Clinical trial NCT02833844
Conditions: Subjects With Hyperlipidemia, Dyslipidemia and HIV Infection
Keywords: Hyperlipidemia Dyslipidemia Proprotein convertase subtilisin/kexin type 9 (PCSK9) Inhibition HIV infection Cluster of differentiation Viral load
Sponsor: Amgen
Start date: 2017-05-22; Completion date: 2020-01-27
Enrollment: 467 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is divided into 2 parts. The first part of the study will be double-blinded and will last for 24 weeks. During this time, participants will be randomized in a ratio of 2:1 to receive either evolocumab once monthly (QM) or placebo QM. The second part of the study is a 24-week open label extension period. During this time all participants will receive evolocumab QM.

The clinical hypothesis is that subcutaneous evolocumab QM will be well tolerated and will result in greater reduction of low density lipoprotein cholesterol (LDL-C), defined as percent change from baseline at Week 24, compared with placebo QM in human immunodeficiency virus (HIV)-positive participants with hyperlipidemia or mixed dyslipidemia.

Detailed description:

Arms: arm 1: Double-blind placebo subcutaneous (SC) injection every 4 weeks (QM) for 24 weeks, followed by open-label evolocumab 420 mg SC QM for 24 weeks. arm 2: Double-blind evolocumab SC injection QM for 24 weeks, followed by open-label evolocumab 420 mg SC QM for 24 weeks.
Interventions: intervention 1: Evolocumab intervention 2: Placebo
Intervention descriptions: intervention 1: Dose of subcutaneous evolocumab QM intervention 2: Dose of matching placebo QM

Protocol documents:
Prot_000.pdf: 
Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 1 of 73 
Title:  A Double Blind, Randomized, Placebo Controlled, Multicenter Study to 
Evaluate Safety, Tolerability, and Efficacy on LDL-C of Evolocumab (AMG 145) in 
Subjects With HIV and With Hyperlipidemia and/or Mixed Dyslipidemia 
Amgen Protocol Number (AMG 145/Evolocumab) 20130286 
BEIJERINCK: evolocumaB Effect on LDL-C lowerIng in subJEcts with human 
immunodeficiency viRus and INcreased Cardiovascular risK 
EudraCT number 2015‐004735‐12 
Clinical Study Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
United States 
1-805-447-1000
Key Sponsor Contact(s): 
 
Uxbridge Business Park 
Uxbridge, Middlesex, UB8 1DH 
United Kingdom  
Phone:  
  
Email:  
 
Date: 
19 November 2015 
Amendment 1: 
30 January 2017 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN, Canadian sites, 
1-866-50-AMGEN; Amgen’s general number in the US (1-805-447-1000).
CONFIDENTIAL 
NCT Number: NCT02833844
This NCT number has been applied to the document for
purposes of posting on clinicaltrials.gov


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 2 of 73 
Investigator’s Agreement 
I have read the attached protocol entitled A Double Blind, Randomized, Placebo 
Controlled, Multicenter Study to Evaluate Safety, Tolerability, and Efficacy on LDL-C of 
Evolocumab (AMG 145) in Subjects with HIV and with Hyperlipidemia and/or Mixed 
Dyslipidemia, dated 30 January 2017, 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) 
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 3 of 73 
Protocol Synopsis 
Title:  A Double Blind, Randomized, Placebo Controlled, Multicenter Study to Evaluate Safety, 
Tolerability, and Efficacy on LDL-C of Evolocumab (AMG 145) in Subjects with HIV and with 
Hyperlipidemia and/or Mixed Dyslipidemia 
Study Phase:  3b 
Indication:  Hypercholesterolemia and/or mixed dyslipidemia 
Primary Objective:  To evaluate the effect of 24 weeks of subcutaneous (SC) evolocumab 
administered every month (QM) compared with placebo QM on percent change from baseline in 
low-density lipoprotein cholesterol (LDL-C) in human immunodeficiency virus (HIV)-positive 
subjects with hyperlipidemia or mixed dyslipidemia. 
Secondary Objectives:   
• 
To assess the effects of 24 weeks of SC evolocumab QM compared with placebo QM on 
change from baseline in LDL-C, and percent change from baseline in non-high-density 
lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol (TC), 
lipoprotein(a) [Lp(a)], triglycerides, HDL-C, and very low-density lipoprotein cholesterol 
(VLDL-C), in HIV-positive subjects with hyperlipidemia or mixed dyslipidemia 
• 
To assess the effects of 24 weeks of SC evolocumab QM compared with placebo QM on 
percent of subjects attaining LDL-C < 70 mg/dL (1.8 mmol/L) in HIV-positive subjects with 
hyperlipidemia or mixed dyslipidemia 
• 
To assess the effects of 24 weeks of SC evolocumab QM compared with placebo QM on 
percent of subjects attaining a 50% reduction in LDL-C from baseline in HIV-positive subjects 
with hyperlipidemia or mixed dyslipidemia 
Safety Objective:  To evaluate the safety and tolerability of SC evolocumab QM compared with 
placebo QM in HIV-positive subjects with hyperlipidemia or mixed dyslipidemia 
Hypotheses:  Subcutaneous evolocumab QM will be well tolerated and will result in greater 
reduction of LDL-C, defined as percent change from baseline at week 24 compared with placebo 
QM in HIV-positive subjects with hyperlipidemia or mixed dyslipidemia. 
