possibly related to the 
prefilled AI/Pen or 3.5 mL Personal Injector device used to administer IP.  
Section:  9.2.2, Reporting Procedures for Serious Adverse Events, 5th paragraph 
Add: 
The investigator must assess whether the serious adverse event is possibly related to 
the prefilled AI/Pen or 3.5 mL Personal Injector device used to administer IP.  
Section:  9.3, Pregnancy and Lactation Reporting, 3rd paragraph 
Replace: 
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 C).  The Pregnancy 
Surveillance Program (PSP) will seek to follow the pregnant woman throughout her 
pregnancy and her baby up to 12 months after birth. 
With: 
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C).   


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 10 of 14 
CONFIDENTIAL 
 
 
 
Section:  9.3, Pregnancy and Lactation Reporting, 6th paragraph 
Replace: 
Any lactation case should be reported to Amgen’s global Lactation Surveillance Program 
(LSP) within 24 hours of the investigator’s knowledge of event.  Report a lactation case 
on the Lactation Notification Worksheet (Appendix C). 
With: 
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours 
of the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C). 
Section:  10.1.1.4, Exploratory Endpoints 
Delete: 
subject incidence of adjudicated events: 
− 
death by any cause 
− 
cardiovascular death 
− 
myocardial infarction 
− 
hospitalization for unstable angina 
− 
coronary revascularization 
− 
stroke 
− 
hospitalization for heart failure 
− 
transient ischemic attack (TIA) 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 11 of 14 
CONFIDENTIAL 
 
 
 
Section:  Appendix C:  Pregnancy and Lactation Notification.Worksheets 
Replace: 
 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 12 of 14 
CONFIDENTIAL 
 
 
 
With: 
 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 13 of 14 
CONFIDENTIAL 
 
 
 
Section:  Appendix C:  Pregnancy and Lactation Notification Worksheets 
Replace: 
 


Product:  Evolocumab 
Protocol Number:  20120119 
Date:  11 November 2015 
Page 14 of 14 
CONFIDENTIAL 
 
 
 
With: 
 


Product:  Evolocumab (AMG 145) 
Protocol Number:  20120119 
Date:  07 February 2014 
Page 1 of 38 
 
Superseding Amendment 1 
A Double-blind, Randomized, Placebo-Controlled, Multicenter Study to Evaluate 
Safety and Efficacy of Evolocumab (AMG 145) in Combination With Statin Therapy 
in Diabetic Subjects With Hyperlipidemia or Mixed Dyslipidemia 
Evolocumab (AMG 145) 
Amgen Protocol Number Evolocumab 20120119 
 
Superseding Amendment 1 Date: 
07 February 2014 
Rationale: 
This document provides the rationale and detailed list of changes for Superseding 
Amendment 1, dated 07 February 2014, from the original protocol, dated 
22 February 2013.  
The purpose of the amendment is to: 
Add mixed meal tolerance testing (MMTT) with 1 timepoint for all subjects, and optional 
MMTT substudy with 2 additional timepoints for approximately 240 subjects 
Replace the Amgen product number “AMG 145” with the generic name “evolocumab” 
Update the contraception language 
Minor updates and clarifications, including clarification that atorvastatin in this study is 
background therapy 


Product:  Evolocumab (AMG 145) 
Protocol Number:  20120119 
Date:  10 December 2013 
Page 1 of 30 
 
Amendment 1 
A Double-blind, Randomized, Placebo-Controlled, Multicenter Study to Evaluate 
Safety and Efficacy of Evolocumab (AMG 145) in Combination With Statin Therapy 
in Diabetic Subjects With Hyperlipidemia or Mixed Dyslipidemia 
Evolocumab (AMG 145) 
Amgen Protocol Number Evolocumab 20120119 
 
Amendment 1 Date: 
10 December 2013 
Rationale: 
This document provides the rationale and detailed list of changes for Amendment 1, 
dated 10 December 2013, from the original protocol, dated 22 February 2013.  
The purpose of the amendment is to: 
• 
Add mixed meal tolerance testing (MMTT) with 1 timepoint for all subjects 
• 
Replace the Amgen product number “AMG 145” with the generic name “evolocumab” 
• 
Update the contraception language 
• 
Minor updates and clarifications 

SAP_001.pdf: 
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