Conditions: Hypercholesterolemia Mixed Dyslipidemia Type 2 Diabetes
Keywords: diabetes type 2 diabetes high blood cholesterol hypercholesterolemia mixed dyslipidemia high cholesterol statin intolerant
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 424
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the effect of 12 weeks of subcutaneous evolocumab taken monthly compared with subcutaneous placebo taken monthly on low density lipoprotein cholesterol (LDL-C) in adults with type 2 diabetes mellitus and high blood cholesterol on a maximally tolerated oral dose of statin of at least moderate-intensity.

Detailed description:
This study will enroll adults with type 2 diabetes mellitus and elevated LDL-C or non-high-density lipoprotein cholesterol (non-HDL-C) levels on a stable, maximally tolerated statin dose of at least moderate-intensity at signing of the informed consent; statin therapy must remain unchanged during screening and the remainder of the study.

Arms:
arm 1: Participants received placebo subcutaneous injection once every month (QM) for 12 weeks. arm 2: Participants received 420 mg evolocumab subcutaneous injection once every month (QM) for 12 weeks.

Interventions: intervention 1: Evolocumab intervention 2: Placebo to Evolocumab
Intervention descriptions: intervention 1: Administered by subcutaneous injection with an automated mini doser intervention 2: Administered by subcutaneous injection with an automated mini doser

Protocol document:
Prot_000.pdf: 
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Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 2 of 69 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled “A Double-blind, Randomized, 
Placebo-controlled, Multicenter Study to Evaluate Safety, Tolerability, and Efficacy of 
Evolocumab (AMG 145) on LDL-C in Subjects With Type 2 Diabetes Mellitus and 
Hypercholesterolemia/Mixed Dyslipidemia”, dated 06 January 2016, and agree to abide 
by all provisions set forth therein.  
I agree to comply with the International Conference on Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines. 
I agree to ensure that Financial Disclosure Statements will be completed by: 
• 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
• 
my 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:  20130287 
Date:  06 January 2016 
Page 3 of 69 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate Safety, 
Tolerability, and Efficacy of Evolocumab (AMG 145) on LDL-C in Subjects With Type 2 Diabetes 
Mellitus and Hypercholesterolemia/Mixed Dyslipidemia 
Study Phase:  3b 
Indication:  Hypercholesterolemia/Mixed Dyslipidemia 
Primary Objective:  To evaluate the effect of 12 weeks of subcutaneous (SC) evolocumab 
monthly (QM) compared with placebo QM on percent change from baseline in low-density 
lipoprotein cholesterol (LDL-C) in subjects with type 2 diabetes mellitus and hypercholesterolemia 
or mixed dyslipidemia on maximally tolerated dose of statin of at least moderate-intensity oral 
daily. 
Secondary Objective(s):  To assess the effects of 12 weeks of SC evolocumab QM compared 
with placebo QM, in subjects with type 2 diabetes mellitus and hypercholesterolemia or mixed 
dyslipidemia in combination with maximally tolerated dose of statin of at least moderate-intensity 
oral daily on the following: 
• 
Change from baseline in LDL-C, and percent change from baseline in non-high-density 
lipoprotein cholesterol (HDL-C), apolipoprotein B (ApoB), total cholesterol (TC), lipoprotein(a) 
(Lp[a]), triglycerides, HDL-C, and very low-density lipoprotein cholesterol (VLDL-C) 
• 
Percent of subjects attaining LDL-C < 70 mg/dL (1.8 mmol/L) 
• 
Percent of subjects attaining a 50% reduction in LDL-C from baseline 
Safety Objective:  To evaluate the safety and tolerability of SC evolocumab QM compared with 
placebo QM in subjects with type 2 diabetes mellitus and hypercholesterolemia or mixed 
dyslipidemia in combination with maximally tolerated dose of statin of at least moderate-intensity 
oral daily. 
Hypotheses:  Subcutaneous evolocumab 420 mg QM in combination with statin once daily 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 QM in subjects with type 2 diabetes mellitus and hypercholesterolemia or mixed 
dyslipidemia on maximally tolerated dose of statin of at least moderate-intensity daily. 
Co-primary Endpoints: 
• 
mean percent change from baseline in LDL-C at weeks 10 and 12 
• 
percent change from baseline in LDL-C at week 12 
Co-secondary Endpoints: 
For the mean of weeks 10 and 12 and for week 12: 
• 
Tier 1 
− 
Change from baseline in LDL-C 
− 
Percent change from baseline in non-HDL-C 
− 
Percent change from baseline in ApoB 
− 
Percent change from baseline in TC 
− 
Achievement of target LDL-C < 70 mg/dL (1.8 mmol/L) 
− 
LDL-C response (50% reduction of LDL-C from baseline) 
• 
Tier 2 
− 
Percent change from baseline in Lp(a) 
− 
Percent change from baseline in triglycerides 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 4 of 69 
CONFIDENTIAL 
 
 
− 
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 
Study Design:  This is a phase 3b, multicenter, double-blind, randomized, placebo-controlled 
study designed to assess the efficacy and safety of evolocumab in subjects with type 2 diabetes 
mellitus with hypercholesterolemia or mixed dyslipidemia. 
Sample Size:  Approximately 400 subjects with type 2 diabetes mellitus with 
hypercholesterolemia or mixed dyslipidemia. 
Summary of Subject Eligibility Criteria:  The study will enroll adult subjects (≥ 18 years of age) 
with type 2 diabetes mellitus and elevated LDL-C or non-HDL-C levels on a stable, maximally 
tolerated statin dose of at least moderate-intensity at signing of the informed consent; statin 
therapy must remain unchanged during screening and the remainder of the study.  
Subjects must have hemoglobin A1c (HbA1c) < 10%, must have been receiving pharmacologic 
treatment for diabetes mellitus for ≥ 6 months prior to screening, with stable diabetes therapy 
prior to randomization to investigational product (IP) and not expected to change throughout the 
duration of study participation.  For a full list of eligibility criteria, please refer to Section 4.1 
through Section 4.1.2.  
Investigational Product:  The Amgen investigational medicinal product (IMP) is evolocumab and 
placebo.  The Amgen IP is the IMP plus the device (automated mini-doser [AMD] or prefilled 
autoinjector [AI]/Pen).  In this document, IMP will be referred to as IP. 
Amgen Investigational Product Dosage and Administration:  Evolocumab 420 mg or 
matching placebo will be administered QM at day 1 and weeks 4 and 8 as an SC injection.  The 
IP is expected to be delivered by AMD but may be achieved by 3 injections with AI/Pen if AMD is 
not available.  Observed, in-clinic dosing should occur at day 1 and week 8 ± 3 days, and 
subjects will self-administer in an appropriate non-clinic setting (eg, at home) for week 4 
± 3 days. 
Procedures:  The study will consist of 2 periods: the screening/lipid stabilization period and the 
double-blind treatment period. 
After signing the informed consent, subjects will enter a screening period up to 6 weeks including 
a 4-week lipid stabilization during which their appropriate-dose statin is continued.  Subjects are 
required to be on a stable, maximally tolerated statin of at least moderate-intensity during 
screening.  Screening laboratory tests, including lipid testing, will be conducted during week 2 of 
screening/lipid stabilization.  Subjects must tolerate a SC injection of placebo with device 
anticipated to be used during the study (either AI/Pen or AMD) prior to randomization.  
Subjects who meet all eligibility criteria at the end of the screening/lipid stabilization period will be 
randomized and initiate their first dose of IP within 5 days of randomization. 
During the double-blind treatment period, study visits will occur at day 1, week 8 (± 3 days), 
week 10 (± 3 days), and week 12 (± 3 days); with baseline evaluations performed on day 1 of 
treatment before subjects receive the first dose of IP.  All subjects will complete a mixed meal 
tolerance test (MMTT) at the day 1 and week 12 study visits with a baseline and 2-hour 
(± 10 min) postprandial blood collection after the meal.  Up to approximately 100 subjects not 
treated with prandial insulin or glucagon-like peptide-1 agonists will participate in MMTT Extended 
Timepoints assessments with 3 additional postprandial blood draws at 30 minutes (± 10 min), 
1 hour (± 10 min), and 3 hours (± 10 min) after the meal.  End of study for all subjects will be at 
the week 12 (± 3 days) visit. 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 5 of 69 
CONFIDENTIAL 
 
 
The overall study design is described by a study schema at the end of this synopsis section.  For 
a full list of study procedures, including the timing of each procedure, please refer to Section 7 
and the Schedule of Assessments (Table 1). 
Statistical Considerations:  The primary analysis will be performed when all randomized 
subjects in the double-blind treatment period have either completed all scheduled study visits in 
the double-blind treatment period or have terminated from the study.  The superiority of 
evolocumab to placebo will be assessed for all efficacy endpoints on the full analysis set (FAS), 
which includes all randomized subjects who receive at least one dose of IP.  Methods of adjusting 
for multiplicity due to multiple endpoints are provided in Section 10.5.1.  To assess the co-primary 
endpoints of the mean percent change from baseline (mean of screening week 2 and day 1) in 
LDL-C at weeks 10 and 12 and the percent change in LDL-C from baseline at week 12, a 
repeated measures linear effects model will be used on the FAS to compare the efficacy of 
evolocumab QM with placebo QM.  The repeated measures model will include terms for 
treatment group, stratification factor, scheduled visit and the interaction of treatment with 
scheduled visit.  Analysis of co-secondary endpoints will use the same analysis model as the 
co-primary endpoints.  The co-secondary endpoints of LDL-C response (achievement of LDL-C 
< 70 mg/dL and achievement of > 50% LDL-C reduction from baseline) will be analyzed using the 
Cochran-Mantel Haenszel test adjusted by the stratification factor.  Safety endpoints will be 
summarized descriptively by treatment group. 
Sponsor:  Amgen Inc. 
Data Element Standards 
Version(s)/Date(s):  
Version 5/ 20 March 2015 
 


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Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 7 of 69 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ADE 
adverse device effect 
AE 
adverse event 
AI 
autoinjector 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AMD 
automated mini-doser 
ApoA1 
apolipoprotein A-I 
ApoB 
apolipoprotein B 
ApoB48 
apolipoprotein B48 
AST 
aspartate aminotransferase 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CAS 
completer analysis set 
CHD 
coronary heart disease 
CK 
creatinine kinase 
CPK 
creatinine phosphokinase 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVD 
cardiovascular disease 
CYP 
cytochrome P450 
DILI 
drug-induced liver injury 
DRE 
device related event 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
End of Study (end of trial) defined as the date when the last subject has completed all planned 
study procedures up to and including the visit as outlined in the 
Schedule of Assessments 
End of Study for 
Individual Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject or the day the subject withdraws 
from the study early 
End of Treatment 
defined as the day a subject receives the last treatment with 
investigational product before the subject completes the study or 
ends the treatment early 
EOS 
end of study 
FAS 
full analysis set 
FBG  
fasting blood glucose 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 8 of 69 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GLP-1 
glucagon-like peptide-1 
HbA1c 
hemoglobin A1c 
HCV 
hepatitis C virus 
HDL-C 
high-density lipoprotein cholesterol 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IFU 
Information for Use 
IL-6 
interleukin-6 
IMP 
investigational medicinal product 
IP 
investigational product 
IPIM 
Investigational Product Instruction Manual 
IRB/IEC 
institutional review board/independent ethics committee 
IVRS 
interactive voice response system, telecommunication technology 
that is linked to a central computer in real time as an interface to 
collect and process information.  
IWRS 
interactive web response system 
LDH 
lactate dehydrogenase 
LDL-C 
low-density lipoprotein cholesterol 
LDLR 
low-density lipoprotein receptor 
LH 
luteinizing hormone 
Lp(a) 
lipoprotein(a) 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MMTT 
mixed meal tolerance test 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
PO 
orally 
PT 
prothrombin time 
QD 
once daily 
QM 
once monthly 
RBC 
red blood cells 
RDW 
red blood cell distribution width 
SAE 
serious adverse event 
SD 
standard deviation 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 9 of 69 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
Source Data 
information from an original record or certified copy of the original 
record containing patient information for use in clinical research.  
The information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained 
in source documents (original records or certified copies).  
(ICH Guideline (E6)).  Examples of source data include subject 
identification, randomization identification, and stratification value. 
Study day 1 
defined as the first day that protocol-specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject 
TBL 
total bilirubin 
TC 
total cholesterol 
ULN 
upper limit of normal 
VLDL-C 
very low-density lipoprotein cholesterol 
WBC 
white blood cells 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 10 of 69 
CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
Page 
Protocol Synopsis ............................................................................................................ 3 
Study Design and Treatment Schema ............................................................................. 6 
Study Glossary ................................................................................................................ 7 
1. 
OBJECTIVES ....................................................................................................... 14 
1.1 
Primary ..................................................................................................... 14 
1.2 
Secondary ................................................................................................. 14 
1.3 
Safety ........................................................................................................ 14 
1.4 
Exploratory ................................................................................................ 14 
2. 
BACKGROUND AND RATIONALE ...................................................................... 15 
2.1 
Disease ..................................................................................................... 15 
2.2 
Amgen Investigational Product Background .............................................. 15 
2.3 
Rationale ................................................................................................... 16 
2.4 
Clinical Hypotheses ................................................................................... 16 
3. 
EXPERIMENTAL PLAN ........................................................................................ 16 
3.1 
Study Design ............................................................................................. 16 
3.2 
Number of Sites ........................................................................................ 17 
3.3 
Number of Subjects ................................................................................... 17 
3.4 
Replacement of Subjects .......................................................................... 17 
3.5 
Estimated Study Duration .......................................................................... 17 
3.5.1 
Study Duration for Subjects ....................................................... 17 
3.5.2 
End of Study .............................................................................. 18 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 18 
4.1 
Inclusion and Exclusion Criteria ................................................................ 18 
4.1.1 
Inclusion Criteria ........................................................................ 18 
4.1.2 
Exclusion Criteria ...................................................................... 19 
5. 
SUBJECT ENROLLMENT .................................................................................... 20 
5.1 
Randomization/Treatment Assignment ...................................................... 21 
5.2 
Site Personnel Access to Individual Treatment Assignments .................... 22 
6. 
TREATMENT PROCEDURES .............................................................................. 22 
6.1 
Classification of Product(s) and/or Medical Device(s) ................................ 22 
6.2 
Investigational Product .............................................................................. 22 
6.2.1 
Dosage, Administration, and Schedule ...................................... 23 
6.2.1.1 
Screening/Lipid Stabilization ................................... 23 
6.2.1.2 
Double-blind Treatment Period ................................ 23 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 11 of 69 
CONFIDENTIAL 
 
 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 24 
6.3 
Other Protocol-required Therapies ............................................................ 24 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules ....................................... 24 
6.4.1 
Criteria for Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required 
Therapies due to Potential Hepatotoxicity ................................. 24 
6.4.2 
Criteria for Conditional Withholding of Amgen 
Investigational Product and Other Protocol-required 
Therapies due to Potential Hepatotoxicity ................................. 25 
6.4.3 
Criteria for Rechallenge of Amgen Investigational 
Product and Other Protocol-required Therapies After 
Potential Hepatotoxicity ............................................................. 26 
6.5 
Concomitant Therapy ................................................................................ 26 
6.6 
Medical Devices ........................................................................................ 26 
6.7 
Product Complaints ................................................................................... 27 
6.8 
Excluded Treatments, Medical Devices, and/or Procedures 
During Study Period .................................................................................. 28 
7. 
STUDY PROCEDURES ....................................................................................... 28 
7.1 
Schedule of Assessments ......................................................................... 29 
7.2 
General Study Procedures ........................................................................ 30 
7.2.1 
Screening Enrollment and Randomization ................................. 31 
7.2.2 
Rescreening .............................................................................. 31 
7.2.3 
Double-blind Treatment Period .................................................. 32 
7.2.4 
End of Study Visit ...................................................................... 32 
7.2.5 
Safety Follow-up ........................................................................ 32 
7.3 
Description of Study Procedures ............................................................... 32 
7.3.1 
Informed Consent ...................................................................... 32 
7.3.2 
Demographic Data..................................................................... 33 
7.3.3 
Medical History .......................................................................... 33 
7.3.4 
Vital Signs ................................................................................. 33 
7.3.5 
Physical Examination ................................................................ 33 
7.3.6 
Concomitant Therapy ................................................................ 33 
7.3.7 
Height, Weight, and Waist Circumference ................................. 34 
7.4 
Laboratory Assessments ........................................................................... 34 
7.4.1 
Blinding of Laboratory Test Results ........................................... 35 
7.4.2 
Mixed Meal Tolerance Test (All Subjects) .................................. 36 
7.4.3 
Mixed Meal Tolerance Test Extended Timepoints ..................... 36 
7.4.4 
Serum Pregnancy Test .............................................................. 37 
7.5 
Biomarker Development ............................................................................ 37 
7.6 
Pharmacogenetic Studies ......................................................................... 37 
7.7 
Sample Storage and Destruction ............................................................... 38 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 39 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 12 of 69 
CONFIDENTIAL 
 
 
8.1 
Subjects’ Decision to Withdraw ................................................................. 39 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 39 
8.3 
Reasons for Removal From Treatment or Study ....................................... 40 
8.3.1 
Reasons for Removal From Treatment ...................................... 40 
8.3.2 
Reasons for Removal From Study ............................................. 40 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 40 
9.1 
Definition of Safety Events ........................................................................ 40 
9.1.1 
Disease-related Events ............................................................. 40 
9.1.2 
Adverse Events ......................................................................... 41 
9.1.3 
Adverse Device Effects ............................................................. 41 
9.1.4 
Serious Adverse Events ............................................................ 42 
9.2 
Safety Event Reporting Procedures .......................................................... 43 
9.2.1 
Disease-related Events ............................................................. 43 
9.2.2 
Adverse Events ......................................................................... 43 
9.2.2.1 
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria ............................ 43 
9.2.2.2 
Reporting Procedures for Serious Adverse 
Events ..................................................................... 44 
9.2.2.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 46 
9.2.2.4 
Serious Adverse Events That are not to be 
Reported in an Expedited Manner ........................... 46 
9.3 
Pregnancy and Lactation Reporting .......................................................... 46 
10. 
STATISTICAL CONSIDERATIONS ...................................................................... 47 
10.1 
Study Endpoints, Analysis Sets, and Covariates ....................................... 47 
10.1.1 
Study Endpoints ........................................................................ 47 
10.1.1.1 
Co-primary Endpoints .............................................. 47 
10.1.1.2 
Co-secondary Endpoints ......................................... 47 
10.1.1.3 
Exploratory Endpoints ............................................. 47 
10.1.1.4 
Safety Endpoints ..................................................... 48 
10.1.2 
Analysis Sets ............................................................................. 48 
10.1.3 
Covariates and Subgroups ........................................................ 48 
10.2 
Sample Size Considerations ..................................................................... 49 
10.3 
Access to Individual Subject Treatment Assignments by Amgen 
or Designees ............................................................................................. 50 
10.4 
Planned Analyses ..................................................................................... 50 
10.5 
Planned Methods of Analysis .................................................................... 50 
10.5.1 
General Considerations ............................................................. 50 
10.5.1.1 
Multiplicity Adjustment Method ................................ 50 
10.5.2 
Co-primary Efficacy Endpoints .................................................. 51 
10.5.2.1 
Sensitivity Analysis .................................................. 52 
10.5.2.2 
Subgroup Analysis .................................................. 52 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 13 of 69 
CONFIDENTIAL 
 