Primary Endpoint:  Percent change from baseline in LDL-C at week 24 
Secondary Endpoints: 
For week 24 the following secondary endpoints will be characterized: 
• 
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 
Safety Endpoint(s): 
• 
Subject incidence of treatment emergent adverse events 
• 
Safety laboratory values and vital signs at each scheduled assessment 
• 
Incidence of anti-evolocumab antibody (binding and neutralizing) formation 
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 4 of 73 
Study Design:  This is a phase 3b, multicenter, double-blind, randomized, placebo-controlled 
study designed to assess the efficacy and safety of evolocumab in HIV-positive subjects with 
hyperlipidemia and/or mixed dyslipidemia. 
Sample Size:  Approximately 450 subjects will be enrolled in the study, with approximately 
300 subjects in the evolocumab group. 
Summary of Subject Eligibility Criteria:   The study will enroll adult subjects (≥ 18 years of age) 
with known HIV infection, who have received stable HIV therapy for ≥ 6 months prior to 
randomization and that is not expected to change during the duration of study 
participation. Subjects must be on stable doses of lipid-lowering therapy for ≥ 4 weeks and 
not expected to change during the duration of the study. Subjects should be on maximally 
tolerated dose of statins. For some subjects, “maximally tolerated” may indicate no statin 
at all due to statin intolerance or contraindication to statin therapy. A statin-intolerant 
subject must meet the criteria described in Section 4.1.1, criterion 106. Subjects without 
known clinical atherosclerotic cardiovascular disease (ASCVD) must have fasting LDL-C 
of ≥ 100 mg/dL (2.6 mmol/L) or non-HDL-C of ≥ 130 mg/dL (3.4 mmol/L) as determined by 
the central laboratory at screening. Subjects with known clinical ASCVD must have fasting 
LDL-C of ≥ 70 mg/dL (1.8 mmol/L) or non-HDL-C of ≥ 100 mg/dL (2.6 mmol/L) as 
determined by the central laboratory. Clinical ASCVD 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. Subjects must also have fasting triglycerides ≤ 600 mg/dL (6.8 mmol/L). 
For a full list of eligibility criteria, please refer to Section 4.1 through Section 4.1.2.  
Investigational Product:  Evolocumab or matching placebo administered by automated 
mini-doser (AMD) or prefilled autoinjector (AI)/Pen. 
Amgen Investigational Product Dosage and Administration:   
The Amgen investigational medicinal product (IMP) is evolocumab and placebo. The Amgen 
investigational product (IP) is the IMP plus the device (AMD [called an “on-body infuser 
prefilled cartridge” in the United States or AI/pen). In this document, IMP will be referred to as 
IP.  
Double-blind Treatment Period: 
Evolocumab 420 mg or matching placebo will be administered QM at day 1 and weeks 4, 8, 12, 
16, and 20 as an SC injection. The IP may be delivered by AMD or by 3 injections with AI/pen. 
Observed, in-clinic dosing should occur at day 1 and week 20.  
Open-label Period: 
Subjects who receive a dose of IP at week 20 will continue in an open-label period where all 
subjects will be treated with evolocumab 420 mg QM at weeks 24, 28, 32, 36, 40, 44, and 48. 
Dosing at week 24 is expected to be in-clinic while the remaining doses will be at an appropriate 
non-clinic setting (eg, at the subject’s home). Subjects who do not wish to self-inject in a 
non-clinic setting (eg, at the subject’s home) may return to clinic for injection. 
Procedures: 
After subjects complete the informed consent form, screening should be completed and the 
subject randomized or screen failed after 4 weeks (± 1 week) of signing the informed consent. 
Subjects will undergo SC placebo injection with the device anticipated to be used during study 
(AMD or AI/pen) during screening. Subjects who tolerate the placebo injection, complete all 
screening procedures, and successfully meet all eligibility criteria at the end of screening will 
enter the double-blind treatment period.  
Subjects will be randomized via interactive voice response system/interactive web response 
system (IVRS/IWRS) and will return to the study site for day 1 procedures while continuing their 
background HIV and lipid-lowering (if applicable) treatment. Baseline evaluations will be 
performed on day 1 of treatment before subjects receive the first dose of IP. Laboratory tests will 
be conducted at day 1 and week 12. Vital signs, safety data reporting, urine pregnancy testing 
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 5 of 73 
(as applicable), and concomitant therapy will be recorded at each visit. At the end of the 
double-blind treatment period at week 24, laboratory tests will be conducted, and vital signs, 
safety data reporting, urine pregnancy testing (as applicable) concomitant therapy, physical 
examination, and body weight/waist circumference will be recorded. 
Following the double-blind treatment period, subjects who received a dose of IP at week 20 will 
continue to a 24-week open-label period in which all subjects will be treated with QM evolocumab 
at weeks 24, 28, 32, 36, 40, 44, and 48. Laboratory tests will be conducted at week 36 and 
week 52 . Vital signs, safety data reporting, urine pregnancy testing (as applicable), and 
concomitant therapy will be recorded at week 36. At end of study week 52, vital signs, safety data 
reporting, urine pregnancy testing (as applicable), concomitant therapy, physical examination, 
body weight, and waist circumference will be recorded. 
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 3).  
Statistical Considerations:  The primary analysis will be performed when all randomized 
subjects in 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. 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 1 dose of IP in the double-blind 
treatment period. To assess the primary endpoint of the mean percent change from baseline in 
LDL-C at week 24, a repeated measures linear effects model will be used on the FAS to compare 
the efficacy of evolocumab with placebo. The repeated measures model will include terms for 
treatment group, stratification factors, scheduled visit and the interaction of treatment with 
scheduled visit. Missing values will not be imputed for primary analysis. To evaluate the 
robustness of the analysis results, sensitivity analyses will be performed as follows:  the primary 
analysis will be repeated using the computer analysis set (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. The 
statistical model and testing of the tier 1 secondary efficacy endpoints will be similar to the 
primary analysis of primary endpoint. Analysis of the tier 2 secondary efficacy endpoints will use 
the same analysis model as the tier 1 endpoints. Safety endpoints will be summarized 
descriptively by treatment group. 
Sponsor:  Amgen Inc. 
Data Element Standards 
Version(s)/Date(s):   
Version 5/20 March 2015 
 
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 6 of 73 
Study Design and Treatment Schema 
 
QM=once monthly; SC=subcutaneous 
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 7 of 73 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ASCVD 
atherosclerotic cardiovascular disease 
ADE 
adverse device effect 
AI 
Autoinjector 
AIDS 
acquired immunodeficiency syndrome 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ApoA1 
apolipoprotein A-I 
ApoB 
apolipoprotein B 
AMD 
automated mini-doser (known as “on-body infuser prefilled 
cartridge” in the United States) 
AST 
aspartate aminotransferase 
BID  
twice daily 
CAS 
computer analysis set 
CD 
cluster of differentiation 4 
CK 
creatinine kinase 
CPK 
creatinine phosphokinase 
CMV 
cytomegalovirus 
CRF 
case report form 
CTCAE 
common terminology criteria for adverse events 
CVD 
cardiovascular disease 
CYP 
cytochrome P450 
D-dimer 
fibrin degradation product consisting of 2 crosslinked D fragments of 
fibrin  
DILI 
drug induced liver injury  
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
End of Study (end of trial) the date when the last subject has completed the assessments for 
week 52 
End of Study (primary 
completion) 
the date when the last subject has completed the assessments for 
week 24 
End of Study for 
Individual Subject 
the last day that protocol-specified procedures are conducted for an 
individual subject or the day the subject withdraws from study early 
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 8 of 73 
Abbreviation or Term 
Definition/Explanation 
End of Treatment 
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 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HbA1c 
hemoglobin A1c 
HDL-C 
high-density lipoprotein cholesterol 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
hsCRP 
high sensitivity C-reactive protein 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IFU 
Information for Use 
IL-6 
Interleukin-6 
IL-10 
Interleukin-10 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IP 
Investigational product 
IPIM 
Investigational Product Instruction Manual 
IRB/IEC 
institutional review board/independent ethics committee 
IVRS 
interactive voice response system, elecommunication technology 
that is linked to a central computer in real time as an interface to 
collect and process information.  
IWRS 
interactive web response system 
LAS 
long-term analysis set 
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 
MI 
myocardial infarction 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 9 of 73 
Abbreviation or Term 
Definition/Explanation 
PI 
protease inhibitor 
PT 
prothrombin time 
QM 
once monthly 
RBC 
red blood cells 
RDW 
red blood cell distribution width 
SC 
subcutaneous 
sCD14 
soluble cell differentiation antigen 14 
SD 
standard deviation 
SMART 
Strategies for Management of Antiretroviral Therapy 
Source Data 
Information from an original record or certified copy of the original 
record containing patient IFU 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 
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 10 of 73 
TABLE OF CONTENTS 
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 ........................................................................ 14 
2.1 
Disease ....................................................................................................... 14 
2.2 
Amgen Investigational Product Background ............................................... 16 
2.3 
Rationale .................................................................................................... 16 
2.4 
Clinical Hypotheses .................................................................................... 17 
3. 
EXPERIMENTAL PLAN ......................................................................................... 17 
3.1 
Study Design .............................................................................................. 17 
3.2 
Number of Sites .......................................................................................... 18 
3.3 
Number of Subjects .................................................................................... 18 
3.4 
Replacement of Subjects ............................................................................ 18 
3.5 
Estimated Study Duration ........................................................................... 18 
3.5.1 
Study Duration for Subjects ........................................................ 18 
3.5.2 
End of Study ............................................................................... 18 
4. 
SUBJECT ELIGIBILITY .......................................................................................... 18 
4.1 
Inclusion and Exclusion Criteria ................................................................. 19 
4.1.1 
Inclusion Criteria ......................................................................... 19 
4.1.2 
Exclusion Criteria ........................................................................ 20 
5. 
SUBJECT ENROLLMENT ..................................................................................... 22 
5.1 
Randomization/Treatment Assignment ...................................................... 23 
5.2 
Site Personnel Access to Individual Treatment Assignments .................... 23 
6. 
TREATMENT PROCEDURES ............................................................................... 23 
6.1 
Classification of Product(s) and/or Medical Device(s) ................................ 23 
6.2 
Investigational Product ............................................................................... 24 
6.2.1 
Dosage, Administration, and Schedule ...................................... 24 
6.2.1.1 
Screening ................................................................. 24 
6.2.1.2 
Double-blind Treatment Period ................................ 24 
6.2.1.3 
Open-label Period .................................................... 25 
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 11 of 73 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ...................................... 26 
6.3 
Hepatotoxicity Stopping and Rechallenge Rules ........................................ 26 
6.3.1 
Criteria for Withholding and/or Permanent 
Discontinuation of Amgen Investigational Product and 
Other Protocol-required Therapies Due to Potential 
Hepatotoxicity ............................................................................. 26 
6.3.2 
Criteria for Rechallenge of Amgen Investigational 
Product and Other Protocol-required Therapies After 
Potential Hepatotoxicity .............................................................. 28 
6.4 
Other Protocol-required Therapies ............................................................. 28 
6.5 
Concomitant Therapy ................................................................................. 28 
6.6 
Medical Devices ......................................................................................... 28 
6.7 
Product Complaints .................................................................................... 28 
6.8 
Excluded Treatments, Medical Devices, and/or Procedures 
During Study Period ................................................................................... 29 
7. 