 
10.5.3 
Co-secondary Efficacy Endpoints .............................................. 52 
10.5.4 
Safety Endpoints ....................................................................... 52 
11. 
REGULATORY OBLIGATIONS ............................................................................ 53 
11.1 
Informed Consent ...................................................................................... 53 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 53 
11.3 
Subject Confidentiality ............................................................................... 54 
11.4 
Investigator Signatory Obligations ............................................................. 54 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................. 55 
12.1 
Protocol Amendments and Study Termination .......................................... 55 
12.2 
Study Documentation and Archive ............................................................ 55 
12.3 
Study Monitoring and Data Collection ....................................................... 56 
12.4 
Investigator Responsibilities for Data Collection ........................................ 57 
12.5 
Language .................................................................................................. 57 
12.6 
Publication Policy ...................................................................................... 58 
12.7 
Compensation ........................................................................................... 58 
13. 
REFERENCES ..................................................................................................... 59 
14. 
APPENDICES ...................................................................................................... 60 
List of Tables 
Table 1.  Schedule of Assessments ............................................................................... 29 
Table 2.  Analyte Listing ................................................................................................ 35 
Table 3.  Example Standardized Mixed Meal per 240 mL .............................................. 36 
Table 4.  Power Associated With Standard Deviation Assumptions ............................... 49 
List of Figures 
Figure 1.  Multiplicity Adjustment Methods ..................................................................... 51 
List of Appendices 
Appendix A.  Additional Safety Assessment Information ................................................ 61 
Appendix B.  Sample Serious Adverse Event Report Form ........................................... 63 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................... 66 
Appendix D.  High, Moderate, and Low-intensity Statin Therapy ................................... 68 
Appendix E.  Child-Pugh Score ..................................................................................... 69 
 


 
 
 
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1. 
OBJECTIVES 
1.1 
Primary 
• 
To evaluate the effect of 12 weeks of subcutaneous (SC) evolocumab monthly (QM) 
compared with placebo QM on percent change from baseline in low-density 
lipoprotein cholesterol (LDL-C) in subjects with type 2 diabetes mellitus and 
hypercholesterolemia or mixed dyslipidemia on maximally tolerated dose of statin of 
at least moderate-intensity oral daily. 
1.2 
Secondary 
• 
To assess the effects of 12 weeks of SC evolocumab QM compared with placebo 
QM, in subjects with type 2 diabetes mellitus and hypercholesterolemia or mixed 
dyslipidemia in combination with maximally tolerated dose of statin of at least 
moderate-intensity oral daily on the following: 
− 
Change from baseline in LDL-C, and percent change from baseline in 
non-high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (ApoB), total 
cholesterol (TC), lipoprotein(a) [Lp(a)], triglycerides, HDL-C, and very low-density 
lipoprotein cholesterol (VLDL-C) 
− 
Percent of subjects attaining LDL-C < 70 mg/dL (1.8 mmol/L) 
− 
Percent of subjects attaining a 50% reduction in LDL-C from baseline 
1.3 
Safety 
• 
To evaluate the safety and tolerability of SC evolocumab QM compared with placebo 
QM in subjects with type 2 diabetes mellitus and hypercholesterolemia or mixed 
dyslipidemia in combination with maximally tolerated dose of statin of at least 
moderate-intensity oral daily. 
1.4 
Exploratory 
To describe the effects over time of SC evolocumab QM compared with placebo QM, in 
subjects with type 2 diabetes mellitus and hypercholesterolemia or mixed dyslipidemia in 
combination with maximally tolerated statin of at least moderate-intensity oral daily 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, TC, 
non-HDL-C, ApoB, VLDL-C, HDL-C, apolipoprotein A-I (ApoA1), triglycerides, and 
Lp(a) 
• 
change and percent change from baseline on fasting and postprandial plasma 
laboratory parameters of interest including glucose, insulin, pro-insulin, C-peptide, 
free fatty acids, glucagon, lipids, chylomicrons, apolipoprotein B48 (ApoB48), 
interleukin-6 (IL-6), adiponectin after a mixed meal tolerance test (MMTT) 
• 
the relationship between novel and established biochemical cardiovascular and lipid 
biomarkers and effects of evolocumab 
• 
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 pharmacogenetic analysis 


 
 
 
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2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
Cardiovascular diseases (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).  Type 2 diabetes mellitus is a major independent 
risk factor for CVD-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 of Chinese Medical Association, 2011). 
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 
Amgen Investigational Product Background 
Recycling of the hepatic cell surface LDLR plays a critical role in regulating serum LDL-C 
levels.  Proprotein convertase subtilisin/kexin type 9 binds to the LDLR and down 
regulates hepatic cell surface LDLR, which, in turn, leads to increased levels of 
circulating LDL-C.  Humans with PCSK9 loss-of-function mutations have cholesterol 
levels lower than normal and reduced incidence of CHD (Abifadel et al, 2009).  
Evolocumab (formerly referred to as AMG 145) is a fully human monoclonal 
immunoglobulin G2, developed at Amgen Inc., that specifically binds to PCSK9 
preventing its interaction with the LDLR.  The inhibition of PCSK9 by evolocumab leads 
to increased LDLR expression and subsequent decreased circulating concentrations of 
LDL-C. 
Refer to the Evolocumab Investigator’s Brochure for more information on evolocumab. 


 
 
 
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2.3 
Rationale 
It is anticipated that evolocumab may be used in diabetic individuals who cannot achieve 
their LDL-C goals despite the use of maximally tolerated 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. 
2.4 
Clinical Hypotheses 
The primary hypothesis of this study is that SC evolocumab 420 mg QM in combination 
with statin once daily 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 QM in subjects with type 2 diabetes 
and hypercholesterolemia or mixed dyslipidemia on maximally tolerated dose of statin of 
at least moderate intensity daily. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a phase 3b, multicenter, double-blind, randomized, placebo-controlled study 
designed to assess the efficacy and safety of evolocumab in subjects with type 2 
diabetes mellitus with hypercholesterolemia or mixed dyslipidemia.  All subjects will be 
treated with maximally tolerated statin of at least moderate-intensity (intensity as 
specified by the 2013 American College of Cardiology/American Heart Association 
guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular 
risk in adults; see Appendix D).  Baseline lipid-lowering therapy is expected to be 
continued unchanged throughout the study.  
The study will consist of 2 periods: 
• 
Screening up to 6 weeks including a 4-week lipid stabilization and placebo injection  
• 
Double-blind treatment period (12 weeks) 
After signing the informed consent, subjects will enter the screening/lipid stabilization 
period during which their appropriate-dose statin is continued.  Screening laboratory 
tests including lipid testing will be conducted during week 2 of the screening/lipid 
stabilization period.  Subjects must tolerate a SC injection of placebo with device 
anticipated to be used during the study (either AI/Pen or AMD) prior to 
randomization.  Subjects who meet all eligibility criteria at the end of the screening/lipid 
stabilization period will be randomized in a 2:1 ratio into the following treatment arms:  


 
 
 
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• 
SC evolocumab 420 mg QM (~270 subjects) 
• 
SC placebo QM (~130 subjects) 
Randomization will be stratified by LDL-C (above or below 130 mg/dL). 
Day 1 is defined as the calendar day when treatment with investigational product 
(IP) is initiated.  Subjects should initiate their first dose of IP within 5 days of 
randomization.  During the double-blind treatment period, study visits will occur at day 1, 
week 8 (± 3 days), week 10 (± 3 days), and week 12 (± 3 days); with baseline 
evaluations performed on day 1 of treatment before subjects receive the first dose of IP.  
All subjects will complete a MMTT at the day 1 and week 12 study visits with baseline 
(0 hours) and postprandial blood collection at 2 hours (± 10 min) after the meal.  Up to 
approximately 100 subjects not treated with prandial insulin or glucagon-like peptide-1 
(GLP-1) agonists will participate in MMTT Extended Timepoints assessments with 
3 postprandial blood draws at 30 minutes (± 10 min), 1 hour (± 10 min), and 3 hours 
(± 10 min) after the meal in addition to the blood draws at 0 and 2 hours (± 10 min) after 
the meal for all subjects. 
3.2 
Number of Sites 
Approximately 80 sites globally will participate in this study.  Sites that do not enroll 
subjects within 3 months of site initiation may be closed. 
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”.  
Approximately 400 subjects with type 2 diabetes mellitus with hypercholesterolemia 
or mixed dyslipidemia will be enrolled. 
3.4 
Replacement of Subjects 
Subjects who are withdrawn or removed from investigational medicinal product (IMP) 
treatment or the study will not be replaced.  
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
Including the screening/lipid stabilization period and study treatment period, the 
maximum total duration of study participation for a subject will be approximately 
18 weeks, or approximately 4.5 months.  After signing the informed consent, subjects 
should be randomized within 6 weeks. 


 
 
 
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3.5.2 
End of Study 
The primary completion is defined as the date when the last subject has completed the 
assessments for week 12 or has terminated the study early, whichever is later. 
4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).  This log may be completed and updated via an interactive voice response 
system (IVRS)/interactive web response system (IWRS). 
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 years of age at signing of informed consent 
103 
Type 2 diabetes mellitus: 
• 
with hemoglobin A1c (HbA1c) < 10% 
• 
receiving pharmacologic treatment for diabetes mellitus for ≥ 6 months prior 
to screening 
• 
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, and no dose change of any 
antihyperglycemic drug within 2 months prior to randomization and daily 
insulin dose not changed by > 25% and > 25 units within 1 month prior to 
randomization 
104 
Subject must be on maximally tolerated dose of statin of at least moderate 
intensity at signing of the informed consent (see Appendix D) and is 
expected to remain on stable statin intensity for the duration of study in the 
opinion of the investigator: 
• 
Subjects without known clinical CVD must be on at least moderate-intensity 
statin 
• 
Subjects with known clinical CVD must be on high intensity statin (or 
moderate intensity if certified by principal investigator to be highest tolerated 
dose).  Clinical CVD is defined as a history of myocardial infarction, 
stable or unstable angina, coronary or other arterial revascularization, 
stroke, transient ischemic attack, or peripheral arterial disease 
presumed to be of atherosclerotic origin 
105 
Subjects without known clinical CVD must have a fasting LDL-C during lipid 
stabilization of ≥ 100 mg/dL (2.6 mmol/L) or non-HDL-C ≥ 130 mg/dL 
(3.4 mmol/L) as determined by the central laboratory 


 
 
 
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106 
Subjects with known clinical CVD must have a fasting LDL-C during lipid 
stabilization of ≥ 70 mg/dL (1.8 mmol/L) or Non-HDL-C ≥ 100 mg/dL (2.6 mmol/L) 
as determined by the central laboratory 
107 
Fasting triglycerides ≤ 600 mg/dL (6.8 mmol/L) by central laboratory prior to 
randomization 
108 
Subject tolerates screening placebo injection 
4.1.2 
Exclusion Criteria 
201 
Myocardial infarction, unstable angina, percutaneous coronary intervention, 
coronary artery bypass graft or stroke within 3 months prior to randomization 
202 
Uncontrolled hypertension defined as sitting systolic blood pressure (BP) 
> 180 mmHg or diastolic BP > 110 mmHg 
203 
Subject has taken a cholesterylester transfer protein inhibitor in the last 
12 months prior to randomization, such as: anacetrapib, dalcetrapib, or 
evacetrapib 
204 
Moderate to severe renal dysfunction, defined as an estimated glomerular 
filtration rate < 20 mL/min/1.73 m2 during screening 
205 
Persistent active liver disease or hepatic dysfunction, defined as Child-Pugh 
score of C (see Appendix E) 
206 
Female subject of childbearing potential not willing to use an acceptable 
method(s) of effective birth control during the screening/lipid stabilization period, 
during treatment with IP and for an additional 15 weeks after the end of treatment 
with IP. 
Female subjects of non-childbearing potential are not required to use 
contraception during the study and include those who have had a hysterectomy, 
bilateral salpingectomy, bilateral oophorectomy, or who are postmenopausal.  
Postmenopausal is defined as 12 months of spontaneous and continuous 
amenorrhea in a female ≥ 55 years old; or age < 55 years but no spontaneous 
menses for at least 2 years; or age < 55 years and spontaneous menses within 
the past 1 year, but currently amenorrheic (eg, spontaneous or secondary to 
hysterectomy), and with postmenopausal gonadotropin levels (luteinizing 
hormone and follicle stimulating hormone levels > 40 IU/L) or postmenopausal 
estradiol levels (< 5 ng/dL) or according to the definition of "postmenopausal 
range" for the laboratory involved. 
Acceptable methods of effective birth control include: 
− 
true sexual abstinence when this is in line with the preferred and usual 
lifestyle of the subject (periodic abstinence [eg, calendar, ovulation, 
symptothermal, post-ovulation methods], declaration of abstinence for the 
duration of a trial, and withdrawal are not acceptable methods of 
contraception),  
− 
vasectomized partner (provided that partner is the sole sexual partner of the 
female participant who is of childbearing potential and that the vasectomized 
partner has received medical assessment of the surgical success),  
− 
bilateral tubal ligation/occlusion, use of hormonal birth control methods (oral, 
intravaginal [eg, vaginal ring], transdermal, injectable, or implantable),  
− 
intrauterine devices,  


 
 
 
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− 
intrauterine hormonal releasing system, or  
− 
2 barrier methods (each partner must use one barrier method) and the female 
partner must use if available spermicide in addition to a barrier – males must 
use a condom; females must choose either a diaphragm, OR cervical cap, 
OR contraceptive sponge.  (Note:  If spermicide is not commercially 
available in the country or region, the two barrier method without spermicide 
would then be considered acceptable). 
Note: Additional medications given during the study may alter the 
contraceptive requirements.  These additional medications may require an 
increase in the number of contraceptive methods, the change in type of 
contraceptive methods and/or length of time that contraception is to be 
utilized and/or length of time breastfeeding is to be avoided.  The investigator 
is to discuss these contraceptive changes with the study subject. 
207 
Female subject is pregnant or breast feeding, or planning to become pregnant or 
planning to breastfeed during the screening/lipid stabilization period, during 
treatment with IP and for an additional 15 weeks after the end of treatment with 
IP 
208 
Malignancy (except non-melanoma skin cancers, cervical in situ carcinoma, 
breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 
1 year prior to randomization 
209 
Subject has previously received evolocumab or any other therapy to inhibit 
PCSK9 
210 
Currently receiving treatment in another investigational device or IP, or < 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 
211 
Subject has known sensitivity to any of the active substances or their excipients 
to be administered during dosing, eg, carboxymethylcellulose 
212 
Subject likely to not be available to complete all protocol required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject and investigator’s knowledge 
213 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures, or completion 
5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form (ICF), and all other 
subject information and/or recruitment material, if applicable (see Section 11.2).  All 
subjects must personally sign and date the ICF before commencement of study specific 
activities/procedures. 


 
 
 
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A subject is considered enrolled upon randomization in IVRS/IWRS, when the 
investigator decides that the subject has met all eligibility criteria, including 4 weeks of 
tolerating the appropriate dose of statin.  The investigator is to document this decision 
and date, in the subject’s medical record and in/on the enrollment case report form 
(CRF). 
Each subject who enters into the screening period for the study (defined as the point at 
which the subject signs the ICF) receives a unique subject identification number before 
any study-related activities/procedures are performed.  The subject identification number 
will be assigned by the IVRS/IWRS.  This number will be used to identify the subject 
throughout the clinical study and must be used on all study documentation related to that 
subject.  
Subjects who are unable to complete or meet eligibility on initial screening will be 
permitted to re-screen once except for subjects without known clinical CVD and fasting 
LDL-C < 100 mg/dL and non-HDL-C < 130 mg/dL and subjects with known clinical 
CVD and LDL-C < 70 mg/dL and non-HDL-C < 100 mg/dL by central lab result during 
screening (see Section 7.2.2) who are considered screen failures and who cannot 
be rescreened. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.  This number will not necessarily be the same as the randomization number 
assigned for the study.  
5.1 
Randomization/Treatment Assignment 
Subjects who meet the eligibility requirements (Section 4.1) will be randomly assigned in 
a 2:1 allocation ratio to 2 treatment groups (evolocumab and placebo) in a double-blind 
manner.  Randomization will be stratified by LDL-C (above or below 130 mg/dL).  
The randomization date is to be documented in the subject’s medical record and on the 
enrollment CRF.  Randomization numbers will be provided to the site through an 
IVRS/IWRS. 
Subjects can only be randomized 1 time for this study.  Once subjects are randomized 
their first dose of IP must be administered within 5 days of randomization (day 1 visit). 


 
 
 
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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. 
Refer to the Investigational Product Instruction Manual (IPIM) for a description regarding 
how responsible pharmacists and investigators will access treatment information via the 
IVR/IWR system, in the event that there is a need to break the blind.  
The investigator is strongly encouraged to contact the Amgen Clinical Study Manager or 
clinical research associate 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 Product(s) and/or Medical Device(s) 
The Amgen IP used in this study is evolocumab and matching placebo.  In several 
countries, IP is referred to as IMP.  In this document, IMP will be referred to as IP. 
The investigational medical device is the automated mini-doser (AMD), or the spring 
based prefilled autoinjector (AI)/pen if AMD is not available.  Note: Ancillary device(s) 
(ie, any medical device[s] not under study) are described in Section 6.6. 
The IPIM, a document external to this protocol, contains detailed information regarding 
the storage, preparation, destruction, and administration of evolocumab and placebo. 
6.2 
Investigational Product 
Evolocumab and matching placebo will be manufactured and packaged by Amgen Inc. 
and distributed using Amgen clinical study drug distribution procedures. 
Evolocumab 420 mg and placebo SC will be supplied as an AMD but may be supplied 
as a prefilled an AI/Pen if AMD not available: 
• 
An AMD as a single use, disposable, on-body electro-mechanical injection device 
that is co-packaged with a prefilled Crystal Zenith cartridge containing 3.5 mL 
deliverable volume of 120 mg/mL evolocumab or an identical volume of placebo 
• 
An AI/Pen as a single use, disposable, handheld mechanical (spring-based) for fixed 
dose, subcutaneous injection of 140 mg evolocumab in 1.0 mL deliverable volume or 
an identical volume of placebo 
Placebo will be presented in identical containers and stored/packaged the same as 
evolocumab. 


 
 
 
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6.2.1 
Dosage, Administration, and Schedule 
6.2.1.1 
Screening/Lipid Stabilization 
During screening/lipid stabilization, subjects will undergo SC placebo injection with the 
device to be used during the study (AMD or AI/Pen).  Subjects must tolerate the placebo 
injection prior to randomization. 
6.2.1.2 
Double-blind Treatment Period 
The IP (420 mg evolocumab or matching placebo via AMD, or AI/Pen if the AMD is not 
available) will be administered QM on day 1, week 4, and week 8.  The IP is expected to 
be delivered by AMD but may be achieved by 3 injections with AI/Pen if AMD not 
available. 
Subcutaneous evolocumab and placebo will be administered at the study site or in an 
appropriate non-clinic setting (eg, at home).  Observed, in-clinic dosing should occur at 
day 1 and week 8 and at home by the subject at week 4.  Subjects who do not wish to 
self-inject at home may return to the clinic for injection. 
The IP will be administered in accordance with instructions in the IPIM and the 
Information for Use (IFU).  The subject (or designee, if not a qualified healthcare 
professional) must have demonstrated competency, as per site judgment, 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.  If IP is 
to be administered during the study visit, administration must occur after all other 
procedures have been completed. 
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 
administered fully, or partially, or not at all administered, in addition to the reason for a 
partial/lack of injection, are to be recorded on each subject’s CRF provided.  When IP 
can be administered at an appropriate non-clinic setting (eg, at home) a non-investigator 
site location, at a minimum, the dates the devices were dispensed and returned, the 
used devices returned, the number of devices dispensed and returned, and number of 
devices administered fully, partially, or not at all, in addition to the reason for a 
partial/lack of injection, must be provided whether each device was returned fully or 
partially used are to be recorded on each subject’s CRF. 
Overdose with this product has not been reported. 