STUDY PROCEDURES ......................................................................................... 31 
7.1 
Schedule of Assessments .......................................................................... 32 
7.2 
General Study Procedures ......................................................................... 35 
7.2.1 
Screening Enrollment and Randomization ................................. 35 
7.2.2 
Rescreening ............................................................................... 36 
7.2.3 
Double-blind Treatment Period ................................................... 36 
7.2.4 
Open-label Period ....................................................................... 36 
7.2.5 
End of Study / Safety Follow-up ................................................. 36 
7.3 
Description of Study Procedures ................................................................ 37 
7.3.1 
Informed Consent ....................................................................... 37 
7.3.2 
Demographics ............................................................................ 37 
7.3.3 
Medical History ........................................................................... 37 
7.3.4 
Vital Signs ................................................................................... 37 
7.3.5 
Safety Data Reporting ................................................................ 37 
7.3.6 
Prior Therapies, Substance Use History, and 
Concomitant Medications ........................................................... 38 
7.3.7 
Physical Examination ................................................................. 38 
7.3.8 
Body Weight, Waist Circumference, and Height ........................ 38 
7.4 
Laboratory Assessments ............................................................................ 39 
7.4.1 
Blinding of Laboratory Test Results ............................................ 40 
7.4.2 
Pregnancy Tests ......................................................................... 41 
7.5 
Antibody Testing Procedures ..................................................................... 41 
7.6 
Biomarker Development ............................................................................. 41 
7.7 
Pharmacogenetic Studies ........................................................................... 42 
7.8 
Sample Storage and Destruction ................................................................ 42 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 43 
8.1 
Subjects’ Decision to Withdraw .................................................................. 43 
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Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 12 of 73 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 44 
8.3 
Reasons for Removal From Treatment or Study ........................................ 44 
8.3.1 
Reasons for Removal From Treatment ...................................... 44 
8.3.2 
Reasons for Removal From Study ............................................. 44 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 45 
9.1 
Definition of Safety Events ......................................................................... 45 
9.1.1 
Disease-related Events .............................................................. 45 
9.1.2 
Adverse Events .......................................................................... 45 
9.1.2.1 
Worsening of HIV Disease ....................................... 46 
9.1.3 
Adverse Device Effects .............................................................. 46 
9.1.4 
Serious Adverse Events ............................................................. 47 
9.2 
Safety Event Reporting Procedures ........................................................... 47 
9.2.1 
Reporting Procedures for Disease-related Events ..................... 47 
9.2.2 
Adverse Events .......................................................................... 48 
9.2.2.1 
Reporting Procedures for Adverse Events 
That Do Not Meet Serious Criteria ........................... 48 
9.2.2.2 
Reporting Procedures for Serious Adverse 
Events ...................................................................... 49 
9.2.2.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 50 
9.2.2.4 
Serious Adverse Events That are not to be 
Reported in an Expedited Manner ........................... 51 
9.3 
Pregnancy and Lactation Reporting ........................................................... 51 
10. 
STATISTICAL CONSIDERATIONS ....................................................................... 52 
10.1 
Study Endpoints, Analysis Sets, and Covariates ........................................ 52 
10.1.1 
Study Endpoints ......................................................................... 52 
10.1.1.1 
Primary Endpoint ..................................................... 52 
10.1.1.2 
Secondary Endpoints ............................................... 52 
10.1.1.3 
Safety Endpoints ...................................................... 52 
10.1.1.4 
Exploratory Endpoints .............................................. 53 
10.1.2 
Analysis Sets .............................................................................. 53 
10.1.2.1 
Double-blind Treatment Period ................................ 53 
10.1.2.2 
Open-label Period .................................................... 54 
10.1.3 
Covariates and Subgroups ......................................................... 54 
10.2 
Sample Size Considerations ...................................................................... 54 
10.3 
Access to Individual Subject Treatment Assignments by Amgen 
or Designees .............................................................................................. 55 
10.4 
Planned Analyses ....................................................................................... 55 
10.4.1 
Primary Analysis ......................................................................... 55 
10.4.2 
Final Analysis ............................................................................. 55 
10.5 
Planned Methods of Analysis ..................................................................... 55 
10.5.1 
General Considerations .............................................................. 55 
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Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 13 of 73 
10.5.1.1 
Multiplicity Adjustment Method ................................ 56 
10.5.2 
Primary Efficacy Endpoint .......................................................... 57 
10.5.2.1 
Sensitivity Analysis .................................................. 57 
10.5.3 
Secondary Efficacy Endpoints .................................................... 57 
10.5.4 
Safety Endpoints ........................................................................ 57 
10.5.5 
Exploratory Endpoints ................................................................ 58 
11. 