 
 
 
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6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation  
No dose adjustments are allowed 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 return for all other study procedures and measurements until the end of 
study (EOS).  
If a dose of evolocumab is missed, administration should occur as soon as possible if 
there are more than 7 days until the next scheduled dose.  If there are less than 7 days 
before the next scheduled dose, the missed dose should be omitted and the next dose 
should be administered according to the original schedule. 
6.3 
Other Protocol-required Therapies 
All other protocol-required therapies including, at least moderate intensity statin and 
pharmacologic treatment for type 2 diabetes mellitus, that are commercially available are 
not provided or reimbursed by Amgen (except if required by local regulation).  The 
investigator will be responsible for obtaining supplies of these protocol-required 
therapies.  
Additional details regarding these protocol-required therapies are provided in the IPIM. 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or signs/symptoms of hepatitis (as described below) may meet the criteria for 
withholding or permanent discontinuation of Amgen IP or other protocol-required 
therapies as specified in the Guidance for Industry Drug-Induced Liver Injury:  
Premarketing Clinical Evaluation (July 2009). 
6.4.1 
Criteria for Permanent Discontinuation of Amgen Investigational 
Product and Other Protocol-required Therapies due to Potential 
Hepatotoxicity 
Amgen IP (evolocumab/placebo) and other protocol-required therapies should be 
discontinued permanently and the subject should be followed according to the 
recommendations in Appendix A (Additional Safety Assessment Information) for possible 
drug-induced liver injury (DILI), if ALL of the criteria below are met:  
• 
TBL ≥ 2x ULN 
• 
AND increased AST or ALT ≥ 3x ULN if baseline value were less than the ULN  
• 
AND ALP < 2x ULN 


 
 
 
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• 
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  
− 
Non-hepatic causes (eg, rhabdomyolysis, hemolysis) 
6.4.2 
Criteria for Conditional Withholding of Amgen Investigational 
Product and Other Protocol-required Therapies due to Potential 
Hepatotoxicity 
For subjects who do not meet the criteria for permanent discontinuation of Amgen IP 
(evolocumab or placebo) 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 
recommended for withholding of Amgen IP and other protocol-required therapies:  
• 
Elevation of either AST or ALT according to the following schedule: 
Baseline AST or ALT value 
AST or ALT elevation  
Any 
> 8 × ULN at any time 
Any 
> 5 × ULN but < 8 × ULN for ≥ 2 weeks 
Any 
> 5 × ULN but < 8 × ULN and unable to adhere to 
enhanced monitoring schedule 
Any 
> 3 × ULN with clinical signs or symptoms that are 
consistent with hepatitis (such as right upper quadrant 
pain/tenderness, fever, nausea, vomiting, and jaundice).  
• 
OR: TBL > 3 × ULN at any time 
• 
OR: ALP > 8 × ULN at any time 


 
 
 
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Evolocumab/placebo and other protocol-required therapies should be withheld pending 
investigation into alternative causes of DILI.  If IP is withheld, the subject is to be 
followed according to recommendations in Appendix A for possible DILI.  Rechallenge 
may be considered if an alternative cause for impaired liver tests (ALT, AST, ALP) 
and/or elevated TBL, is discovered and the laboratory abnormalities resolve to normal or 
baseline (Section 6.4.3). 
6.4.3 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then evolocumab/placebo should be 
permanently discontinued.  Subjects who clearly meet the criteria for permanent 
discontinuation (as described in Section 6.4.1) should never be rechallenged. 
6.5 
Concomitant Therapy 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.8.  Concomitant therapies are to be collected in the CRF from the 
signing of the ICF through the EOS. 
Prior general and targeted therapies (ie, statins, other lipid-lowering therapies, and 
pharmacologic treatment for type 2 diabetes mellitus), taken 120 days prior to 
randomization should be collected with the following information: therapy name, 
indication, dose, unit, frequency, route, start date and stop date. 
If a targeted therapy is begun, discontinued, or changed during study, in addition to 
updates for the above information, the reason for adjusting medication (eg, adverse 
event, noncompliance, etc.) should be recorded. 
For all other concomitant therapies, collect therapy name, indication, unit, frequency, 
route, start date and stop date. 
6.6 
Medical Devices 
The AMD and prefilled AI/Pen used in this study will be provided by Amgen.  Additional 
details for the AMD and AI/Pen is to be provided in the IPIM and IFU.  
Ancillary medical devices (eg, syringes, sterile needles, alcohol prep pads), which are 
not considered test articles, may be used in the conduct of this study as part of standard 
care.  These devices that are commercially available are not usually provided or 


 
 
 
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reimbursed by Amgen (except, for example, if required by local regulation).  The 
investigator will be responsible for obtaining supplies of these devices. 
6.7 
Product Complaints 
A product complaint is defined by Amgen as any written, electronic or oral 
communication that alleges deficiencies related to the identity, quality, durability, 
reliability, safety, effectiveness, or performance of a drug(s) or device(s) after it is 
released for distribution to market or clinic by either Amgen or by distributors and 
partners for whom Amgen manufactures the material.  This includes any drug(s) or 
device(s) provisioned and/or repackaged/modified by Amgen.  Drugs or devices include 
evolocumab/placebo and AMD or prefilled AI/Pen. 
Concerns or irregularities about the packaging, appearance or usage of the IP or device 
are to be reported to Amgen within 24 hours of discovery or notification of the concern or 
irregularity.  Should any such concerns or irregularities occur please do not use the IP 
until Amgen confirms that it is permissible to use. 
Examples of potential product complaints that need to be reported to Amgen include, but 
are not limited to: 
• 
Broken container or cracked container; 
• 
Subject or healthcare provider cannot appropriately use the product despite training 
(eg, due to malfunction of the AMD or the prefilled AI/Pen); 
• 
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 amount of fluid in the study drug 
prefilled cartridge, or 
• 
Evidence of tampering or stolen material. 
If possible, please have the suspect product available for examination when making a 
product complaint and maintain the IP at appropriate storage conditions until further 
instructions are received from Amgen. 
The investigator is responsible for ensuring that all product or device complaints 
observed by the investigator or reported by the subject that occur after signing of the ICF 
through 30 days after the last dose of IP or EOS, whichever is later, are reported to 
Amgen within 24 hours of discovery or notification of the product and/or device 
complaint.  


 
 
 
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Additional details regarding the identification and reporting of any product and/or device 
complaint(s) associated with an investigational product(s) or non-investigational 
product(s) or device(s) supplied by Amgen are provided in the IPIM. 
6.8 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
The following treatments are not permitted during the study: 
• 
Any investigational therapies other than study provided IP 
• 
Any lipid lowering therapies not taken at the time of screening and enrollment 
Please contact the Amgen medical monitor or designee if any of these therapies should 
be initiated during the study.  Note that a change in lipid-lowering therapy does not 
necessarily require ending IP. 
The following treatments are not recommended in subjects treated with statins 
metabolized by cytochrome P450 (CYP) 3A4 (eg, simvastatin or atorvastatin) 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, human immunodeficiency 
virus or hepatitis C virus (HCV) protease inhibitors, antidepressant nefazodone and 
grapefruit juice in large quantities (> 1 quart daily [approximately 1 L]) should not be 
used during the study. 
7. 
STUDY PROCEDURES 
Screening assessments and study procedures outlined in this section and in Table 1 can 
only be performed after obtaining informed consent.  
All on-study visits and dosing should be scheduled from day 1 (first IP administration). 
For example, the week 4 dose is 4 calendar weeks after the study day 1 visit, 
corresponding to study day 28.  When it is not possible to perform the study visit at the 
specified time point, the visit should be performed within the visit window specified in 
Table 1.  If a study visit is missed or late, including visits outside the visit window, 
subsequent visits should resume on the original visit schedule.  Missed assessments at 
prior visits should not be duplicated at subsequent visits.  With the exception of 
screening, all study procedures for a visit should be completed on the same day if 
possible. 
Refer to the applicable supplemental laboratory manuals for detailed collection and 
handling procedures. 


 
 
 
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7.1 
Schedule of Assessments  
Screening assessments and study procedures are outlined in this section and in Table 1 
(Schedule of Assessments). 
Table 1.  Schedule of Assessments 
 
Screening/ 
Lipid Stabilization  
(up to 6 weeks including 
4-week lipid stabilization) 
Double-blind Treatment Period 
Study Day / Week / 
Timepoint 
Screening 
Day 1 
Screening 
Week 2 
± 3 days Day 1 
Week 4 
± 3 
days 
Week 8 
± 3 days 
Week 10 
± 3 days 
Week 
12  
EOS 
± 3 
days 
General Procedures 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Vital Signs (BP and 
heart rate) 
X 
X 
X 
 
X 
X 
X 
Physical Exam 
X 
X 
X 
 
X 
X 
X 
Safety Data 
Collection/Reportinga 
X 
X 
X 
 
X 
X 
X 
Concomitant therapy 
X 
X 
X 
 
X 
X 
X 
Body weight, waist 
circumference 
 
 
X 
 
 
 
X 
Body height 
 
 
X 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
Central Laboratoryb 
 
 
 
 
 
 
 
Fasting lipidsc 
 
X 
X 
 
 
X 
X 
ApoA1, ApoB, Lp(a) 
 
 
X 
 
 
X 
X 
PCSK9 
 
 
X 
 
 
X 
X 
Chemistry 
 
X 
X 
 
 
 
X 
eGFR 
 
X 
 
 
 
 
 
Hematology 
 
 
X 
 
 
 
 
Coagulation 
(Prothrombin time) 
 
X 
 
 
 
 
 
HbA1c 
 
X 
X 
 
 
 
X 
MMTTd 
 
 
X 
 
 
 
X 
MMTT Extended 
Timepoints d 
 
 
X 
 
 
 
X 
Biomarkers (blood)e 
 
 
X 
 
 
 
X 
HCV antibody testing 
 
X 
 
 
 
 
 
HCV viral loadf 
 
X 
X 
 
 
 
X 
Serum pregnancyg; 
FSH/LH or estradiolh 
 
X 
 
 
 
 
X 
Local urine pregnancy 
 
 
X 
 
 
 
 
Page 1 of 2 
Footnote defined on the next page of this table 


 
 
 
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Table 1.  Schedule of Assessments 
 
Screening/ 
Lipid Stabilization  
(up to 6 weeks including 
4-week lipid 
stabilization) 
Double-blind Treatment Period 
Study Day / Week / 
Timepoint 
Screening 
Day 1 
Screening 
Week 2 
± 3 days Day 1 
Week 4 
± 3 
days 
Week 8 
± 3 
days 
Week 10 
± 3 days 
Week 12 
EOS 
± 3 days 
Urinalysis, Urine protein, 
Urine creatinine, urine 
microalbumin 
 
 
X 
 
 
 
X 
Investigational Product 
 
 
 
 
 
 
 
Screening placebo 
injection 
 
X 
 
 
 
 
 
In-clinic IP injection QM 
 
 
X 
 
X 
 
 
Non-clinic setting IP 
injection QM 
 
 
 
X 
 
 
 
IP dispense 
 
 
X 
 
X 
 
 
IP reconciliation QM 
 
 
 
 
X 
 
 
Page 2 of 2 
ApoA1=apolipoprotein A-I; ApoB=apolipoprotein B; ApoB48=apolipoprotein B48; BP=blood pressure; 
eGFR=estimated glomerular filtration rate; EOS=end of study; HbA1c=hemoglobin A1c; HCV=hepatitis 
C virus; IL-6=interleukin-6; FSH/LH=follicle-stimulating hormone/luteinizing hormone; IP=investigational 
product; Lp(a)=lipoprotein(a); MMTT=mixed meal tolerance test; PCSK9=proprotein convertase 
subtilisin/kexin type 9; QM=once monthly 
a Review for adverse events/serious adverse events/disease-related events/adverse device effects. Only 
adverse events possibly related to study procedures, adverse device effects and serious adverse events 
are collected during screening from signing of the informed consent.  All serious adverse events must 
be collected through 30 days after the last administration of IP or the EOS/ safety follow-up visit, 
whichever is later, and submitted to Amgen. 
b Blood samples must be taken prior to IP administration, if applicable. 
c If subject is not fasting on screening week 2 and 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. 
d Postprandial blood draw at 120 ± 10 mins after standardized mixed meal for all subjects; additional 
postprandial blood draws at 30 ± 10 mins, 60 ± 10 mins, and 180 ± 10 mins for subjects participating in the 
MMTT Extended Timepoints.  Analytes collected include: plasma glucose, insulin, proinsulin, C-peptide, 
free fatty acids, glucagon, lipids, chylomicrons, ApoB48, IL-6, adiponectin, measured after an overnight 
fast just prior to a standardized meal (0 minutes), and then 120 minutes.  Other markers for metabolic 
status may be assessed as well. 
e Anti-evolocumab antibodies may be tested, if needed.  If the subject consented to pharmacogenetic 
portion of the study, DNA analysis may be performed. One cell pellet is collected only at day 1 
(residual cell pellet from the plasma biomarker sample). 
f Viral load only in subjects positive for HCV. 
g Serum pregnancy testing in females of childbearing potential.  Additional on-treatment local pregnancy 
testing may be performed at the investigator’s discretion or as required by local laws and regulations. 
h FSH/LH or estradiol only at screening, and only if applicable per exclusion criteria. 
7.2 
General Study Procedures  
The procedures performed at each study visit are outlined Table 1.  Details regarding 
each type of procedure are provided in subsequent sub-sections.  


 
 
 
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Before each study visit where fasting lipid samples are obtained, subjects must be 
fasting overnight.  If the subject is not fasting for the screening or the day 1 visit, no visit 
procedures are performed and the visit should be rescheduled within the applicable 
protocol windows.  If subject is not fasting after day 1, all procedures except fasting labs 
and IP administration, if applicable, will be performed and another visit should be 
scheduled, within the visit window if possible, for fasting labs and IP administration. 
For each study visit when IP is administered at the site, administration must be after 
completion of blood draw procedures, if applicable. 
Subjects will be encouraged to complete all planned visits regardless of their adherence 
to IP administration. 
7.2.1 
Screening Enrollment and Randomization 
Informed consent must be obtained before completing any other screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  After signing the written 
ICF, site will register the subject in the IVRS/IWRS and screen the subject in order to 
assess eligibility for participation. 
Subjects will undergo subcutaneous placebo injection with device anticipated to be used 
during study (either AI/Pen or AMD) prior to randomization.  Subject must tolerate 
injection prior to randomization. 
The screening window is 6 weeks.  If a subject has not met all eligibility criteria at the 
end of the 6-week window, the subject will be registered as a screen fail.  Screen fail 
subjects may be eligible for rescreening once as described in Section 7.2.2. 
Subjects on maximally tolerated statin (as determined by the PI) of at least 
moderate-intensity meeting study eligibility criteria will continue with screening/lipid 
stabilization.  On week 2 of screening/lipid stabilization, study labs including lipid panel 
will be obtained.  Subjects who continue to tolerate appropriate intensity statin therapy 
and meet laboratory eligibility criteria will be eligible for enrollment at the end of 
screening/ lipid stabilization. 
7.2.2 
Rescreening 
Subjects who are unable to complete or meet eligibility on initial screening will be 
permitted to rescreen once.  Rescreen subjects must first be registered as screen failed 
in IVRS/IWRS and subsequently registered as rescreened. Subjects will retain the same 
subject identification number assigned at the original screening.  Subjects without known 
clinical CVD and fasting LDL-C < 100 mg/dL and non-HDL-C < 130 mg/dL during 


 
 
 
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screening are considered screen failures and cannot be rescreened for this study.  
Subjects with known clinical CVD and LDL-C < 70 mg/dL and non-HDL-C 
< 100 mg/dL during screening are considered screen failures and cannot be 
rescreened for this study.  Subjects who are to be rescreened must be re-consented 
and repeat all screening procedures other than the screening placebo injection. 
7.2.3 
Double-blind Treatment Period 
Visits will occur per the Schedule of Assessments (Table 1) during the treatment period 
from day 1 through week 12.  Visits during the treatment period must be completed 
within ± 3 days of the target visit date.  For visits with IP administration at the study site, 
administration should be the last procedure to be performed during each visit. 
Evolocumab/placebo is to be self-administered in an appropriate non-clinic setting 
(eg, at home) at week 4 ± 3 days.  Subjects who do not wish to self-inject at home may 
return to clinic for injection.  Observed, in-clinic dosing should occur at day 1 and at 
week 8 ± 3 days.  
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.  The 
procedures for the EOS visit should be completed at the time of withdrawal 
(Section 7.2.4). 
7.2.4 
End of Study Visit 
An EOS visit is scheduled to occur at week 12 ± 3 days. 
Subjects who discontinue study participation before their week 12 ± 3 days visit 
per protocol are considered early termination. 
7.2.5 
Safety Follow-up 
Sites are responsible for reporting safety information through 30 days after the last dose 
of IP or EOS, as applicable. For further details, see Section 9.2. 
7.3 
Description of Study Procedures 
The sections below provide a description of the individual study procedures. 
7.3.1 
Informed Consent 
All subjects must sign and personally date the IRB/IEC approved informed consent 
before any study specific procedures are performed. 


 
 
 
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7.3.2 
Demographic Data 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness. 
Additionally demographic data will be used to study the impact on biomarkers variability 
of the protocol-required therapies. 
7.3.3 
Medical History 
The investigator or designee will collect a complete medical covering the period within 
120 days prior to randomization.  Medical history will include information on the subject’s 
concurrent medical conditions.  Record all findings on the medical history CRF. 
In addition, a targeted cardiovascular history including, but not limited to, cardiovascular 
risk factors, history of cardiovascular disease, revascularization procedures, family 
history, and potential familial hypercholesterolemia diagnostic criteria will be collected. 
Targeted diabetes mellitus history including, but not limited to, duration, complications, 
and history of ketoacidosis from diagnosis will be collected. 
7.3.4 
Vital Signs 
The following measurements must be performed:  BP and heart rate will be determined 
after the subject has been seated for at least 5 minutes.  The appropriate size cuff 
should be used.  
During screening, blood pressure measurements can be repeated if the previous reading 
was outside of the eligibility range.  The repeat blood pressure measurement should be 
taken at least 2 minutes after the previous one. 
7.3.5 
Physical Examination 
A physical examination will be conducted as per standard of care.  Physical examination 
findings should be recorded on the appropriate CRF (eg, medical history, event). 
7.3.6 
Concomitant Therapy 
Prior general and targeted therapies (eg, statins, other lipid-lowering therapies, 
pharmacologic treatment for type 2 diabetes mellitus) will be collected as specified 
in Section 6.5. 
Concomitant therapies are to be collected from the signing of the ICF through the EOS 
visit, and should include the therapy name, indication, dose, unit, frequency, route, start 
date, and stop date.  Concomitant medications include over-the-counter products and 
vitamins administered while the subject is on study. 


 
 
 
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7.3.7 
Height, Weight, and Waist Circumference 
Body weight and height should be measured without shoes. 
For measurement of waist circumference, subjects should wear minimal clothing to 
ensure that the measuring tape is correctly positioned.  Subjects should stand erect with 
the abdomen relaxed, arms at the sides, feet together and with their weight equally 
divided over both legs.  To perform the waist measurement, the lowest rib margin is first 
located and marked with a pen.  The iliac crest is then palpated in the midaxillary line. It 
is recommended to apply an elastic tape horizontally midway between the lowest rib 
margin and the iliac crest, and tie firmly so that it stays in position around the abdomen 
about the level of the umbilicus.  The elastic tape thus defines the level of the waist 
circumference, which can then be measured by positioning the measuring tape over the 
elastic tape.  Subjects are asked to breathe normally, and to breathe out gently at the 
time of the measurement to prevent them from contracting their muscles or from holding 
their breath.  Measurements should be performed using the same procedure throughout 
the study.  The reading is taken to the nearest centimeter or half an inch and entered in 
the source document. 
7.4 
Laboratory Assessments 
Central laboratory assessments are to be used to assess subject eligibility (except 
for the urine pregnancy test, Section 7.1). All other screening or scheduled study 
laboratory assessments will also be by the central laboratory.  Concentration values 
are provided in mmol/L for investigator convenience.  Conventional concentrations 
(mg/mL) will be used for the protocol, including for eligibility determination.  The 
estimated glomerular filtration rate (eGFR) will be calculated by the central laboratory 
and provided to the site for eligibility determination.  
The central laboratory will provide a study manual that outlines handling, labeling, and 
shipping procedures for all samples. 
All blood samples will be obtained by venipuncture before IP administration.  The date 
and time of sample collection will be recorded in the source documents at the site. 
Specific analytes for serum chemistry, coagulation, urinalysis, hematology, and other 
labs to be conducted on blood and urine samples are shown in Table 2.  Although not 
specifically listed, additional components, abnormal, and/or atypical cells will also be 
reported if present.  


 
 
 
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Table 2.  Analyte Listing 
Chemistry  
Hematology 
Coagulation Urinalysis 
Other Labs 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Calcium 
Magnesium 
Phosphorus 
Uric Acid 
CK 
Alkaline 
phosphatase 
LDH 
Albumin 
FBG 
BUN or Urea 
Creatinine 
Total bilirubin 
Direct bilirubin 
AST 
ALT 
eGFR 
Hemoglobin 
Hematocrit 
RBC 
RDW 
MCV 
MCH 
MCHC 
Platelets  
WBC  
Morphology 
and differential: 
• Neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes 
 
PT 
Specific gravity 
pH 
Blood 
Protein 
Glucose 
Bilirubin 
WBC 
RBC 
Epithelial cells 
Bacteria 
Casts 
Crystals 
Microalbumin 
Creatinine 
Fasting lipids 
• Total cholesterol 
• HDL-C 
• LDL-C 
• Triglycerides 
• VLDL-C 
• non-HDL-C 
ApoA1 
ApoB 
ApoB48 
Lp(a) 
Insulin 
Proinsulin 
C-peptide 
Free fatty acids 
Glucagon 
Chylomicrons 
IL-6 
Adiponectin 
PCSK9 
HbA1c 
Urine and serum 
pregnancy test (females 
of childbearing potential) 
FSH/LH or Estradiol (if 
needed per exclusion 206) 
HCV antibody 
HCV viral load (if required) 
7.4.1 
Blinding of Laboratory Test Results 
In order to protect the blinding of the double-blind treatment period, the following labs will 
be blinded post screening until unblinding of the clinical database and not reported to 
sites except as noted below: 
• 
Blinded to the Amgen study team and site staff:  lipid panel, ApoA1,ApoB, 
lipoprotein(a), PCSK9 
• 
Blinded to the site staff:  insulin, proinsulin, C-peptide, free fatty acids, glucagon, 
chylomicrons, ApoB48, IL-6, and adiponectin, Analyses of proinsulin, C-peptide, free 
fatty acids, glucagon, chylomicrons, ApoB48, IL-6, and adiponectin may not be 
completed until end of study so results are not expected to be available during the 
trial. 


 
 
 
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In addition, investigators should not perform non-protocol testing of these analytes 
during a subject’s study participation.  Investigators will be informed if triglycerides 
are > 1000 mg/dL (11.3 mmol/L) so that appropriate subject follow-up can be 
initiated. 
7.4.2 
Mixed Meal Tolerance Test (All Subjects) 
A liquid MMTT will be performed after an overnight fast at the day 1 and the week 12 
study visits.  Each MMTT should be done at approximately the same time of day 
throughout the study (± 2 hours) and must be completed prior to dosing with IP at day 1.  
The fasting venous blood samples at each of these 2 visits should be collected as close 
as possible before the subject consumes a standardized mixed meal (Table 3) and 
before the subject receives any food or drink (other than water).  
Subjects are then fed a standardized mixed meal, as defined in Table 3, for example 
Boost.  The same standardized mixed meal should be used for day 1 and week 12.  
The subject should consume the standard meal in less than 20 minutes, and 
consumption should be observed by study staff.  
The beginning of the consumption of the liquid mixed meal is considered time “0” of the 
MMTT.  Postprandial blood samples are to be collected at 120 ± 10 minutes after 
consumption of the standardized mixed meal for assessment of plasma glucose, insulin, 
proinsulin, C-peptide, free fatty acids, glucagon, lipids, chylomicrons, ApoB48, IL-6, and 
adiponectin. 
Table 3.  Example Standardized Mixed Meal per 240 mL 
Content  
Protein (grams) 
10 
Total Fat (grams) 
4 
Carbohydrate (grams) 
41 
Calories (kcals) 
240 
Note the component weight in the standardized mixed meal used should not differ by more than ± 15%.  The 
same type standard mixed meal should be used for day 1 and week 12. 
7.4.3 
Mixed Meal Tolerance Test Extended Timepoints  
Approximately the first 100 subjects not on prandial insulin or GLP-1 agonists will 
undergo the MMTT Extended Timepoints assessments.  The assessments consist of 
4 postprandial blood draws in the MMTT on day 1 and week 12.  Postprandial blood 
draws for subjects participating in the assessments will be at the following timepoints 
after consumption of the standardized meal: 


 
 
 
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• 
30 ± 10 min 
• 
60 ± 10 min 
• 
120 ± 10 min 
• 
180 ± 10 min 
The same postprandial analytes will be measured at each of these timepoints.  
7.4.4 
Serum Pregnancy Test 
All females, except those who are confirmed surgically sterile or at least 2 years 
postmenopausal or 1 year postmenopausal if ≥ 55 years old must have a negative 
serum pregnancy test at screening week 2, prior to administering the first dose of 
evolocumab/placebo.  The central laboratory will provide the baseline pregnancy tests. 
Additional on-treatment local pregnancy testing may be performed at the investigator’s 
discretion or as required by local laws and regulations. 
7.5 
Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biological 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention.  Biomarker development can be useful in developing markers to identify 
disease subtypes, guide therapy, and/or predict disease severity.  Amgen may attempt 
to develop test(s) designed to identify subjects most likely to respond positively or 
negatively to evolocumab. 
For all subjects in the study, blood will be collected at day 1 and week 12 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 cellular adhesion molecules may be 
studied.  The samples must be kept at -70°C at all times and shipped in 1 batch on dry 
ice at the end of the study. 
7.6 
Pharmacogenetic Studies 
No additional blood will be collected for the pharmacogenetic analyses.  If the subject 
consents to the optional pharmacogenetic portion of this study, DNA analyses may be 
performed.  These optional pharmacogenetic 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 


 
 
 
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investigation of cardiovascular disease, hypercholesterolemia, and other metabolic 
disorders and/or to identify subjects who may have positive or negative response to 
evolocumab. 
7.7 
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.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study. Results are stored in a secure database to ensure 
confidentiality.  
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
hypercholesterolemia/mixed dyslipidemia, the dose response and/or prediction of 
response to evolocumab, and characterize aspects of the molecule (eg, mechanism of 
action/target, metabolites).  Results from this analysis are to be documented and 
maintained, but are not necessarily reported as part of this study.  Samples can be 
retained for up to 20 years from the EOS.  
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 to be 
made available to the subject, members of the family, the personal physician, or other 
third parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood samples and any other components from the cells 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. 


 
 
 
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The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  
See Section 11.3 for subject confidentiality. 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects (or a legally acceptable representative) can decline to continue receiving 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.  
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from IP and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
prior to study completion.  


 
 
 
Product:  Evolocumab 
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Date:  06 January 2016 
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Subjects may be eligible for continued treatment with Amgen IP and/or other 
protocol-required therapies by a separate protocol or as provided for by the local 
country’s regulatory mechanism, based on parameters consistent with Section 12.1. 
8.3 
Reasons for Removal From Treatment or Study 
8.3.1 
Reasons for Removal From Treatment 
Reasons for removal from protocol-required IP or procedural assessments include any 
of the following, but not limited to: 
• 
subject request  
• 
safety concern (eg, due to an adverse event, pregnancy in a female subject)  
• 
death 
• 
lost to follow-up  
• 
decision by Sponsor (other than subject request, safety concern or lost to follow-up) 
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
• 
decision by Sponsor 
• 
withdrawal of consent from study 
• 
death 
• 
lost to follow-up 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
Disease-related Events 
Disease-related events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease.  In this study, subjects are at risk or are 
known to have cardiovascular disease.  Therefore, disease-related events potentially 
include manifestations and complications of atherosclerotic vascular disease such as 
coronary artery disease, angina, myocardial infarction, ischemic stroke, transient 
ischemic attack, carotid artery disease, peripheral vascular disease, and testing 
suggesting progression of atherosclerotic vascular disease.  Such events do not meet 
the definition of an adverse event unless assessed to be more severe than expected for 
the subject’s condition. 
Disease-related events and/or disease-related outcomes that do not qualify as serious 
adverse events:  
• 
An event which is part of the normal course of disease under study, with no causal 
relationship with IP/protocol-required therapies (eg, disease progression or 


 
 
 
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hospitalization due to disease progression) is to be reported as a disease-related 
event.  
• 
Death is due to the disease under study; the event is to be recorded on the Event 
CRF as a disease-related event. 
If the outcome of the underlying disease is worse than that which would normally be 
expected for the subject, or if the investigator believes there is a causal relationship 
between the IP/study treatment protocol-required therapies and disease worsening, the 
event must be reported as an adverse event or serious adverse event. 
9.1.2 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment. 
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.  
The definition of adverse events includes worsening of a pre-existing medical condition. 
Worsening indicates that the pre-existing medical condition or underlying disease 
(eg, diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
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.  
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study. 
9.1.3 
Adverse Device Effects 
An ADE is any adverse event related to the use of a medical device.  Adverse device 
effects include adverse events resulting from insufficient or inadequate instructions for 
use, adverse events resulting from any malfunction of the device, or adverse events 
resulting from use error or from intentional misuse of the device. 


 
 
 
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9.1.4 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria (unless it meets the definition of a disease-related event as 
defined in Section 9.1.1): 
• 
fatal 
• 
life threatening (places the subject at immediate risk of death) 
• 
requires in-patient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
congenital anomaly/birth defect 
• 
other medically important serious event 
A disease-related event as described above is to be reported as a serious adverse event 
if:  
• 
the event meets at least 1 of the serious criteria above, AND 
• 
the subject’s pre-existing condition becomes worse than what the investigator would 
consider typical for a patient with the same underlying condition, OR 
• 
the investigator believes a causal relationship exists between the 
IP/protocol-required therapies and the 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 
DILI reporting criteria), or events that necessitate an emergency room visit, outpatient 
surgery, or urgent intervention. 
If adverse events correspond to grade 4 “life threatening” Common Terminology Criteria 
for Adverse Events (CTCAE) grading scale criteria (eg, laboratory abnormality reported 
as Grade 4 without manifestation of life threatening status), it will be left to the 
investigator’s judgment to also report these abnormalities as serious adverse events.  
For any adverse event that applies to this situation, comprehensive documentation of the 
event’s severity status must be recorded in the subject’s medical record. 


 
 
 
Product:  Evolocumab 
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9.2 
Safety Event Reporting Procedures  
9.2.1 
Disease-related Events 
The investigator is responsible for ensuring that all disease-related events observed by 
the investigator or reported by the subject that occur from the time of randomization 
through the EOS/safety follow-up visit are reported using the Event CRF.  Additionally, 
the investigator is required to report a fatal disease-related event on the Event CRF. 
Events assessed by the investigator to be related to the IP/study 
treatment/protocol-required therapies, and determined to be serious, require reporting of 
the event on the Event CRF.  
9.2.2 
Adverse Events 
9.2.2.1 
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
Adverse events possibly related to study procedures, adverse device effects and 
serious adverse events are reported from signing of the ICF.  All other adverse 
events are reported from the time of randomization.  The investigator is responsible 
for ensuring that all adverse events observed by the investigator or reported by the 
subject that occur from signing of the ICF or from the time of randomization through 
the EOS/safety follow-up visit are reported using the Event CRF.   
The investigator must assign the following adverse event attributes: 
• 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
• 
Dates of onset and resolution (if resolved), 
• 
Severity (and/or toxicity per protocol), 
• 
Assessment of relatedness to IP (evolocumab/placebo and/or the medical devices: 
AMD or the AI/Pen), or any study-mandated activity or procedure or other protocol 
required therapies, and 
• 
Action taken. 
The adverse event grading scale used will be the CTCAE).  The grading scale used in 
this study is described in Appendix A.  
The investigator must assess whether the adverse event is possibly related to the 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 
the IP?”  
The investigator must assess whether the adverse event is possibly related to the 
AI/Pen or the AMD investigational device used to administer IP.  The relationship is 


 
 
 
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indicated by a “yes” or “no” response to the question: “Is there a reasonable possibility 
that the event may have been caused by the investigational device?” 
The investigator must assess whether the adverse event is possibly related to any 
other study-mandated activity or procedure (eg. administration of IP, 
protocol-required therapies, device(s) and/or procedure (including any screening 
procedure[s]). This relationship is indicated by a “yes” or “no” response to the 
question: “Is there a reasonable possibility that the event may have been caused 
by a study activity/procedure” (eg. administration of IP, protocol-required 
therapies, device(s) and/or procedure?) 
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 Event CRF. 
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the investigator's judgment) are not to be 
recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. 
The investigator is expected to follow reported adverse events until stabilization or 
reversibility. 
9.2.2.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the ICF through 
30 days after the last administration of IP or the EOS/ safety follow-up visit, whichever is 
later, are recorded in the subject’s medical record and are submitted to Amgen.  All 
serious adverse events must be submitted to Amgen within 24 hours following the 
investigator’s knowledge of the event via the Event CRF.  
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
serious adverse event Contingency Report Form within 24 hours of the investigator’s 
knowledge of the event.  See Appendix B for a sample of the Serious Adverse Event 
Worksheet /electronic Serious Adverse Event Contingency Report Form.  For EDC 


 
 
 
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studies where the first notification of a serious adverse event is reported to Amgen via 
the eSerious Adverse Event Contingency Report Form, the data must be entered into 
the EDC system when the system is again available. 
The investigator must assess whether the serious adverse event is possibly related to 
any study mandated activity or procedure.  This relationship is indicated by a “yes” or 
“no” response to the question:  “Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure”? 
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility.  
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours 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 Event CRF. 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities.  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 
in compliance with all reporting requirements according to local regulations and GCP.  
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local procedures and statutes. 
In addition to the attributes listed in Section 9.2.2.1, the investigator must also complete 
the serious adverse event section of the Event CRF. 


 
 
 
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9.2.2.3 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after EOS.  However, these serious adverse 
events can be reported to Amgen. In some countries (eg, European Union member 
states), investigators are required to report serious adverse events that they become 
aware of after EOS.  If serious adverse events are reported, the investigator is to report 
them to Amgen within 24 hours following the investigator’s knowledge of the event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases for the purposes of expedited 
reporting.  
9.2.2.4 
Serious Adverse Events That are not to be Reported in an Expedited 
Manner 
Hospitalizations due to chronic diabetic complications are anticipated to occur in the 
patient population enrolled in this study and are therefore not planned to be 
reported individually in an expedited manner. The Amgen safety and medical teams 
will review accumulating events on a regular basis. 
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 evolocumab/placebo. 
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C).  Amgen Global Patient Safety will 
follow-up with the investigator regarding additional information that may be requested.  
If a 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 evolocumab/placebo. 


 
 
 
Product:  Evolocumab 
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Date:  06 January 2016 
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Any lactation case should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up with 
the investigator regarding additional information that may be requested. 
10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Co-primary Endpoints 
• 
mean percent change from baseline in LDL-C at weeks 10 and 12 
• 
percent change from baseline in LDL-C at week 12 
10.1.1.2 
Co-secondary Endpoints 
For the mean of weeks 10 and 12 and for week 12: 
• 
Tier 1 
− 
Change from baseline in LDL-C 
− 
Percent change from baseline in non-HDL-C 
− 
Percent change from baseline in ApoB 
− 
Percent change from baseline in TC 
− 
Achievement of target LDL-C <70 mg/dL (1.8 mmol/L) 
− 
LDL-C response (50% reduction of LDL-C from baseline) 
• 
Tier 2 
− 
Percent change from baseline in Lp(a) 
− 
Percent change from baseline in triglycerides 
− 
Percent change from baseline in HDL-C 
− 
Percent change from baseline in VLDL-C 
10.1.1.3 
Exploratory Endpoints 
• 
change and percent change from baseline at each scheduled assessment in each of 
the following parameters: 
− 
LDL-C 
− 
non-HDL-C 
− 
ApoB 
− 
TC 
− 
VLDL-C 
− 
HDL-C  
− 
ApoA1 


 
 
 
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− 
triglycerides 
− 
Lp(a) 
• 
HbA1c at each scheduled assessment 
• 
Fasting blood glucose (FBG) at each scheduled assessment 
• 
PCSK9 change from baseline at each scheduled assessment 
• 
fasting and post-prandial laboratory parameters of interest (including Mixed Meal 
Tolerance Test (MMTT) Extended Timepoints assessments) change and percent 
change from day 1 to week 12 in response to a MMTT in glucose, insulin, pro-insulin, 
C-peptide, free fatty acids, glucagon, lipids, chylomicrons, ApoB48, IL-6, adiponectin 
10.1.1.4 
Safety Endpoints 
• 
subject incidence of treatment emergent adverse events 
• 
safety laboratory values and vital signs at each scheduled assessment 
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 analysis, subjects will be analyzed according to their randomized treatment 
group assignment.  For safety analysis, subjects will be analyzed according to their 
randomized treatment group assignment except for the following case: if a subject 
receives a treatment that is different than the randomized treatment assignment 
throughout the study, then this subject will be analyzed by the treatment received. 
The completer analysis set (CAS) includes subjects in the FAS who adhered to the 
scheduled IP regimen in the double-blind treatment period and have observed value for 
the primary endpoints.  
10.1.3 
Covariates and Subgroups 
Baseline covariates include, but are not limited to: 
• 
Stratification factor in the double-blind treatment period: 
• 
LDL-C < 130 mg/dL/ ≥ 130 mg/dL 
• 
Age: < 65 years/ ≥ 65 years 
• 
Sex 
• 
Race 
• 
Study baseline LDL-C: < median/ ≥ median 
• 
Family history of premature CHD: yes/no 
• 
Baseline PCSK9 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
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10.2 
Sample Size Considerations 
The planned sample size for the comparison between evolocumab 420 mg QM and 
placebo at a ratio of 2:1 in the double-blind treatment period is 400 total subjects. 
The primary analysis will require the 2-sided tests of co-primary endpoints to be 
significant at a level of 0.05.  The planned sample size should provide adequate power 
to determine the superiority of evolocumab 420 mg QM relative to placebo as measured 
by the co-primary endpoints.  From the phase 3 studies integrated efficacy analysis, the 
treatment effect of evolocumab 420 mg QM compared to placebo and the corresponding 
95% confidence interval at week 12 was -61.98% [-69.51%, -60.45%], with treatment 
effect ranges between -55.1% to -62.33% from Studies 20110114, 20110115, and 
20110117.  The assumed treatment effect between the primary endpoint in evolocumab 
420 mg QM is 40%, with a common standard deviation (SD) of 20%. This SD 
assumption is based on evolocumab phase 3 results. 
This sample size will provide approximately 99% power for the primary endpoint in 
testing the superiority of evolocumab dose regimen over placebo, assuming a dropout 
rate of 10%.  
From the phase 3 studies the treatment effects measured as mean of week 10 and 
week 12 were as large or larger than week 12 and highly correlated (> 85%) with ones at 
week 12.  Therefore the sample size as planned will provide at least 98% (99% × 99%) 
power in testing the superiority of evolocumab over placebo on the co-primary 
endpoints. 
From the phase 3 evolocumab studies the treatment effect of evolocumab over placebo 
in the percentage reduction in triglycerides at week 12 was approximately 12% with a 
common SD of 35%.  However, the SD for triglycerides in a diabetic population may be 
higher.  Table 4 displays the power associated with various SD assumptions. 
Table 4.  Power Associated With Standard Deviation Assumptions 
Treatment effect = 12% reduction 
Sample size = 400 (5% dropout) 
Significance level = 5% 
Standard Deviation 
Power 
35 
0.88 
40 
0.78 
45 
0.68 
50 
0.59 


 
 
 
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For HDL-C the treatment effect of evolocumab over placebo observed in the phase 3 
studies at week 12 was a percentage increase of approximately 5% with a common SD 
of 15%.  Assuming 400 subjects and a 5% drop out rate, this would provide 
approximately 86% power to test the superiority of evolocumab over placebo 
10.3 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
Blinded individuals will not have access to unblinded information until the study is 
formally unblinded.  Unblinding and potentially unblinding information should not be 
distributed to the study team, investigators or subjects prior to the study being formally 
unblinded (eg, the formal unblinding may occur at the final analysis rather than during 
the primary analysis) except as specified (eg, Section 5.2 and Section 9.2.2.2).  
10.4 
Planned Analyses 
To evaluate efficacy and safety of 12 weeks of evolocumab 420 mg QM compared with 
placebo, the primary analysis will be performed when all randomized subjects in the 
double-blind treatment period have either completed all the scheduled study visits in the 
double-blind treatment period or have early terminated from the study.  At that time, the 
database of the study will be cleaned, processed and a snapshot will be taken; the study 
will also be unblinded. 
10.5 
Planned Methods of Analysis  
10.5.1 
General Considerations 
Efficacy and safety analyses will be performed on FAS unless otherwise specified, and 
data will be summarized by randomized treatment group.  
Subject disposition, demographics, baseline characteristics and exposure to IP will be 
summarized by treatment group.  Summary statistics for continuous variables will 
include the number of subjects, mean, median, SD, 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 below.  
Missing data will not be imputed for safety endpoints.  
10.5.1.1 
Multiplicity Adjustment Method 
Methods of adjusting for multiplicity due to multiple endpoints (primary and secondary 
efficacy endpoints) in order to preserve the familywise error rate at 0.05 are described in 
Figure 1. 