REGULATORY OBLIGATIONS ............................................................................. 58 
11.1 
Informed Consent ....................................................................................... 58 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 59 
11.3 
Subject Confidentiality ................................................................................ 59 
11.4 
Investigator Signatory Obligations .............................................................. 60 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................... 60 
12.1 
Protocol Amendments and Study Termination ........................................... 60 
12.2 
Study Documentation and Archive ............................................................. 60 
12.3 
Study Monitoring and Data Collection ........................................................ 61 
12.4 
Investigator Responsibilities for Data Collection ........................................ 62 
12.5 
Language.................................................................................................... 63 
12.6 
Publication Policy ....................................................................................... 63 
12.7 
Compensation ............................................................................................ 63 
13. 
REFERENCES ....................................................................................................... 64 
14. 
APPENDICES ........................................................................................................ 66 
List of Tables 
Table 1.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................... 27 
Table 2.  Statin Interactions ............................................................................................ 31 
Table 3.  Schedule of Assessments ................................................................................ 33 
Table 4.  Analyte Listing .................................................................................................. 40 
List of Figures 
Figure 1.  Multiplicity Adjustment Methods ...................................................................... 56 
List of Appendices 
Appendix A.  Additional Safety Assessment Information ................................................ 67 
Appendix B.  Sample eSerious Adverse Event Contingency Report Form ..................... 69 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................... 72 
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 14 of 73 
1. 
OBJECTIVES 
1.1 
Primary 
• 
To evaluate the effect of 24 weeks of subcutaneous (SC) evolocumab administered 
every month (QM) compared with placebo QM on percent change from baseline in 
low-density lipoprotein cholesterol (LDL-C) in human immunodeficiency virus 
(HIV)-positive subjects with hyperlipidemia or mixed dyslipidemia 
1.2 
Secondary 
• 
To assess the effects of 24 weeks of SC evolocumab QM compared with placebo 
QM on change from baseline in LDL-C, and percent change from baseline in 
non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total 
cholesterol (TC), lipoprotein(a) [Lp(a)], triglycerides, HDL-C, and very low-density 
lipoprotein cholesterol (VLDL-C), in HIV-positive subjects with hyperlipidemia or 
mixed dyslipidemia 
• 
To assess the effects of 24 weeks of SC evolocumab QM compared with placebo 
QM on percent of subjects attaining LDL-C < 70 mg/dL (1.8 mmol/L) in HIV-positive 
subjects with hyperlipidemia or mixed dyslipidemia 
• 
To assess the effects of 24 weeks of SC evolocumab QM compared with placebo 
QM on percent of subjects attaining a 50% reduction in LDL-C from baseline in 
HIV-positive subjects with hyperlipidemia or mixed dyslipidemia 
1.3 
Safety 
• 
To evaluate the safety and tolerability of SC evolocumab QM compared with placebo 
QM in HIV-positive subjects with hyperlipidemia or mixed dyslipidemia 
1.4 
Exploratory 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
Approximately 35 million individuals are living with HIV worldwide, with 1.3 million in the 
United States (Kohli and Giugliano 2013). In countries with access to highly active 
antiretroviral therapy, the prognosis of HIV infection has changed with mortality from 
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acquired immunodeficiency syndrome (AIDS)-related causes declining while non-AIDS 
related causes, including cardiovascular disease (CVD), have risen. HIV-infected 
patients have an increased risk of CVD as evidenced by increased rate of myocardial 
infarction (MI) after accounting for age and other comorbidities (Triant et al, 2007).  
In the Veterans Aging Cohort Study Virtual Cohort, HIV-positive veterans had an almost 
50% greater risk of incident MI compared with uninfected veterans after statistical 
adjustment for Framingham risk, comorbidities, and substance abuse 
(Freiberg et al, 2013). A study by the Boston healthcare system showed a 20% higher 
risk of ischemic stroke in HIV positive versus matched HIV negative controls, adjusted 
for demographics and stroke risk factors. This study also linked a higher viral load to 
increased stroke risk (Chow et al, 2012). In addition, a worse outcome after MI has been 
reported among HIV-positive patients when compared to the general population 
(Carballo et al, 2015). 
By the year 2015, it is estimated that over half of HIV-infected individuals will be aged 
50 years and older, and CVD will therefore become even more important in this patient 
population. 
The etiology of CVD in HIV-infected patients is multifactorial. HIV infected patients have 
higher rates of significant comorbidities including dyslipidemia, diabetes, hypertension, 
and smoking compared with non-HIV infected patients (Triant et al, 2007; 
Boccara et al, 2013). HIV-infected patients also have higher levels of inflammatory 
markers including interleukin-6 (IL-6), high sensitivity C-reactive protein (hsCRP), 
D-Dimer, and soluble cell differentiation antigen sCD14 (Kuller et al, 2008; 
Neuhaus et al, 2010).  
The Strategies for Management of Antiretroviral Therapy (SMART) Study showed a 
higher rate of CVD events in patients who discontinued antiretroviral treatment 
compared with patients on continuous therapy, with a hazard ratio of 1.57 
(El-Sadr et al, 2006). In groups experiencing treatment interruption, the levels of the 
inflammatory cytokine IL-6 and the coagulation marker D-dimer were significantly 
elevated. Markers of inflammation were also related with the changes in HIV-RNA levels 
in other treatment interruption studies (Calmy et al, 2009). In addition, these 2 markers 
showed a statistically signification correlation with death. Elevations of IL-6 have also 
been statistically associated with the development of CVD (Kuller et al, 2008). 