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Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 52 of 69 
CONFIDENTIAL 
 
 
in LDL-C from baseline at week 12, a repeated measures linear effects model will be 
used on the FAS to compare the efficacy of evolocumab QM with placebo QM.  The 
repeated measures model will include terms for treatment group, stratification factor, 
scheduled visit and the interaction of treatment with scheduled visit.  Missing values will 
not be imputed for primary analysis. 
10.5.2.1 
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 
A sensitivity analysis under the assumption that subjects who discontinued IP with 
missing endpoint data have a mean zero percent change from baseline will be 
conducted. 
10.5.2.2 
Subgroup Analysis 
If applicable, subgroup analyses on the primary endpoint will be conducted using the 
stratification factor or baseline covariates. 
10.5.3 
Co-secondary Efficacy Endpoints 
Analysis of co-secondary endpoints will use the same analysis model as the co-primary 
endpoints.  The co-secondary endpoints of LDL-C response (achievement of LDL-C 
< 70 mg/dL and achievement of > 50% LDL-C reduction from baseline) will be analyzed 
using the Cochran-Mantel Haenszel test adjusted by the stratification factor. 
10.5.4 
Safety Endpoints 
The current Medical Dictionary for Regulatory Activities version at the time of the data 
lock will be used to code all adverse events to a system organ class and a preferred 
term. 
Subject incidence of all treatment emergent adverse events will be tabulated by system 
organ class and preferred term.  Tables of fatal adverse events, serious adverse events, 
adverse events leading to withdrawal from IP, device-related adverse events, and 
significant treatment-emergent adverse events will also be provided.  Subject incidence 
of disease-related events and fatal disease-related events will be tabulated by system 
organ class and preferred term.  Subject-level data may be provided instead of tables if 
the subject incidence is low. 


 
 
 
Product:  Evolocumab 
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11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample ICF is provided for the investigator to prepare the informed consent 
document to be used at his or her site.  Updates to the template are to be communicated 
formally in writing from the Amgen Clinical Study Manager to the investigator.  The 
written informed consent document is to be prepared in the language(s) of the potential 
patient population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol-specific screening procedures or any IP is administered.  
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the ICF is to be signed and personally dated by the subject and by the 
person who conducted the informed consent discussion.  The original signed ICF is to 
be retained in accordance with institutional policy, and a copy of the signed consent form 
is to be provided to the subject. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
ICF to the subject and must allow for questions.  Thereafter, both the subject and the 
witness must sign the ICF to attest that informed consent was freely given and 
understood.  
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed ICF, other written subject information, and any 
proposed advertising material must be submitted to the IRB/IEC for written approval.  A 


 
 
 
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copy of the written approval of the protocol and ICF must be received by Amgen before 
recruitment of subjects into the study and shipment of Amgen IP. 
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 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.  
• 
For Serious Adverse Events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with 
local laws and regulations), and date of birth (in accordance with local laws and 
regulations). 
• 
Documents that are not submitted to Amgen (eg, signed ICFs) are to be kept in 
confidence by the investigator, except as described below. 
In compliance with ICH Tripartite Guideline on 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 multicenter 
studies, the coordinating investigator. 


 
 
 
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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 IP by an extension protocol 
or as provided for by the local country’s regulatory mechanism.  However, Amgen 
reserves the unilateral right, at its sole discretion, to determine whether to supply Amgen 
IP and by what mechanism, after termination of the 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:   
• 
Case report form 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 


 
 
 
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for inspection at any time by representatives from Amgen and/or applicable 
regulatory authorities.  
Elements to include: 
• 
Subject files containing completed CRFs, ICFs, and subject identification list 
• 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
• 
Investigational product-related correspondence including Proof of Receipts, IP 
Accountability Record(s), Return of IP for Destruction Form(s), Final IP 
Reconciliation Statement, as applicable. 
In addition, all original source documents supporting entries in the CRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The 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. 


 
 
 
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Data capture for this study is planned to be electronic: 
• 
All source documentation supporting entries into the CRFs must be maintained and 
readily available. 
• 
Updates to CRFs will be automatically documented through the software’s “audit 
trail”. 
• 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During this 
review, subject data are checked for consistency, omissions, and any apparent 
discrepancies.  In addition, the data are reviewed for adherence to the protocol and 
GCP.  To resolve any questions arising from the clinical data management review 
process, data queries are created in the EDC system database for site resolution 
and subsequently closed by the EDC system or by an Amgen reviewer. 
• 
The investigator signs only the Investigator Verification Form for this EDC study or 
the investigator applies an electronic signature in the EDC system if the study is set 
up to accept an electronic signature.  This signature indicates that investigator 
inspected or reviewed the data on the CRF, the data queries, and agrees with the 
content. 
Amgen (or designee) will perform self-evident corrections to obvious data errors in the 
clinical trial database, as documented in the Study Specific Self Evident Corrections 
Plan.  Examples of obvious data errors that may be corrected by Amgen (or designee) 
include deletion of obvious duplicate data (eg, same results sent twice with the same 
date with different visit-week 4 and early termination) and clarifying “other, specify” if 
data are provided (eg, race, physical examination).  Each investigative site will be 
provided a list of the types of corrections applied to study data at the initiation of the trial 
and at study closeout.  
12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible 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.  


 
 
 
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12.6 
Publication Policy 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors), which states: 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published.  Authors should meet conditions 1, 2, and 3. 
• 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 
• 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
• 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
• 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for 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 
Abifadel M, Rabès JP, Devillers M, et al. Mutations and polymorphisms in the proprotein 
convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. Hum 
Mutat. 2009;30:520–529. 
American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 
2005;(28 Suppl 1):4-36. 
Amgen. AMG 145 Investigator’s Brochure. Thousand Oaks, CA. Amgen Inc. 
Arca M. Atorvastatin efficacy in the prevention of cardiovascular events in patients with 
diabetes mellitus and/or metabolic syndrome. Drugs. 2007;67 Suppl 1:43-54. 
Bruckert E, Hayem G, Dejager S, Yau C, B´egaud B. Mild to Moderate Muscular 
Symptoms With High-dosage Statin Therapy in Hyperlipidemic Patients—The PRIMO 
Study. Cardiovasc Drugs Ther. 2005;19(6):403-414. 
Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with 
cardiometabolic risk: consensus statement from the American Diabetes Association and 
the American College of Cardiology Foundation. Diabetes Care. 2008;31:811-822. 
Chinese Society of Cardiology of Chinese Medical Association, Editorial Board of 
Chinese Journal of Cardiology. Chinese guidelines for prevention of cardiovascular 
diseases. Zhonghua Xin Xue Guan Bing Za Zhi. 2011;39:3-22.  
Franc S, Dejager S, Bruckert E, Chauvenet M, Giral P, Turpin G. A comprehensive 
description of muscle symptoms associated with lipid-lowering drugs. Cardiovasc Drugs 
Ther. 2003;17:459-465. 
Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the 
National Cholesterol Education Program Adult Treatment Panel III Guidelines. 
Circulation. 2004;110:227-239. 
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. 
Biometrika. 1988;75:800-802. 
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. 
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. 
Reiner Z, Catapano AL, De Backer G, et al. ESC/EAS Guidelines for the management of 
dyslipidaemias: the Task Force for the management of dyslipidaemias of the European 
Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart 
J. 2011;32:1769-1818. 
Wiens BL. A fixed sequence Bonferroni procedure for testing multiple endpoints. 
Pharmaceut Statist. 2003;2:211–215. 
Yang W, Xiao J, Yang Z, et al, Serum lipids and lipoproteins in Chinese men and 
women. Circulation. 2012;125:2212-2221. 


 
 
 
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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 Adverse Events (CTCAE) 
Version 4.0.  
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 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, 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 9.2.2.2. 
Additional Clinical Assessments and Observation 
All subjects in whom IP or protocol-required therapies is/are withheld (either permanently 
or conditionally) due to potential DILI as specified in Sections 6.4.1 and 6.4.2 or who 
experience AST or ALT elevations > 3 × ULN are to undergo a period of “close 
observation” until abnormalities return to normal or to the subject’s baseline levels. 
Assessments that are to be performed during this period include:  
• 
AST, ALT, ALP, and bilirubin (total and direct) is to be repeated within 2 hours  
• 
In cases of TBL ≥ 2 × ULN, retesting of liver tests, and bilirubin (total and direct) is to 
be performed every 24 hours until laboratory abnormalities improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the IP 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 with differential to assess for eosinophilia 
− 
Obtain serum total immunoglobulin G, Anti-nuclear antibody, Anti-Smooth Muscle 
Antibody, and Liver Kidney Microsomal antibody 1 to assess for autoimmune 
hepatitis 


 
 
 
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− 
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, 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, and TBL) 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 IP 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 Serious Adverse Event Report Form 
 


 
 
 
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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 


 
 
 
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Appendix D.  High, Moderate, and Low-intensity Statin Therapy 
Criteria modified from American College of Cardiology/American Heart Association 
(ACC/AHA) guidelines: 
High-intensity 
Statin 
Therapy 
Moderate-intensity 
Statin Therapy 
Low-intensity 
Statin 
Therapy 
Notes (Modifications 
from ACC/AHA 
Guideline) 
Atorvastatin 
≥ 40 mg QD 
10 mg to < 40 mg 
QD 
<10 mg QD 
Atorvastatin 30 mg QD 
is moderate intensity. 
Rosuvastatin 
≥ 20 mg QD 
5 mg to < 20 mg 
QD 
< 5 mg QD 
Rosuvastatin < 5 mg QD 
is low intensity, 
Rosuvastatin 15 mg 
QD = moderate 
Simvastatin 
≥ 80 mg QD 
20 mg to 80 mg 
QD 
< 20 mg QD 
Simvastatin > 40 and 
< 80 mg QD is moderate 
intensity 
Simvastatin 80 mg or 
greater QD is high 
intensity 
Simvastatin < 20 mg QD 
is low-intensity 
Pravastatin 
– 
≥ 40 mg QD 
< 40 mg QD 
Pravastatin < 10 mg QD 
is low intensity 
Lovastatin 
– 
≥ 40 mg QD 
< 40 mg QD 
Lovastatin 80 mg QD is 
moderate, 
Lovastatin 10 mg QD is 
low-intensity 
Fluvastatin 
– 
80 mg QD 
< 80 mg QD 
Fluvastatin 10 mg QD is 
low-intensity 
Pitavastatin 
– 
≥ 2 mg QD 
< 2 mg QD 
– 
UNKNOWN-INTENSITY STATIN THERAPY if dose frequency is other or dose unit is other and therefore 
total daily dose in mg cannot be derived; NO STATIN THERAPY if subject does not use any statin at 
baseline. 


 
 
 
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Appendix E.  Child-Pugh Score 
 


 
 
 
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Amendment 1 
Protocol Title:  A Double-blind, Randomized, Placebo-controlled, Multicenter 
Study to Evaluate Safety, Tolerability, and Efficacy of Evolocumab (AMG 145) on 
LDL-C in Subjects With Type 2 Diabetes Mellitus and Hypercholesterolemia/Mixed 
Dyslipidemia 
Amgen Protocol Number (Evolocumab) 20130287 
Date: 
20 November 2015 
Amendment 1 Date: 
06 January 2016 
 
Rationale: 
• 
Updated schema to provide additional study design details. 
• 
Reorganized inclusion criteria for better understanding. 
• 
Provided additional details of contraceptive methods in the exclusion criteria. 
• 
Clarified timing of randomization in relation to first dose. 
• 
Added clinical research associate as an additional contact for the investigator prior to 
unblinding of subject’s treatment assignment. 
• 
Added non-clinic IP injection at Week 4 to the Schedule of Assessments table for 
clarity. 
• 
Removed section for safety reporting as another section already details same 
information. 
• 
Removed text kilograms and centimeters for body weight and height so sites can 
record in pounds and inches. 
• 
Added that triglycerides > 1000 mg/dL would be reported to the investigators to allow 
appropriate follow-up to be initiated. 
• 
Revised reasons for removal from treatment to be consistent with template text. 
• 
Updated reporting requirements for adverse events for consistency throughout the 
protocol. 
• 
Added appendix E of Child-Pugh Score to provide additional information. 
• 
Made edits for grammatical and formatting errors. 


 
 
 
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Description of Changes: 
Section:  Global 
Replace: 
20 November 2015 
With: 
06 January 2016 
Section:  Title Page 
Add: 
Amendment 1 Date 
06 January 2016 
Section:  Investigator’s Agreement 
Paragraph 1 
Replace: 
I have read the attached protocol entitled “A Double-blind, Randomized, 
Placebo-controlled, Multicenter Study to Evaluate Safety, Tolerability, and Efficacy of 
Evolocumab on LDL-C in Subjects With Type 2 Diabetes Mellitus and 
Hypercholesterolemia/Mixed Dyslipidemia”, dated 20 November 2015, and agree to 
abide by all provisions set forth therein. 
With: 
I have read the attached protocol entitled “A Double-blind, Randomized, 
Placebo-controlled, Multicenter Study to Evaluate Safety, Tolerability, and Efficacy of 
Evolocumab (AMG 145) on LDL-C in Subjects With Type 2 Diabetes Mellitus and 
Hypercholesterolemia/Mixed Dyslipidemia”, dated 06 January 2016, and agree to abide 
by all provisions set forth therein. 
Section:  Synopsis, Indication 
Replace: 
Hypercholesterolemia and/or Mixed Dyslipidemia 
With: 
Hypercholesterolemia/Mixed Dyslipidemia 


 
 
 
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Section:  Synopsis, Primary Objective 
Replace: 
To evaluate the effect of 12 weeks of subcutaneous (SC) evolocumab monthly (QM) 
compared with placebo QM on percent change from baseline in low-density lipoprotein 
cholesterol (LDL-C) in subjects with type 2 diabetes mellitus and hypercholesterolemia 
or mixed dyslipidemia on maximally tolerated statin of at least moderate-intensity oral 
daily. 
With: 
To evaluate the effect of 12 weeks of subcutaneous (SC) evolocumab monthly (QM) 
compared with placebo QM on percent change from baseline in low-density lipoprotein 
cholesterol (LDL-C) in subjects with type 2 diabetes mellitus and hypercholesterolemia 
or mixed dyslipidemia on maximally tolerated dose of statin of at least 
moderate-intensity oral daily. 
Section:  Synopsis, Secondary Objective(s) 
Sentence 1 
Replace: 
To assess the effects of 12 weeks of SC evolocumab QM compared with placebo QM, in 
subjects with type 2 diabetes mellitus and hypercholesterolemia or mixed dyslipidemia in 
combination with maximally tolerated statin of at least moderate-intensity oral daily on 
the following: 
With: 
To assess the effects of 12 weeks of SC evolocumab QM compared with placebo QM, in 
subjects with type 2 diabetes mellitus and hypercholesterolemia or mixed dyslipidemia in 
combination with maximally tolerated dose of statin of at least moderate-intensity oral 
daily on the following: 
Section:  Synopsis, Safety Objective 
Replace: 
To evaluate the safety and tolerability of SC evolocumab QM compared with placebo 
QM in subjects with type 2 diabetes mellitus and hypercholesterolemia or mixed 
dyslipidemia in combination with maximally tolerated statin of at least moderate-intensity 
oral daily. 


 
 
 
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With: 
To evaluate the safety and tolerability of SC evolocumab QM compared with placebo 
QM in subjects with type 2 diabetes mellitus and hypercholesterolemia or mixed 
dyslipidemia in combination with maximally tolerated dose of statin of at least moderate-
intensity oral daily. 
Section:  Synopsis, Hypotheses 
Replace: 
Subcutaneous evolocumab 420 mg QM in combination with statin once daily 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 QM in subjects with type 2 diabetes and hypercholesterolemia or 
mixed dyslipidemia on maximally tolerated statin of at least moderate-intensity daily. 
With: 
Subcutaneous evolocumab 420 mg QM in combination with statin once daily 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 QM in subjects with type 2 diabetes mellitus and 
hypercholesterolemia or mixed dyslipidemia on maximally tolerated dose of statin of at 
least moderate-intensity daily. 
Section:  Synopsis, Sample Size 
Replace: 
Approximately 400 subjects will be enrolled in the study, with approximately 270 subjects 
in the evolocumab group. 
With: 
Approximately 400 subjects with type 2 diabetes mellitus with hypercholesterolemia 
or mixed dyslipidemia. 