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In addition to the increased risk of CVD attributed directly to HIV infection, HIV 
therapy itself, particularly protease inhibitors (PI), are also linked to increased CVD 
risk. HIV therapy has been shown to promote adipocyte dysfunction which leads 
to a lipodystrophy syndrome (Carr 2000; Grinspoon 2005; Capeau 2007; 
Boccara et al, 2010; Caron-Debarle et al, 2010). The lipodystrophy syndrome is 
manifested as increased visceral fat, elevated triglycerides, and low HDL-C. Increased 
rates of insulin resistance and diabetes mellitus, in addition to lipodystrophy, have also 
been reported in HIV-infected patients. (Carr et al, 1999; Periard et al, 1999; 
Grinspoon 2005). These factors demonstrate the etiology and pathophysiology of 
increased CVD risk seen in HIV-infected patients is multifactorial and includes HIV 
infection itself, therapy for HIV including PI therapy, inflammation, and traditional cardiac 
risk factors including dyslipidemia.  
In an observational cohort study of HIV-infected patients, statin therapy contributed to 
the reduction of all-cause mortality (Rasmussen et al, 2013). Randomized, controlled 
trial data demonstrating statin reduction in cardiovascular mortality in HIV subjects is not 
available although a trial using pitavastatin is now ongoing. In the HIV population, those 
patients treated with statins appear to be relatively resistant to statin effects as 
evidenced by lower than expected decreases in TC and LDL-C (Johns et al, 2007; 
Silverberg et al, 2009). 
2.2 
Amgen Investigational Product Background 
Recycling of the hepatic cell surface LDLR plays a critical role in regulating serum LDL-C 
levels. PCSK9 binds to the LDLR and downregulates hepatic cell surface LDLR, which, 
in turn, leads to increased levels of circulating LDL-C. Humans with PCSK9 
loss-of-function mutations have cholesterol levels lower than normal and reduced 
incidence of coronary heart disease (Abifadel et al, 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. 
2.3 
Rationale 
It has been shown that HIV-infected patients are at higher risk of CVD and have 
limitations with statin therapy including possible statin resistance, and elevations of 
PCSK9 are seen in chronic inflammatory states including HIV infection. Treatment with 
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an anti-PCSK9 monoclonal antibody is therefore a plausible target for LDL-C reduction 
in HIV-infected individuals. 
It is anticipated that evolocumab may be used in HIV-infected individuals who cannot 
achieve optimal LDL-C despite the use of maximally tolerated statin therapy or who are 
intolerant to statin or for whom statin is contraindicated. Therefore, understanding the 
safety and efficacy of evolocumab in patients with HIV is important. 
For further details on evolocumab efficacy and safety results refer to the Evolocumab 
Investigator’s Brochure. 
2.4 
Clinical Hypotheses 
Subcutaneous evolocumab QM will be well tolerated and will result in greater reduction 
of LDL-C, defined as percent change from baseline at week 24, compared with placebo 
QM in HIV-positive subjects with hyperlipidemia or mixed dyslipidemia. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a phase 3b, multicenter, double-blind, randomized, placebo-controlled study with 
an open-label extension period designed to assess the efficacy and safety of 
evolocumab in HIV-positive subjects with hyperlipidemia and/or mixed dyslipidemia. 
Treatment with baseline HIV and lipid-lowering (if applicable) medications being taken at 
randomization will continue throughout the clinical study. The study consists of 
3 periods: 
• 
Screening (to ensure tolerance of SC injections, includes a placebo injection) 
• 
Double-blind treatment period 
• 
Open-label extension period 
Subjects will undergo screening procedures, including laboratory assessments and a 
screening placebo injection, before being randomized 2:1 into the following treatment 
groups for the double-blind treatment period: 
• 
SC evolocumab 420 mg QM  
• 
SC placebo QM  
The overall sample size will be approximately 450 subjects, with approximately 
300 subjects in the evolocumab group. Randomization will be stratified by entry statin 
treatment (yes/no) and by hepatitis C status (yes/no). The size of the subgroup not on 
statin therapy is expected to be approximately 10% and no more than 20% of the 
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subjects. This enrollment projection is expected to be reflective of clinical 
practice. 
The double-blind period will be 24 weeks, after which subjects who received a dose of 
investigational product (IP) at week 20 will continue in an open-label period during which 
all subjects will be treated with QM evolocumab. The open-label period will continue up 
through the end of study (EOS) visit at week 52.  
SC evolocumab and placebo will be administered QM at the study site or appropriate 
non-investigator site settings (eg, at the subject’s home) by automated mini-doser (AMD; 
referred to in the United States as an “on-body infuser prefilled cartridge”) or by 
spring-based prefilled autoinjector/pen (AI/pen). 
3.2 
Number of Sites 
Approximately 75 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 
Approximately 450 subjects will be enrolled, with approximately 300 subjects in the 
evolocumab group. 
3.4 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
Including the screening, study treatment (double-blind treatment and open-label), and 
follow-up, the maximal total duration of study participation for a subject will be 56 weeks. 
After signing the informed consent, subjects should be randomized after 4 weeks 
(± 1 week) of screening. 
3.5.2 
End of Study 
The primary completion is defined as the date when the last subject has completed 
assessments for week 24. 
The end of trial is defined as the time when the last subject has completed the 
assessments for week 52. 
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 
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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/procedures, 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 
Known HIV infection with stable HIV therapy for ≥ 6 months prior to 
randomization and not expected to change during the duration of study 
participation. Stable HIV therapy is defined as no new agents added and no dose 
change of any HIV drug within 6 months prior to randomization  
104 
Cluster of differentiation 4 (CD4) ≥ 250 cells/mm3 for ≥ 6 months prior to 
randomization 
105 
HIV viral load ≤ 50 copies/mL at screening and ≤ 200 copies/mL for ≥ 6 months 
prior to randomization  
106 
Subject on stable lipid-lowering therapy for ≥ 4 weeks prior to randomization 
and not expected to change during the duration of study participation. 