 
 
 
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Section:  Synopsis, Summary of Subject Eligibility Criteria 
Replace: 
The study will enroll adult subjects (≥ 18 years of age) with type 2 diabetes mellitus with 
hemoglobin A1c (HbA1C) < 10%who must be on a stable, maximally tolerated statin of 
at least moderate-intensity at screening.  Subjects must have been receiving 
pharmacologic treatment for diabetes mellitus for ≥ 6 months prior to screening, with 
stable diabetes therapy prior to randomization to investigational product (IP) and not 
expected to change during throughout the duration of study participation.  For a full list of 
eligibility criteria, please refer to Section 4.1 through Section 4.1.2. 
With: 
The study will enroll adult subjects (≥ 18 years of age) with type 2 diabetes mellitus and 
elevated LDL-C or non-HDL-C levels on a stable, maximally tolerated statin dose of at 
least moderate-intensity at signing of the informed consent; statin therapy must 
remain unchanged during screening and the remainder of the study.  Subjects 
must have hemoglobin A1c (HbA1c) < 10%, must have been receiving pharmacologic 
treatment for diabetes mellitus for ≥ 6 months prior to screening, with stable diabetes 
therapy prior to randomization to investigational product (IP) and not expected to change 
throughout the duration of study participation.  For a full list of eligibility criteria, please 
refer to Section 4.1 through Section 4.1.2. 
Section:  Synopsis, Amgen Investigational Product Dosage and Administration 
Sentence 3 
Replace: 
Observed, in-clinic dosing should occur at day 1 and week 8, and subjects will 
self-administer in an appropriate non-clinic setting (eg, at home) for week 4. 
With: 
Observed, in-clinic dosing should occur at day 1 and week 8 ± 3 days, and subjects will 
self-administer in an appropriate non-clinic setting (eg, at home) for week 4 ± 3 days. 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 6 of 37 
CONFIDENTIAL 
 
 
Section:  Synopsis, Procedures 
Paragraph 2, sentence 4 
Replace: 
Subjects must tolerate a SC injection of placebo prior to randomization. 
With: 
Subjects must tolerate a SC injection of placebo with device anticipated to be used 
during the study (either AI/Pen or AMD) prior to randomization. 
Section:  Synopsis, Procedures 
Paragraph 3 
Replace: 
During the double-blind treatment period, study visits will occur at day 1, week 8, 
week 10, and week 12; with baseline evaluations performed on day 1 of treatment 
before subjects receive the first dose of IP.  All subjects will complete a mixed meal 
tolerance test (MMTT) at the day 1 and week 12 study visits with a baseline and 2-hour 
postprandial blood collection after the meal.  Up to approximately 100 subjects not 
treated with prandial insulin or glucagon-like peptide-1 agonists will participate in MMTT 
Extended Timepoints assessments with 3 additional postprandial blood draws at 
30 minutes, 1 hour, and 3 hours after the meal.  End of study for all subjects will be at 
the week 12 visit. 
With: 
During the double-blind treatment period, study visits will occur at day 1, week 8 
(± 3 days), week 10 (± 3 days), and week 12 (± 3 days); with baseline evaluations 
performed on day 1 of treatment before subjects receive the first dose of IP.  All subjects 
will complete a mixed meal tolerance test (MMTT) at the day 1 and week 12 study visits 
with a baseline and 2-hour (± 10 min) postprandial blood collection after the meal.  Up to 
approximately 100 subjects not treated with prandial insulin or glucagon-like peptide-1 
agonists will participate in MMTT Extended Timepoints assessments with 3 additional 
postprandial blood draws at 30 minutes (± 10 min), 1 hour (± 10 min), and 3 hours 
(± 10 min) after the meal.  End of study for all subjects will be at the week 12 (± 3 days) 
visit. 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 7 of 37 
CONFIDENTIAL 
 
 
Section:  Synopsis, Statistical Considerations 
Paragraph 1, sentence 4 
Replace: 
To assess the co-primary endpoints of the mean percent change from baseline (mean of 
week -2 and Day 1) in LDL-C at weeks 10 and 12 and the percent change in LDL-C from 
baseline at week 12, a repeated measures linear effects model will be used on the FAS 
to compare the efficacy of evolocumab QM with placebo QM. 
With: 
To assess the co-primary endpoints of the mean percent change from baseline (mean of 
screening week 2 and day 1) in LDL-C at weeks 10 and 12 and the percent change in 
LDL-C from baseline at week 12, a repeated measures linear effects model will be used 
on the FAS to compare the efficacy of evolocumab QM with placebo QM. 
Section:  Study Schema 
Replaced old study schema with new updated schema and added abbreviations. 
Section:  Study Glossary 
Add: 
AE 
adverse event 
 
DRE 
device related event 
 
SAE 
serious adverse event 
Section:  Study Glossary 
Delete: 
DNA 
deoxyribonucleic acid 
 
INR 
international normalized ratio 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 8 of 37 
CONFIDENTIAL 
 
 
Section:  1.1 Primary 
Replace: 
• 
To evaluate the effect of 12 weeks of subcutaneous (SC) evolocumab monthly (QM) 
compared with placebo QM on percent change from baseline in low-density 
lipoprotein cholesterol (LDL-C) in subjects with type 2 diabetes mellitus and 
hypercholesterolemia or mixed dyslipidemia on maximally tolerated statin of at least 
moderate-intensity oral daily. 
With: 
• 
To evaluate the effect of 12 weeks of subcutaneous (SC) evolocumab monthly (QM) 
compared with placebo QM on percent change from baseline in low-density 
lipoprotein cholesterol (LDL-C) in subjects with type 2 diabetes mellitus and 
hypercholesterolemia or mixed dyslipidemia on maximally tolerated dose of statin of 
at least moderate-intensity oral daily. 
Section:  1.2 Secondary 
Bullet 1 
Replace: 
• 
To assess the effects of 12 weeks of SC evolocumab QM compared with placebo 
QM, in subjects with type 2 diabetes mellitus and hypercholesterolemia or mixed 
dyslipidemia in combination with maximally tolerated statin of at least 
moderate-intensity oral daily on the following: 
With: 
• 
To assess the effects of 12 weeks of SC evolocumab QM compared with placebo 
QM, in subjects with type 2 diabetes mellitus and hypercholesterolemia or mixed 
dyslipidemia in combination with maximally tolerated dose of statin of at least 
moderate-intensity oral daily on the following: 
Section:  1.3 Safety 
Replace: 
• 
To evaluate the safety and tolerability of SC evolocumab QM compared with placebo 
QM in subjects with type 2 diabetes mellitus and hypercholesterolemia or mixed 
dyslipidemia in combination with maximally tolerated statin of at least 
moderate-intensity oral daily. 
With: 
• 
To evaluate the safety and tolerability of SC evolocumab QM compared with placebo 
QM in subjects with type 2 diabetes mellitus and hypercholesterolemia or mixed 
dyslipidemia in combination with maximally tolerated dose of statin of at least 
moderate-intensity oral daily. 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 9 of 37 
CONFIDENTIAL 
 
 
Section:  2.4 Clinical Hypotheses 
Replace: 
The primary hypothesis of this study is that SC evolocumab 420 mg QM in combination 
with statin once daily 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 QM in subjects with type 2 diabetes 
and hypercholesterolemia or mixed dyslipidemia on maximally tolerated statin of at least 
moderate intensity daily. 
With: 
The primary hypothesis of this study is that SC evolocumab 420 mg QM in combination 
with statin once daily 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 QM in subjects with type 2 diabetes 
and hypercholesterolemia or mixed dyslipidemia on maximally tolerated dose of statin of 
at least moderate intensity daily. 
Section:  3.1 Study Design 
Paragraph 3, sentence 3 
Replace: 
Subjects must tolerate a SC injection of placebo prior to randomization. 
With: 
Subjects must tolerate a SC injection of placebo with device anticipated to be used 
during the study (either AI/Pen or AMD) prior to randomization. 
Section:  3.1 Study Design 
Paragraph 4, sentence 1 
Add: 
Day 1 is defined as the calendar day when treatment with investigational product 
(IP) is initiated. 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 10 of 37 
CONFIDENTIAL 
 
 
Section:  3.1 Study Design 
Paragraph 4, sentence 2 
Replace: 
Subjects should initiate their first dose of investigational product (IP) within 5 days of 
randomization. 
With: 
Subjects should initiate their first dose of IP within 5 days of randomization. 
Section:  3.1 Study Design 
Paragraph 4, sentences 4 and 5 
Replace: 
All subjects will complete a MMTT at the day 1 and week 12 study visits with baseline 
(0 hours) and postprandial blood collection at 2 hours after the meal.  Up to 
approximately 100 subjects not treated with prandial insulin or glucagon-like peptide-1 
(GLP-1) agonists will participate in MMTT Extended Timepoints assessments with 
3 postprandial blood draws at 30 minutes, 1 hour, and 3 hours after the meal in addition 
to the blood draws at 0 and 2 hours after the meal for all subjects. 
With: 
All subjects will complete a MMTT at the day 1 and week 12 study visits with baseline 
(0 hours) and postprandial blood collection at 2 hours (± 10 min) after the meal.  Up to 
approximately 100 subjects not treated with prandial insulin or glucagon-like peptide-1 
(GLP-1) agonists will participate in MMTT Extended Timepoints assessments with 
3 postprandial blood draws at 30 minutes (± 10 min), 1 hour (± 10 min), and 3 hours 
(± 10 min) after the meal in addition to the blood draws at 0 and 2 hours (± 10 min) after 
the meal for all subjects. 
Section:  3.3 Number of Subjects 
Replace: 
Approximately 400 subjects will be enrolled. 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 11 of 37 
CONFIDENTIAL 
 
 
With: 
Participants in this clinical investigation shall be referred to as “subjects”.  
Approximately 400 subjects with type 2 diabetes mellitus with hypercholesterolemia 
or mixed dyslipidemia will be enrolled. 
Section:  3.4 Replacement of Subjects 
Replace: 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
With: 
Subjects who are withdrawn or removed from investigational medicinal product (IMP) 
treatment or the study will not be replaced. 
Section:  3.5.2 End of Study 
Replace: 
The primary completion is defined as the date when the last subject has completed the 
assessments for week 12. 
With: 
The primary completion is defined as the date when the last subject has completed the 
assessments for week 12 or has terminated the study early, whichever is later. 
Section:  4.1.1 Inclusion Criteria 
Replace: 
101 
Subject has provided written informed consent 
102 
Male or female ≥ 18 years of age at signing of informed consent 
103 
Type 2 diabetes mellitus defined as: 
• 
with hemoglobin A1c (HbA1C) < 10% 
• 
receiving pharmacologic treatment for diabetes mellitus for ≥ 6 months prior to 
screening 
• 
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, and no dose change of any antihyperglycemic drug within 
2 months prior to randomization and daily insulin dose not changed 
by > 25% and > 25 units within 1 month prior to randomization 
104 
Subjects without known CVD must be on at least moderate-intensity statin prior 
to randomization 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 12 of 37 
CONFIDENTIAL 
 
 
105 
Subjects with known CVD must be on high intensity statin (or moderate intensity 
if certified by principal investigator to be highest tolerated dose) prior to 
randomization 
106 
Fasting triglycerides ≤ 600 mg/dL (6.8 mmol/L) by central laboratory prior to 
randomization 
107 
Subject tolerates screening placebo injection 
108 
Subjects without known CVD must have a fasting LDL-C during lipid stabilization 
of ≥ 100 mg/dL (2.6 mmol/L) or non-HDL-C ≥ 130 mg/dL (3.4 mmol/L) as 
determined by the central laboratory 
109 
Subjects with known CVD must have a fasting LDL-C during lipid stabilization of 
≥ 70 mg/dL (1.8 mmol/L) or Non-HDL-C ≥ 100 mg/dL (2.6 mmol/L) as determined 
by the central laboratory 
110 
Subject must be on maximally tolerated of statin of at least moderate intensity at 
the end of screening/ lipid stabilization and is expected to remain on stable statin 
intensity for duration of study in the opinion of the investigator 
With: 
101 
Subject has provided written informed consent 
102 
Male or female ≥ 18 years of age at signing of informed consent 
103 
Type 2 diabetes mellitus: 
• 
with hemoglobin A1c (HbA1c) < 10% 
• 
receiving pharmacologic treatment for diabetes mellitus for ≥ 6 months prior 
to screening 
• 
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, and no dose change of any 
antihyperglycemic drug within 2 months prior to randomization and daily 
insulin dose not changed by > 25% and > 25 units within 1 month prior to 
randomization 
104 
Subject must be on maximally tolerated dose of statin of at least moderate 
intensity at signing of the informed consent (see Appendix D)and is expected 
to remain on stable statin intensity for the duration of study in the opinion of the 
investigator 
• 
Subjects without known clinical CVD must be on at least moderate-intensity 
statin  
• 
Subjects with known clinical CVD must be on high intensity statin (or 
moderate intensity if certified by principal investigator to be highest tolerated 
dose).  Clinical CVD is defined as a history of myocardial infarction, 
stable or unstable angina, coronary or other arterial revascularization, 
stroke, transient ischemic attack, or peripheral arterial disease 
presumed to be of atherosclerotic origin 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 13 of 37 
CONFIDENTIAL 
 
 
105 
Subjects without known clinical CVD must have a fasting LDL-C during lipid 
stabilization of ≥ 100 mg/dL (2.6 mmol/L) or non-HDL-C ≥ 130 mg/dL 
(3.4 mmol/L) as determined by the central laboratory 
106 
Subjects with known clinical CVD must have a fasting LDL-C during lipid 
stabilization of ≥ 70 mg/dL (1.8 mmol/L) or Non-HDL-C ≥ 100 mg/dL (2.6 mmol/L) 
as determined by the central laboratory 
107 
Fasting triglycerides ≤ 600 mg/dL (6.8 mmol/L) by central laboratory prior to 
randomization 
108 
Subject tolerates screening placebo injection 
Section:  4.1.2 Exclusion Criteria 
Criterion 205 
Replace: 
205. Persistent active liver disease or hepatic dysfunction, defined as Child-Pugh score 
of C 
With: 
205. Persistent active liver disease or hepatic dysfunction, defined as Child-Pugh score 
of C (see Appendix E) 
Section:  4.1.2 Exclusion Criteria 
Criterion 206, Paragraph 3, subbullet 3 
Replace: 
− 
bilateral tubal ligation/occlusion, use of hormonal birth control methods (PO, 
intravaginal, transdermal, injectable, or implantable),  
With: 
− 
bilateral tubal ligation/occlusion, use of hormonal birth control methods (oral, 
intravaginal [eg, vaginal ring], transdermal, injectable, or implantable), 
Section:  4.1.2 Exclusion Criteria 
Criterion 206, Paragraph 3, subbullet 6 
Replace: 
− 
2 barrier methods (each partner must use one barrier method) and the female 
partner must use spermicide in addition to a barrier – males must use a condom; 
females must choose either a diaphragm, OR cervical cap, OR contraceptive 
sponge.  If spermicide is not available in the country or region, the two barrier 
method without spermicide is acceptable. 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 14 of 37 
CONFIDENTIAL 
 
 
With: 
− 
2 barrier methods (each partner must use one barrier method) and the female 
partner must use if available spermicide in addition to a barrier – males must use a 
condom; females must choose either a diaphragm, OR cervical cap, OR 
contraceptive sponge.  (Note:  If spermicide is not commercially available in the 
country or region, the two barrier method without spermicide would then be 
considered acceptable). 
Section:  4.1.2 Exclusion Criteria 
Criterion 206, Paragraph 4, sentence 2 
Replace: 
These additional medications may require an increase in the number of contraceptive 
methods, the change in type of contraceptive methods and/or length of time that 
contraception is to be utilized or length of time breastfeeding is to be avoided. 
With: 
These additional medications may require an increase in the number of contraceptive 
methods, the change in type of contraceptive methods and/or length of time that 
contraception is to be utilized and/or length of time breastfeeding is to be avoided. 
Section:  4.1.2 Exclusion Criteria 
Criterion 207 
Replace: 
207. 
Female subject is pregnant or breast feeding, or planning to become pregnant or 
planning to breastfeed during the screening/lipid stabilization period, during 
treatment with IP and for an additional 15 weeks after the end of treatment 
With: 
207. 
Female subject is pregnant or breast feeding, or planning to become pregnant or 
planning to breastfeed during the screening/lipid stabilization period, during 
treatment with IP and for an additional 15 weeks after the end of treatment with 
IP 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 15 of 37 
CONFIDENTIAL 
 
 
Section:  5. SUBJECT ENROLLMENT 
Paragraph 2, sentence 1 
Replace: 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria, including 4 weeks of tolerating the appropriate dose of statin. 
With: 
A subject is considered enrolled upon randomization in IVRS/IWRS, when the 
investigator decides that the subject has met all eligibility criteria, including 4 weeks of 
tolerating the appropriate dose of statin. 
Section:  5. SUBJECT ENROLLMENT 
Paragraph 4 
Replace: 
Subjects who are unable to complete or meet eligibility on initial screening will be 
permitted to re-screen except for subjects without known CVD and fasting LDL-C 
< 100 mg/dL and non-HDL-C < 130 mg/dL by central lab result during screening 
(see Section 7.2.2). 
With: 
Subjects who are unable to complete or meet eligibility on initial screening will be 
permitted to re-screen once except for subjects without known clinical CVD and fasting 
LDL-C < 100 mg/dL and non-HDL-C < 130 mg/dL and subjects with known clinical 
CVD and LDL-C < 70 mg/dL and non-HDL-C < 100 mg/dL by central lab result during 
screening (see Section 7.2.2) who are considered screen failures and who cannot 
be rescreened. 
Section:  5.1 Randomization/Treatment Assignment 
Paragraph 3 
Replace: 
Subjects can only be randomized 1 time for this study.  Subjects should be randomized 
before or on the date of the day 1 visit, and initiate their first dose of IP within 5 days of 
randomization. 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 16 of 37 
CONFIDENTIAL 
 
 
With: 
Subjects can only be randomized 1 time for this study.  Once subjects are randomized 
their first dose of IP must be administered within 5 days of randomization (day 1 visit). 
Section:  5.2 Site Personnel Access to Individual Treatment Assignments 
Paragraph 3 
Replace: 
The investigator is strongly encouraged to contact the Amgen Clinical Study Manager 
before unblinding any subject’s treatment assignment, but must do so within 1 working 
day after the event. 
With: 
The investigator is strongly encouraged to contact the Amgen Clinical Study Manager or 
clinical research associate before unblinding any subject’s treatment assignment, but 
must do so within 1 working day after the event. 
Section:  6.1 Classification of Product(s) and/or Medical Device(s) 
Paragraph 1 
Replace: 
The Amgen IP used in this study is evolocumab and matching placebo.  In several 
countries, IP is referred to as investigational medicinal product (IMP).  In this document, 
IMP will be referred to as IP. 
With: 
The Amgen IP used in this study is evolocumab and matching placebo.  In several 
countries, IP is referred to as IMP.  In this document, IMP will be referred to as IP. 
Section:  6.4.1 Criteria for Permanent Discontinuation of Amgen Investigational 
Product and Other Protocol-required Therapies due to Potential Hepatotoxicity 
Paragraph 1, bullet 2 
Replace: 
• 
AND increased AST or ALT ≥ 3x ULN from a baseline value were less than the ULN  
With: 
• 
AND increased AST or ALT ≥ 3x ULN if baseline value were less than the ULN  


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 17 of 37 
CONFIDENTIAL 
 
 
Section:  6.4.2 Criteria for Conditional Withholding of Amgen Investigational 
Product and Other Protocol-required Therapies due to Potential Hepatotoxicity 
Paragraph 1 
Replace: 
For subjects who do not meet the criteria for permanent discontinuation of Amgen IP 
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 recommended for withholding 
of Amgen IP and other protocol-required therapies: 
With: 
For subjects who do not meet the criteria for permanent discontinuation of Amgen IP 
(evolocumab or placebo) 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 
recommended for withholding of Amgen IP and other protocol-required therapies: 
Section:  6.5 Concomitant Therapy 
Paragraphs 2 and 3 
Replace: 
Prior general and targeted therapies (eg, statins, other lipid-lowering, and diabetes 
therapy), taken 120 days prior to randomization should be collected with the following 
information: therapy name, indication, dose, unit, frequency, route, start date and stop 
date. 
If a targeted therapy is begun, discontinued, or changed during study, in addition to 
updates for the above information, the reason for adjusting medication (adverse event, 
worsening of underlying condition, noncompliance etc.) should be recorded. 
With: 
Prior general and targeted therapies (ie, statins, other lipid-lowering therapies, and 
pharmacologic treatment for type 2 diabetes mellitus), taken 120 days prior to 
randomization should be collected with the following information: therapy name, 
indication, dose, unit, frequency, route, start date and stop date. 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 18 of 37 
CONFIDENTIAL 
 
 
If a targeted therapy is begun, discontinued, or changed during study, in addition to 
updates for the above information, the reason for adjusting medication (eg, adverse 
event, noncompliance, etc.) should be recorded. 
Section:  6.7 Product Complaints 
Paragraph 5 and 6 
Replace: 
The investigator is responsible for ensuring that all product or device complaints 
observed by the investigator or reported by the subject that occur after signing of the ICF 
through 30 days after the last dose of IP or EOS, whichever is later, are reported to 
Amgen within 24 hours of discovery or notification of the product complaint.  
Additional details regarding the identification and reporting of any product complaint(s) 
associated with an investigational product(s) or non-investigational product(s) or 
device(s) supplied by Amgen are provided in the IPIM. 
With: 
The investigator is responsible for ensuring that all product or device complaints 
observed by the investigator or reported by the subject that occur after signing of the ICF 
through 30 days after the last dose of IP or EOS, whichever is later, are reported to 
Amgen within 24 hours of discovery or notification of the product and/or device 
complaint.  
Additional details regarding the identification and reporting of any product and/or device 
complaint(s) associated with an investigational product(s) or non-investigational 
product(s) or device(s) supplied by Amgen are provided in the IPIM. 
Section:  7 STUDY PROCEDURES 
Paragraph 2, sentence 2 
Replace: 
For example, the week 4 visit is 4 calendar weeks after the study day 1 visit, 
corresponding to study day 28. 
With: 
For example, the week 4 dose is 4 calendar weeks after the study day 1 visit, 
corresponding to study day 28. 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 19 of 37 
CONFIDENTIAL 
 
 
Section:  7.1 Schedule of Assessments 
Table 1 
Replace: 
 
Screening/ 
Lipid Stabilization  
(up to 6 weeks 
including 4-week lipid 
stabilization) 
Double-blind Treatment Period 
Study Day / Week / Other Timepoint 
Screening 
Day 1 
Screening 
Week 2 
± 3 days 
Day 1 
Week 8 
± 3 days 
Week 10 
± 3 days 
Week 12 
EOS 
± 3 days 
General Procedures 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Vital Signs (BP and heart rate) 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
X 
X 
X 
X 
X 
Safety Data Reportinga 
X 
X 
X 
X 
X 
X 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
Body weight, waist circumference 
 
 
X 
 
 
X 
Body height 
 
 
X 
 
 
 
Randomization 
 
 
X 
 
 
 
Central Laboratoryb 
 
 
 
 
 
 
Fasting lipidsc 
 
X 
X 
 
X 
X 
ApoA1, ApoB, Lp(a) 
 
 
X 
 
X 
X 
PCSK9 
 
 
X 
 
X 
X 
Chemistry 
 
X 
X 
 
 
X 
Hematology 
 
 
X 
 
 
 
HbA1c 
 
X 
X 
 
 
X 
MMTTd 
 
 
X 
 
 
X 
MMTT Extended Timepoints d 
 
 
X 
 
 
X 
Biomarkers (blood)e 
 
 
X 
 
 
X 
HCV antibody testing 
 
X 
 
 
 
 
HCV viral loadf 
 
X 
X 
 
 
X 
Serum pregnancyg; FSH/LH/estradiolh 
 
X 
 
 
 
X 
Urine pregnancyh 
 
 
X 
 
 
 
Urinalysis, Urine protein, Urine 
creatinine, urine microalbumin 
 
 
X 
 
 
X 
Investigational Product 
 
 
 
 
 
 
Screening placebo injection 
 
X 
 
 
 
 
In-clinic IP injection QMi 
 
 
X 
X 
 
 
IP dispense 
 
 
X 
 
 
 
IP reconciliation QM 
 
 
 
X 
 
 
ApoA1=apolipoprotein A-I; ApoB=apolipoprotein B; ApoB48=apolipoprotein B48; BP=blood pressure; 
EOS=end of study; HbA1c=hemoglobin A1c; HCV=hepatitis C virus; IL-6=interleukin-6; 
FSH/LH=follicle-stimulating hormone/luteinizing hormone; IP=investigational product; Lp(a)=lipoprotein(a); 
MMTT=mixed meal tolerance test; PCSK9=proprotein convertase subtilisin/kexin type 9; QM=once 
monthly 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 20 of 37 
CONFIDENTIAL 
 
 
With: 
 
Screening/ 
Lipid Stabilization  
(up to 6 weeks 
including 4-week lipid 
stabilization) 
Double-blind Treatment Period 
Study Day / Week / Timepoint 
Screening 
Day 1 
Screening 
Week 2 
± 3 days Day 1 
Week 4 
± 3 days 
Week 8 
± 3 days 
Week 10 
± 3 days 
Week 12  
EOS 
± 3 days 
General Procedures 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Vital Signs (BP and heart rate) 
X 
X 
X 
 
X 
X 
X 
Physical Exam 
X 
X 
X 
 
X 
X 
X 
Safety Data Collection/Reportinga 
X 
X 
X 
 
X 
X 
X 
Concomitant therapy 
X 
X 
X 
 
X 
X 
X 
Body weight, waist circumference 
 
 
X 
 
 
 
X 
Body height 
 
 
X 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
Central Laboratoryb 
 
 
 
 
 
 
 
Fasting lipidsc 
 
X 
X 
 
 
X 
X 
ApoA1, ApoB, Lp(a) 
 
 
X 
 
 
X 
X 
PCSK9 
 
 
X 
 
 
X 
X 
Chemistry 
 
X 
X 
 
 
 
X 
eGFR 
 
X 
 
 
 
 
 
Hematology 
 
 
X 
 
 
 
 
Coagulation (Prothrombin time) 
 
X 
 
 
 
 
 
HbA1c 
 
X 
X 
 
 
 
X 
MMTTd 
 
 
X 
 
 
 
X 
MMTT Extended Timepoints d 
 
 
X 
 
 
 
X 
Biomarkers (blood)e 
 
 
X 
 
 
 
X 
HCV antibody testing 
 
X 
 
 
 
 
 
HCV viral loadf 
 
X 
X 
 
 
 
X 
Serum pregnancyg; FSH/LH or 
estradiolh 
 
X 
 
 
 
 
X 
Local urine pregnancy 
 
 
X 
 
 
 
 
Urinalysis, Urine protein, Urine 
creatinine, urine microalbumin 
 
 
X 
 
 
 
X 
Investigational Product 
 
 
 
 
 
 
 
Screening placebo injection 
 
X 
 
 
 
 
 
In-clinic IP injection QM 
 
 
X 
 
X 
 
 
Non-clinic setting IP injection 
QM 
 
 
 
X 
 
 
 
IP dispense 
 
 
X 
 
X 
 
 
IP reconciliation QM 
 
 
 
 
X 
 
 
ApoA1=apolipoprotein A-I; ApoB=apolipoprotein B; ApoB48=apolipoprotein B48; BP=blood pressure; 
eGFR=estimated glomerular filtration rate; EOS=end of study; HbA1c=hemoglobin A1c; HCV=hepatitis 
C virus; IL-6=interleukin-6; FSH/LH=follicle-stimulating hormone/luteinizing hormone; IP=investigational 
product; Lp(a)=lipoprotein(a); MMTT=mixed meal tolerance test; PCSK9=proprotein convertase 
subtilisin/kexin type 9; QM=once monthly 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 21 of 37 
CONFIDENTIAL 
 
 
Section:  7.1 Schedule of Assessments 
Table 1, footnote a 
Replace: 
a. Including review for adverse events/serious adverse events/disease related 
events/adverse device effects. Only adverse events/adverse device effects possibly 
related to study procedures and serious adverse events are collected during the 
screening from signing of the informed consent. 
With: 
a. Review for adverse events/serious adverse events/disease related events/adverse 
device effects. Only adverse events possibly related to study procedures, adverse 
device effects and serious adverse events are collected during screening from signing of 
the informed consent.  All serious adverse events must be collected through 
30 days after the last administration of IP or the EOS/ safety follow-up visit, 
whichever is later, and submitted to Amgen. 
Section:  7.1 Schedule of Assessments 
Table 1, footnote e 
Replace: 
e. If the subject consented to pharmacogenetic analyses, DNA will be extracted from 
some of the blood samples, eg, biomarker samples. 
With: 
e. Anti-evolocumab antibodies may be tested, if needed.  If the subject consented to 
pharmacogenetic portion of the study, DNA analysis may be performed. One cell 
pellet is collected only at day 1 (residual cell pellet from the plasma biomarker 
sample). 
Section:  7.1 Schedule of Assessments 
Table 1, footnote g 
Replace: 
g. Pregnancy testing in females of childbearing potential.  Additional on-treatment 
pregnancy testing may be performed at the investigator’s discretion or as required by 
local laws and regulations. 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 22 of 37 
CONFIDENTIAL 
 
 
With: 
g. Serum pregnancy testing in females of childbearing potential.  Additional on-treatment 
local pregnancy testing may be performed at the investigator’s discretion or as required 
by local laws and regulations. 
Section:  7.1 Schedule of Assessments 
Table 1, footnote h 
Replace: 
h. FSH/LH/estradiol only at screening in females of childbearing potential if applicable. 
With: 
h. FSH/LH or estradiol only at screening, and only if applicable per exclusion criteria. 
Section:  7.1 Schedule of Assessments 
Table 1, footnote i 
Delete: 
i. In addition to the in-clinic QM IP administration at day 1 and week 8, QM non-clinic IP 
administration is expected to occur once prior to the week 8 visit at week 4. 
Section:  7.2.2 Rescreening 
Sentence 4 
Replace: 
Subjects without known CVD and fasting LDL-C < 100 mg/dL or non-HDL-C 
< 130 mg/dL during screening are considered screen failures and cannot be rescreened 
for this study. 
With: 
Subjects without known clinical CVD and fasting LDL-C < 100 mg/dL and non-HDL-C 
< 130 mg/dL during screening are considered screen failures and cannot be rescreened 
for this study. 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 23 of 37 
CONFIDENTIAL 
 
 
Section:  7.2.2 Rescreening 
Sentence 5 
Add: 
Subjects with known clinical CVD and LDL-C < 70 mg/dL and non-HDL-C 
< 100 mg/dL during screening are considered screen failures and cannot be 
rescreened for this study. 
Section:  7.2.3 Double-blind Treatment Period 
Paragraph 2, sentence 1 
Replace: 
Evolocumab/placebo is to be self-administered in an appropriate non-clinic setting (eg, 
at home) at week 4. 
With: 
Evolocumab/placebo is to be self-administered in an appropriate non-clinic setting (eg, 
at home) at week 4 ± 3 days. 
Section:  7.2.3 Double-blind Treatment Period 
Paragraph 2, sentence 3 
Replace: 
Observed, in-clinic dosing should occur at day 1 and at week 8. 
With: 
Observed, in-clinic dosing should occur at day 1 and at week 8 ± 3 days. 
Section:  7.2.4 End of Study Visit, 7.2.5 Safety Follow-up 
Replace: 
7.2.4 End of Study Visit 
An EOS visit is scheduled to occur at week 12. 
7.2.5 Safety Follow-up 
Sites are responsible for reporting any safety information up to 30 days after the last 
dose of IP. 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 24 of 37 
CONFIDENTIAL 
 
 
Subjects who do not complete their EOS visit and assessments are considered early 
termination.  
With: 
7.2.4 End of Study Visit 
An EOS visit is scheduled to occur at week 12 ± 3 days. 
Subjects who discontinue study participation before their week 12 ± 3 days visit 
per protocol are considered early termination. 
7.2.5 Safety Follow-up 
Sites are responsible for reporting safety information through 30 days after the last dose 
of IP or EOS, as applicable. For further details, see Section 9.2. 
Section:  7.3.3 Medical History 
Paragraph 2, sentence 2 
Replace: 
Targeted diabetes history including, but not limited to, duration, complications, and 
history of ketoacidosis from diagnosis will be collected. 
With: 
Targeted diabetes mellitus history including, but not limited to, duration, complications, 
and history of ketoacidosis from diagnosis will be collected. 
Section:  7.3.6 Safety Data Reporting 
Delete: 
7.3.6 Safety Data Reporting 
Adverse events, serious adverse events, adverse device effects (ADEs), and 
disease-related events observed by the investigator or reported by the subject will be 
collected at all study visits from the signing of the ICF through the EOS visit. 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 25 of 37 
CONFIDENTIAL 
 
 
Section:  7.3.6 Concomitant Therapy 
Paragraph 1 
Replace: 
Prior general and targeted therapies (eg, statins, other lipid-lowering, and diabetes 
therapy) will be collected as specified in Section 6.5. 
With: 
Prior general and targeted therapies (eg, statins, other lipid-lowering therapies, 
pharmacologic treatment for type 2 diabetes mellitus) will be collected as specified 
in Section 6.5. 
Section:  7.3.7 Height, Weight, and Waist Circumference 
Paragraph 1 
Replace: 
Body weight in kilograms and height in centimeters should be measured without shoes. 
With:  
Body weight and height should be measured without shoes. 
Section:  7.4 Laboratory Assessments 
Paragraph 1, sentences 1 and 2 
Replace: 
All laboratory samples will be sent to the central laboratory.   
With: 
Central laboratory assessments are to be used to assess subject eligibility (except 
for the urine pregnancy test, Section 7.1). All other screening or scheduled study 
laboratory assessments will also be by the central laboratory. 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 26 of 37 
CONFIDENTIAL 
 
 
Section:  7.4 Laboratory Assessments 
Table 2:  Analyte Listing 
Replace: 
Chemistry  
Hematology 
Coagulation 
Urinalysis 
Other Labs 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Calcium 
Magnesium 
Phosphorus 
Uric Acid 
CK 
Alkaline 
phosphatase 
LDH 
Albumin 
FBG 
BUN or Urea 
Creatinine 
Total bilirubin 
Direct bilirubin 
AST 
ALT 
eGFR 
Hemoglobin 
Hematocrit 
RBC 
RDW 
MCV 
MCH 
MCHC 
WBC 
Platelets 
 
PT/INR  
Specific gravity 
pH 
Blood 
Protein 
Glucose 
Bilirubin 
WBC 
RBC 
Epithelial cells 
Bacteria 
Casts 
Crystals 
Microalbumin 
Creatinine 
Fasting lipids 
• Total cholesterol 
• HDL-C 
• LDL-C 
• Triglycerides 
• VLDL-C 
• non-HDL-C 
ApoA1 
ApoB 
ApoB48 
Lp(a) 
Insulin 
Proinsulin 
C-peptide 
Free fatty acids 
Glucagon 
Chylomicrons 
IL-6 
Adiponectin 
PCSK9 
HbA1c 
Leutinizing Hormone (LH) 
Estradiol 
Urine and serum pregnancy 
test (females of 
childbearing potential) 
FSH (if needed per 
exclusion 206) 
HCV antibody 
HCV viral load (if required)  
 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 27 of 37 
CONFIDENTIAL 
 
 
With: 
Chemistry  
Hematology 
Coagulation Urinalysis 
Other Labs 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Calcium 
Magnesium 
Phosphorus 
Uric Acid 
CK 
Alkaline 
phosphatase 
LDH 
Albumin 
FBG 
BUN or Urea 
Creatinine 
Total bilirubin 
Direct bilirubin 
AST 
ALT 
eGFR 
Hemoglobin 
Hematocrit 
RBC 
RDW 
MCV 
MCH 
MCHC 
Platelets 
WBC  
Morphology 
and differential: 
• Neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes 
 
PT 
Specific gravity 
pH 
Blood 
Protein 
Glucose 
Bilirubin 
WBC 
RBC 
Epithelial cells 
Bacteria 
Casts 
Crystals 
Microalbumin 
Creatinine 
Fasting lipids 
Total cholesterol 
HDL-C 
LDL-C 
Triglycerides 
VLDL-C 
non-HDL-C 
ApoA1 
ApoB 
ApoB48 
Lp(a) 
Insulin 
Proinsulin 
C-peptide 
Free fatty acids 
Glucagon 
Chylomicrons 
IL-6 
Adiponectin 
PCSK9 
HbA1c 
Urine and serum 
pregnancy test (females 
of childbearing potential) 
FSH/LH or Estradiol (if 
needed per exclusion 206) 
HCV antibody 
HCV viral load (if required) 
Section:  7.4.1 Blinding of Laboratory Test Results 
Paragraph 2, sentence 2 
Add: 
Investigators will be informed if triglycerides are > 1000 mg/dL (11.3 mmol/L) so 
that appropriate subject follow-up can be initiated. 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 28 of 37 
CONFIDENTIAL 
 
 
Section:  7.4.2 Mixed Meal Tolerance Test (All Subjects) 
Paragraph 1, sentence 2 
Replace: 
Each MMTT should be done at approximately the same time of day throughout the study 
(± 2 hours) and must be completed prior to dosing with IP (if applicable). 
With: 
Each MMTT should be done at approximately the same time of day throughout the study 
(± 2 hours) and must be completed prior to dosing with IP at day 1. 
Section:  7.4.4 Serum Pregnancy Test 
Paragraph 2 
Replace: 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required by local laws and regulations. 
With: 
Additional on-treatment local pregnancy testing may be performed at the investigator’s 
discretion or as required by local laws and regulations. 
Section:  7.6 Pharmacogenetic Studies 
Sentence 2 
Replace: 
If the subject consents to the optional pharmacogenetic portion of this study, 
deoxyribonucleic acid (DNA) analyses may be performed. 
With: 
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed. 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 29 of 37 
CONFIDENTIAL 
 
 
Section:  7.7 Sample Storage and Destruction 
Paragraph 3, sentence 1 
Replace: 
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
hypercholesterolemia and/or mixed dyslipidemia, the dose response and/or prediction of 
response to evolocumab, and characterize aspects of the molecule (eg, mechanism of 
action/target, metabolites). 
With: 
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
hypercholesterolemia/mixed dyslipidemia, the dose response and/or prediction of 
response to evolocumab, and characterize aspects of the molecule (eg, mechanism of 
action/target, metabolites). 
Section:  8.3.1 Reasons for Removal From Treatment 
Sentence 1 
Replace: 
Reasons for removal from protocol-required IP or procedural assessments include any 
of the following: 
With: 
Reasons for removal from protocol-required IP or procedural assessments include any 
of the following, but not limited to: 
Section:  8.3.1 Reasons for Removal From Treatment 
Bullet 2 
Delete: 
• 
subject request to end IP administration 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 30 of 37 
CONFIDENTIAL 
 
 
Section:  8.3.1 Reasons for Removal From Treatment 
Bullet 5 
Replace: 
• 
administrative decision by Amgen (other than subject request, safety concern or lost 
to follow-up) 
With: 
• 
decision by Sponsor (other than subject request, safety concern or lost to follow-up) 
Section:  8.3.1 Reasons for Removal From Treatment 
Bullet 6 
Delete: 
• 
decision by the primary investigator/physician 
Section:  8.3.2 Reasons for Removal From Study 
Bullet 1 
Replace: 
• 
decision by Amgen 
With: 
• 
decision by Sponsor 
Section:  9.1.1 Disease-related Events 
Paragraph 2, Bullets 1 and 2 
Replace: 
• 
An event which is part of the normal course of disease under study (eg, disease 
progression in oncology or hospitalization due to disease progression) is to be 
reported as a disease-related event.  
• 
Death due to the disease under study is to be recorded on the Event CRF. 
With: 
• 
An event which is part of the normal course of disease under study, with no causal 
relationship with IP/protocol-required therapies (eg, disease progression or 
hospitalization due to disease progression) is to be reported as a disease-related 
event.  