Subjects should be on maximally tolerated dose of statins. For some 
subjects, “maximally tolerated” may indicate no statin at all due to statin 
intolerance or contraindication to statin therapy. Statin intolerance or 
contraindication must be documented. A subject with statin intolerance 
must be evidenced by the following: 
a. Must have tried at least 2 statins with failure to at least 1 of the statins 
at an average daily dose at or below the following doses due to 
intolerable myopathy (ie, myalgia [muscle pain, ache, or weakness 
without creatine kinase elevation]), myositis (muscle symptoms with 
increased creatine kinase levels), or rhabdomyolysis (muscle 
symptoms with marked creatine elevation, as defined under “b”):  
• 
atorvastatin: 10 mg  
• 
simvastatin: 10 mg  
• 
pravastatin: 40 mg  
• 
rosuvastatin: 5 mg  
• 
lovastatin: 20 mg  
• 
fluvastatin: 40 mg 
• 
pitavastatin: 2 mg  
AND 
b. Symptoms resolved or improved when statin dose was decreased or 
discontinued  
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For subjects that developed rhabdomyolysis, defined as creatine kinase > 10 × 
upper limit of normal (ULN), failure of only 1 statin at any dose is acceptable.  
107 
Subject without known clinical atherosclerotic CVD (ASCVD): fasting 
LDL-C of ≥ 100 mg/dL (2.6 mmol/L) or non-HDL-C of ≥ 130 mg/dL 
(3.4 mmol/L) as determined by the central laboratory at screening. Subject 
with known clinical ASCVD: fasting LDL-C of ≥ 70 mg/dL (1.8 mmol/L) or 
non-HDL-C of ≥ 100mg/dL (2.6 mmol/L) as determined by the central laboratory. 
Clinical ASCVD 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. 
108 
Fasting triglycerides ≤ 600 mg/dL (6.8 mmol/L) as determined by central 
laboratory during screening 
109 
Subject tolerates screening placebo injection 
4.1.2 
Exclusion Criteria 
201 
Subject taking a combination of background lipid-lowering therapy and HIV 
therapy known to have significant drug-drug interaction as per Table 2 
202 
New York Heart Association III or IV heart failure, or last known left ventricular 
ejection fraction < 30% 
203 
Known opportunistic infection/AIDS defining illness (including but not limited to 
candidiasis of bronchi, trachea, esophagus, or lungs, invasive cervical cancer, 
coccidioidomycosis, cryptococcosis, chronic intestinal (> 1-month duration) 
cryptosporidiosis, cytomegalovirus disease (particularly cytomegalovirus [CMV] 
retinitis), HIV-related encephalopathy, herpes simplex: chronic ulcer(s) 
(> 28 days duration); or bronchitis, pneumonitis, or esophagitis, histoplasmosis, 
chronic intestinal (> 28 days duration) isosporiasis, Kaposi's sarcoma, 
lymphoma, mycobacterium avium complex, tuberculosis, pneumocystis carinii 
pneumonia, recurrent pneumonia, progressive multifocal leukoencephalopathy, 
salmonella septicemia, toxoplasmosis of brain, or wasting syndrome due to HIV 
within 1 year prior to randomization 
204 
Myocardial infarction, unstable angina, percutaneous coronary intervention, 
coronary artery bypass graft or stroke within 3 months prior to randomization 
205 
Type 1 diabetes, new-onset (hemoglobin A1c [HbA1c] ≥ 6.5% or fasting plasma 
glucose ≥ 126 mg/dL at screening without known diagnosis) or poorly controlled 
(HbA1c ≥ 10%) type 2 diabetes by central laboratory during screening 
206 
Uncontrolled hypertension defined as sitting systolic blood pressure > 180 mmHg 
or diastolic blood pressure > 110 mmHg during screening 
207 
Subject has taken a cholesterylester transfer protein inhibitor in the last 
12 months prior to randomization 
208 
Moderate to severe renal dysfunction, defined as an estimated glomerular 
filtration rate < 30 mL/min/1.73 m2 during screening 
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209 
Persistent active liver disease or hepatic dysfunction defined as Child-Pugh 
score of C. Stable (in the opinion of the primary investigator and with aspartate 
aminotransferase [AST] and alanine aminotransferase [ALT] < 5 times ULN and 
not expected to require new treatment[s] during study) chronic hepatitis C of at 
least 1 year duration prior to randomization is allowed 
210 
Female subject of childbearing potential not willing to use acceptable method(s) 
of effective birth control 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, postovulation methods], declaration of abstinence for the 
duration of a trial, and withdrawal are not acceptable methods of 
contraception]),  
− 
surgical contraceptive methods (vasectomy or bilateral tubal 
ligation/occlusion),  
− 
use of hormonal birth control methods (oral, intravaginal, transdermal, 
injectable, or implantable),  
− 
intrauterine devices, 
− 
 intrauterine hormonal releasing system, or  
− 
2 barrier methods (each partner must use 1 barrier method) and at least 1 of 
barrier methods must include spermicide (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 2-barrier method 
without spermicide is acceptable.  
Note:  Additional medications given during treatment with evolocumab 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 or 
length of time breastfeeding is to be avoided. The investigator is to discuss these 
contraceptive changes with the study subject. 