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 31 of 37 
CONFIDENTIAL 
 
 
• 
Death is due to the disease under study; the event is to be recorded on the Event 
CRF as a disease-related event. 
Section:  9.1.1 Disease-related Events 
Paragraph 3 
Replace: 
If the outcome of the underlying disease is worse than that which would normally be 
expected for the subject, or if the investigator believes there is a causal relationship 
between the IP/study treatment protocol-required therapies and disease worsening, this 
must be reported as an adverse event or serious adverse event. 
With: 
If the outcome of the underlying disease is worse than that which would normally be 
expected for the subject, or if the investigator believes there is a causal relationship 
between the IP/study treatment protocol-required therapies and disease worsening, the 
event must be reported as an adverse event or serious adverse event. 
Section:  9.1.4 Serious Adverse Events 
Bullets 7, 8 and 9 
Replace: 
• 
the subject’s pre-existing condition becomes worse than what the investigator would 
consider typical for a patient with the same underlying condition, OR 
• 
if the investigator believes a causal relationship exists between the 
IP/protocol-required therapies and the event, and 
• 
the event meets at least 1 of the serious criteria above. 
With: 
• 
the event meets at least 1 of the serious criteria above, AND 
• 
the subject’s pre-existing condition becomes worse than what the investigator would 
consider typical for a patient with the same underlying condition, OR 
• 
the investigator believes a causal relationship exists between the 
IP/protocol-required therapies and the event 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 32 of 37 
CONFIDENTIAL 
 
 
Section:  9.2.1 Disease-related Events 
Paragraph 1, sentence 1 
Replace: 
The investigator is responsible for ensuring that all disease-related events observed by 
the investigator or reported by the subject that occur from the time of randomization 
through the EOS/safety follow-up visit, or 30 days after the last administration of IP, 
whichever is later, are reported using the Event CRF. 
With: 
The investigator is responsible for ensuring that all disease-related events observed by 
the investigator or reported by the subject that occur from the time of randomization 
through the EOS/safety follow-up visit are reported using the Event CRF. 
Section:  9.2.2.1 Reporting Procedures for Adverse Events That do not Meet 
Serious Criteria 
Paragraph 1 
Replace: 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after randomization through the 
EOS/safety follow-up visit, or 30 days after the last administration of IP, whichever is 
later, are reported using the Event CRF.  Only adverse events/ADEs possibly related to 
study procedures and serious adverse events are collected during screening after 
signing of the informed consent. 
With: 
Adverse events possibly related to study procedures, adverse device effects and 
serious adverse events are reported from signing of the ICF.  All other adverse 
events are reported from the time of randomization.  The investigator is responsible 
for ensuring that all adverse events observed by the investigator or reported by the 
subject that occur from signing of the ICF or from the time of randomization through 
the EOS/safety follow-up visit are reported using the Event CRF.   


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 33 of 37 
CONFIDENTIAL 
 
 
Section:  9.2.2.1 Reporting Procedures for Adverse Events That do not Meet 
Serious Criteria 
Paragraph 6 
Add: 
The investigator must assess whether the adverse event is possibly related to any 
other study-mandated activity or procedure (eg. administration of IP, protocol-
required therapies, device(s) and/or procedure (including any screening 
procedure[s]). This relationship is indicated by a “yes” or “no” response to the 
question: “Is there a reasonable possibility that the event may have been caused 
by a study activity/procedure” (eg. administration of IP, protocol-required 
therapies, device(s) and/or procedure?) 
Section:  9.2.2.4 Serious Adverse Events That are not to be Reported in an 
Expedited Manner 
Replace: 
Hospitalizations due to chronic diabetic complications are anticipated to occur in the 
enrolled patient population.  The Amgen safety and medical teams will review 
accumulating events on a regular basis. 
With: 
Hospitalizations due to chronic diabetic complications are anticipated to occur in the 
patient population enrolled in this study and are therefore not planned to be 
reported individually in an expedited manner. The Amgen safety and medical teams 
will review accumulating events on a regular basis. 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 34 of 37 
CONFIDENTIAL 
 
 
Section:  Appendix C.  Pregnancy and Lactation Notification Worksheets 
Replace: 
 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 35 of 37 
CONFIDENTIAL 
 
 
With: 
 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 36 of 37 
CONFIDENTIAL 
 
 
 
 


 
 
 
Product:  Evolocumab 
Protocol Number:  20130287 
Date:  06 January 2016 
Page 37 of 37 
CONFIDENTIAL 
 
 
Section:  Appendix E.  Child-Pugh Score 
Add: 
Appendix E.  Child-Pugh Score 
 

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Product:  Evolocumab 
Statistical Analysis Plan:  20130287 
Date:  22 December 2016 
Page 6 
 
1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol amendment 1 for Evolocumab 
Study 20130287 dated 6 January 2016. The scope of this plan includes the final 
analyses that are planned and will be executed by the Biostatistics department unless 
otherwise specified. 
2. 
Objectives 
2.1 
Primary 
To evaluate the effect of 12 weeks of subcutaneous (SC) evolocumab monthly (QM) 
compared with placebo QM on percent change from baseline in low-density lipoprotein 
cholesterol (LDL-C) in subjects with type 2 diabetes mellitus and hypercholesterolemia 
or mixed dyslipidemia on maximally tolerated dose of statin of at least moderate-intensity 
oral (PO) daily (QD). 
2.2 
Secondary 
To assess the effects of 12 weeks of SC evolocumab QM compared with placebo QM, in 
subjects with type 2 diabetes mellitus and hypercholesterolemia  or mixed dyslipidemia 
in combination with maximally tolerated dose of statin of at least moderate-intensity 
PO QD on the following: 
 
Change from baseline in LDL-C, and percent change from baseline in 
non-high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (ApoB), total 
cholesterol, lipoprotein(a) [Lp(a)], triglycerides, HDL-C, and very low-density 
lipoprotein cholesterol (VLDL-C) 
 
Percent of subjects attaining LDL-C < 70 mg/dL (1.8 mmol/L) 
 
Percent of subjects attaining a 50% reduction in LDL-C from baseline 
2.3 
Safety 
 
To evaluate the safety and tolerability of SC evolocumab QM compared with 
placebo QM in subjects with type 2 diabetes mellitus and  hypercholesterolemia 
or mixed dyslipidemia in combination with maximally tolerated dose of statin of at 
least moderate-intensity PO QD 
2.4 
Exploratory 
To describe the effects over time of SC evolocumab QM compared with placebo QM, in 
subjects with type 2 diabetes mellitus and hypercholesterolemia or mixed dyslipidemia in 
combination with maximally tolerated dose of statin of at least moderate-intensity PO 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, 


Product:  Evolocumab 
Statistical Analysis Plan:  20130287 
Date:  22 December 2016 
Page 7 
 
total cholesterol, non-HDL-C, ApoB, VLDL-C, HDL-C, apolipoprotein A-I (ApoA1), 
triglycerides, and Lp(a) 
 
Change and percent change from baseline on fasting and postprandial plasma 
laboratory parameters of interest including glucose, insulin, pro-insulin, 
C-peptide, fatty free acids, glucagon, lipids, chylomicrons, ApoB48, interleukin-6 
(IL-6), adiponectin after a mixed meal tolerance test (MMTT). 
 
The relationship between novel and established biochemical cardiovascular and 
lipid biomarkers and effects of evolocumab 
 
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 pharmacogenetic analysis 
3. 
Study Overview 
3.1 
Study Design 
This is a phase 3b, multicenter, double-blind, randomized, placebo-controlled study 
designed to assess the efficacy and safety of evolocumab in subjects with type 2 
diabetes mellitus with hypercholesterolemia or mixed dyslipidemia.  All subjects will be 
treated with maximally tolerated dose of statin of at least moderate-intensity (intensity as 
specified by the 2013 ACC/AHA guideline on the treatment of blood cholesterol to 
reduce atherosclerotic cardiovascular risk in adults; see Protocol Appendix D). Baseline 
lipid-lowering therapy is expected to be continued unchanged throughout the study.  
The study will consist of 2 periods: 
 
Screening up to 6 weeks including a 4-week lipid stabilization and placebo injection  
 
Double-blind treatment period (12 weeks) 
After signing the informed consent, subjects will enter the screening/lipid stabilization 
period during which their appropriate-dose statin is continued. Screening laboratory tests 
including lipid testing will be conducted during week 2 of the screening/lipid stabilization 
period. Subjects must tolerate a SC injection of placebo with device anticipated to be 
used during the study (either AI/Pen or AMD) prior to randomization.  Subjects who meet 
all eligibility criteria at the end of the screening/lipid stabilization period will be 
randomized in a 2:1 ratio into the following treatment arms:  
 
SC evolocumab 420 mg QM (~270 subjects) 
 
SC placebo QM (~130 subjects) 
Randomization will be stratified by LDL-C (< 130 mg/dL vs ≥ 130 mg/dL). 
Day 1 is defined as the calendar day when treatment with investigational product (IP) is 
initiated. Subjects should initiate their first dose of IP within 5 days of randomization. 


Product:  Evolocumab 
Statistical Analysis Plan:  20130287 
Date:  22 December 2016 
Page 8 
 
During the double-blind treatment period, study visits will occur at day 1, week 8, 
week 10, and week 12, with baseline evaluations performed on day 1 of treatment 
before subjects receive the first dose of IP.  All subjects will complete a MMTT at the 
day 1 and week 12 study visits with a baseline (0 hours) and 2-hour (±10 min) 
postprandial blood collection after the meal. Up to approximately 100 subjects not 
treated with prandial insulin or glucagon-like peptide-1 (GLP-1) agonists will participate 
in MMTT Extended Timepoints assessments with 3 additional postprandial blood draws 
at 30 minutes (±10 min), 1 hour (±10 min), and 3 hours (±10 min)  after the meal in 
addition to the blood draws at 0 and 2 hours (±10 min)  after the meal for all subjects. 
3.2 
Sample Size 
The planned sample size for the comparison between evolocumab 420 mg QM and 
placebo at a ratio of 2:1 in the double-blind treatment period is 400 total subjects. 
The primary analysis will require the 2-sided tests of co-primary endpoints to be 
significant at a level of 0.05. The planned sample size should provide adequate power to 
determine the superiority of evolocumab 420 mg QM relative to placebo as measured by 
the co-primary endpoints.  From the phase 3 studies integrated efficacy analysis, the 
treatment effect of evolocumab 420 mg QM compared to placebo and the corresponding 
95% confidence interval at week 12 was -60.39% [-64.57%, -56.21%], with treatment 
effect ranges between -55.1% to -62.33% from Studies 20110114, 20110115, and 
20110117.  The assumed treatment effect between evolocumab 420 mg QM and 
placebo for the co-primary endpoint at week 12 is 40%, with a common standard 
deviation (SD) of 20%. This SD assumption is based on evolocumab phase 3 results. 
This sample size will provide approximately 99% power for the co-primary endpoint at 
week 12 in testing the superiority of evolocumab dose regimen over placebo, assuming 
a dropout rate of 10%.  
From the phase 3 studies the treatment effects measured as mean of week 10 and 
week 12 were as large or larger than week 12 and highly correlated (> 85%) with ones at 
week 12. Therefore the sample size as planned will provide at least 98% (99% x 99%) 
power in testing the superiority of evolocumab over placebo on the co-primary 
endpoints. 
From the phase 3 evolocumab studies the treatment effect of evolocumab over placebo 
in the percentage reduction in triglycerides at week 12 was approximately 12% with a 


Product:  Evolocumab 
Statistical Analysis Plan:  20130287 
Date:  22 December 2016 
Page 9 
common SD of 35%. However, the SD for triglycerides in a diabetic population may be 
higher. Table 1 displays the power associated with various SD assumptions. 
Table 1.  Power Associated With Standard Deviation Assumptions 
Treatment effect = 12% reduction 
Sample size = 400 (5% dropout) 
Significance level = 5% 
Standard Deviation 
Power 
35
0.88
40
0.78
45
0.68
50
0.59
For HDL-C the treatment effect of evolocumab over placebo observed in the phase 3 
studies at week 12 was a percentage increase of approximately 5% with a common SD 
of 15%. Assuming 400 subjects and a 5% drop out rate, this would provide 
approximately 86% power to test the superiority of evolocumab over placebo. 
4. 
Study Endpoints and Covariates 
4.1
Study Endpoints
4.1.1
Co-primary Endpoints

mean percent change from baseline in LDL-C at weeks 10 and 12

percent change from baseline in LDL-C at week 12
4.1.2 
Co-secondary Endpoints
For the mean of weeks 10 and 12 and for week 12: 

Tier 1
 
Change from baseline in LDL-C
 
Percent change from baseline in non-HDL-C
 
Percent change from baseline in ApoB
 
Percent change from baseline in total cholesterol
 
Achievement of target LDL-C <70 mg/dL (1.8 mmol/L)
 
LDL-C response (50% reduction of LDL-C from baseline)

Tier 2
 
Percent change from baseline in Lp(a)
 
Percent change from baseline in triglycerides
 
Percent change from baseline in HDL-C
 
Percent change from baseline in VLDL-C


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Product:  Evolocumab 
Statistical Analysis Plan:  20130287 
Date:  22 December 2016 
Page 16 
 
8. 
Interim Analysis and Early Stopping Guidelines 
No interim analysis is planned for this study. 
9. 
Data Screening and Acceptance 
9.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
9.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses.  This study will use the RAVE 
database. 
All data collected in the eCRF will be extracted from RAVE. Protocol deviations will be 
transferred from eClinical. Unblinded subject and box ID randomization lists will be 
provided by Amgen’s randomization group and the IVRS when the study stops. Details 
on data transfer will be provided in the Data Transfer Plan. 
9.3 
Handling of Missing and Incomplete Data 
9.3.1 
Patterns of Missing Data 
Subjects may be missing specific data points for various reasons. In general, data may 
be missing due to a subject’s early withdrawal from study, a missed visit, or 
non-evaluability of a data point or an endpoint at a particular point in time. In the Data 
Quality Review (DQR) process, queries will be made to the sites to distinguish true 
missing values from other unknown values (e.g. due to measurement or sample 
processing error). All attempts will be made to capture missing or partial data for this trial 
prior to the database lock.  
The frequency and pattern of missing data for efficacy endpoints will be assessed 
through descriptive summaries of the measurements over time. 
9.3.2 
Missing Lipid Measurements 
For efficacy endpoints, where the analysis method is repeated measures linear effects 
model, missing lipid measurements will not be imputed. The handling of missing LDL-C 
response (50% reduction of LDL-C from baseline) and achievement of target LDL-C 
< 70 mg/dL is provided in Section 6.3. Sensitivity analysis will be performed on the 
co-primary endpoints to evaluate the robustness of the missing at random assumption 
used in the repeated measures linear effects model, details are provided 
in section 10.5.1.2.  


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Product:  Evolocumab 
Statistical Analysis Plan:  20130287 
Date:  22 December 2016 
Page 19 
 
minimum, and maximum. For categorical variables, the frequency and percentage will be 
given. 
Methods of handling missing data for efficacy endpoints will be described below. Missing 
data will not be imputed for safety endpoints. 
Multiplicity Adjustment Method 
Methods of adjusting for multiplicity due to multiple endpoints (primary and secondary 
efficacy endpoints) in order to preserve the familywise error rate at 0.05 are described in 
Figure 1. 
Figure 1.  Multiplicity Adjustment Methods 
 
Testing of each co-endpoint pair will result in a single p-value, and for co-secondary 
endpoints these p-values will then be used in the Hochberg procedure. The following 
method will be used to preserve the family wise error rate for the co-primary and 
co-secondary endpoints: 
 
If the treatment effect from the primary analysis of the co-primary endpoints are both 
significant at a significance level of 0.05, statistical testing of the tier 1 co-secondary 
efficacy endpoints will follow the Hochberg procedure at a significance level of 0.005 
(Hochberg, 1988) 
Co-Primary Endpoint
Evolocumab vs. Placebo
α =0.05
Both Significant
Co-Secondary Endpoints in Tier 1
Evolocumab vs. Control
Hochberg method with α = 0.005
All Significant
Co-Secondary Endpoints in Tier 2
Evolocumab vs. Control
Hochberg method with α = 0.05
One or More Not 
Significant
Co-Secondary Endpoints in Tier 2
Evolocumab vs. Control
Hochberg method with α = 0.045
One or More Not 
Significant
STOP


Product:  Evolocumab 
Statistical Analysis Plan:  20130287 
Date:  22 December 2016 
Page 20 
 
 
If all tier 1 co-secondary efficacy endpoints are significant, the tier 2 co-secondary 
efficacy endpoints will be tested using the Hochberg procedure at a significance level 
of 0.05.  
 
If not all tier 1 co-secondary efficacy endpoints are significant, the tier 2 
co-secondary efficacy endpoints will be tested using the Hochberg procedure at a 
significance level of 0.045 (Wiens, 2003). 
Unless specified otherwise, all other hypothesis testing will be 2-sided with a significance 
level of 0.05. 
10.2 
Subject Accountability 
The number and percent of subjects who were screened, randomized, received IP, 
completed IP, discontinued IP and reasons for discontinuing, completed study, 
discontinued study and reasons for discontinuing will be summarized by treatment 
group. 
Key study dates for the first subject enrolled, last subject enrolled, last subject’s end of 
IP and last subject’s end of study will be presented. 
The number and percent of subjects randomized will be tabulated by the stratification 
factors. 
The number of subjects included in and excluded from each analysis set and reason for 
exclusion will also be summarized. 
10.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s visit and updated during the IPD reviews throughout the study prior to 
database lock.  These definitions of IPD categories, sub-category codes, and 
descriptions will be used during the course of the study.  Eligibility deviations are defined 
in the protocol. 
10.4 
Demographic and Baseline Characteristics 
Demographic (ie, age, geriatric age group [< 65, >= 65 and >= 75], sex, race, ethnicity) 
and baseline disease characteristics (cardiovascular medical history, diabetes disease 
history [eg, family history, complications], diabetes related medication and 
lipid-regulating medication) will be summarized by treatment group and overall using 
descriptive statistics. If multiple races have been reported for a subject, the subject will 
be categorized as multiple race. 
10.5 
Efficacy Analyses 
The following table summarizes the key efficacy analyses that will be conducted. 


Product:  Evolocumab 
Statistical Analysis Plan:  20130287 
Date:  22 December 2016 
Page 21 
 
Table 2.  Key Efficacy Analyses Summary Table 
Endpoint 
Primary Summary 
and Analysis 
Method (Specify 
Analysis Set if 
FAS is Not Used) 
P-values from the 
Statistical Tests 
Hierarchical Testing 
Procedure for testing of 
Treatment Effect vs. 
Placebo. as specified in the 
Multiplicity Adjustment 
Method diagram 
Sensitivity Analysis 
Co-Primary Endpoints 
 
Mean percent 
change from 
baseline at 
weeks 10 and 12 in 
LDL-C  
 
Percent change 
from baseline at 
week 12 in LDL-C  
Repeated 
measures model  
 
P1=Maximum of the 
two p-values for the 
co-endpoint pair from the 
primary analysis  
 
P1 compare to α = 0.05  
 
 
The primary analysis will be 
repeated using the CAS 
 
Non-parametric analyses will 
be performed 
 
Multiple imputation for 
subjects with missing 
endpoint data who 
discontinue evolocumab 
Co-Secondary Endpoints (Tier 1) 
 
Mean LDL-C 
achievement of 
target LDL-C 
< 70 mg/dL and 
LDL-C response of 
≥ 50% reduction 
from baseline at 
weeks 10 and 12  
 
LDL-C achievement 
and response at 
week 12  
Cochran 
Mantel-Haenszel 
(CMH) test  
 
For LDL-C achievement and 
LDL-C response, 
P2a=Maximum of the 
two p-values for the 
co-endpoint pair  
 
If P1 < 0.05,  
Both P2a and all P2b’s 
from each lipid parameter will 
be tested through Hochberg 
method with α = 0.005  
 
Else (i.e. co-primary endpoint 
is not significant)  
No further testing  
 
n/a 
Page 1 of 3 


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