211 
Female subject is pregnant or breast feeding, planning to become pregnant or 
planning to breastfeed during treatment with IP and/or within 15 weeks after the 
end of treatment with IP 
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212 
Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, 
breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 
5 years prior to randomization 
213 
Subject has previously received evolocumab or any other therapy to inhibit 
PCSK9 
214 
Currently receiving treatment in another investigational device or drug study, or 
< 30 days before randomization since ending treatment on another 
investigational device or drug study(s) or planning to receive other investigational 
procedures while participating in this study 
215 
Subject has known sensitivity to any of the active substances or their excipients 
to be administered during dosing, eg, carboxymethylcellulose 
216 
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’s and investigator’s knowledge 
217 
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. 
A subject is considered enrolled upon randomization. The investigator is to document 
this decision and date, in the subject’s medical record and in 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 via 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, except for subjects who do not meet inclusion criterion 107 
(see Section 7.2.2). 
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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 tolerate the placebo injection, complete all screening procedures, and 
successfully meet all eligibility criteria at the end of screening will be randomized via 
IVRS/IWRS and will return to the study site for day 1 procedures while continuing their 
background HIV and lipid-lowering treatment (if applicable). 
Subjects will be randomized in 2:1 ratio to 2 treatment groups (evolocumab and placebo, 
respectively) in a double-blind manner. The randomization will be stratified by entry 
statin treatment and hepatitis C status.  
Subjects can only be randomized 1 time for this study. The randomization date (study 
day 1) is to be documented in the subject’s medical record and on the enrollment CRF. 
Randomization numbers will be provided to the site through an IVRS/IWRS.  
5.2 
Site Personnel Access to Individual Treatment Assignments 
A subject’s treatment assignment should only be unblinded when knowledge of the 
treatment is essential for the further management of the subject on this study. Unblinding 
at the study site for any other reason will be considered a protocol deviation.  
Refer to the Investigational Product Instruction Manual (IPIM) for a description regarding 
how responsible pharmacists and investigators will access treatment information via the 
IVRS/IWRS, in the event that there is a need to break the blind.  
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. 
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 investigational medicinal product (IMP). In this document, 
IMP will be referred to as IP. 
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The investigational medical device is the AMD, or the spring based prefilled AI/pen. 
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 or AI/pen: 
• 
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, SC 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. 
6.2.1 
Dosage, Administration, and Schedule 
6.2.1.1 
Screening 
During screening, 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) will be 
administered QM on day 1, week 4, week 8, week 12, week 16, and week 20.  
SC evolocumab and placebo will be administered at the study site or in an appropriate 
non-clinic setting (eg, at the subject’s home). Observed, in-clinic dosing should occur at 
day 1 and week 20. Subjects who do not wish to self-inject at home may return to the 
clinic for injection. See Table 3 for the schedule of in-clinic visits. 
The IP will be administered SC 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 
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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 time of 
administration, the body location of the injection, and whether the injection was 
administered fully, partially, or not at all, in addition to the reason for a partial/lack of 
injection, are to be provided. When IP can be administered at an appropriate non-clinic 
setting (eg, at the subject’s home), at a minimum, the dates the devices were dispensed 
and 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. 
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 the subject’s home), a 
non-investigator site location, at a minimum, the dates that the devices were dispensed 
and the used devices were 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. 
6.2.1.3 
Open-label Period 
Subjects who receive a dose of IP at week 20 will continue in an open-label period. 
During the open-label period, all subjects will be treated with 420 mg evolocumab via 
AMD, or AI/pen. Dosing at week 24 is expected to be in-clinic while dosing for weeks 28, 
32, 36, 40, 44, and 48 is expected to be in an appropriate non-clinic setting (eg, at the 
subject’s home, even on weeks with in-clinic visits); however, subjects who do not 
wish to self-inject at home may return to the clinic for injection. 
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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 EOS visit. 
If a dose of evolocumab is missed, administration should occur as soon as possible if 
there are > 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 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], AST, 
ALT, total bilirubin [TBL]) and/or international normalized ratio (INR) and/or 
signs/symptoms of hepatitis (as described below) may meet the criteria for withholding 
or permanent discontinuation of Amgen IP or other protocol-required therapies as 
specified in the Guidance for Industry Drug-Induced Liver Injury (DILI): Premarketing 
Clinical Evaluation (July 2009). 
6.3.1 
Criteria for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due 
to Potential Hepatotoxicity 
The following stopping and/or withholding rules (Table 1) apply to subjects for 
whom another cause of their changes in liver biomarkers (TBL, INR and 
transaminases) has not been identified.  
Important alternative causes for elevated AST/ALT and/or TBL values include, but 
are not limited to: 
• 
Hepatobiliary tract disease 
• 
Viral hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr virus, cytomegalovirus, 
herpes simplex virus, varicella, toxoplasmosis, and Parvovirus) 
• 
Right-sided heart failure, hypotension or any cause of hypoxia to the liver 
causing ischemia  
• 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants, and mushrooms  
• 
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 
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• 
Autoimmune hepatitis  
• 
Wilson’s disease and hemochromatosis 
• 
Nonalcoholic fatty liver disease including steatohepatitis 
• 
Nonhepatic causes (eg, rhabdomylosis, hemolysis) 
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 
DILI. 
Rechallenge may be considered if an alternative cause for impaired liver tests 
(ALT, AST, ALP) and/or elevated TBL, is discovered and the laboratory 
abnormalities resolve to normal or baseline (Section 6.3.2). 
Table 1.  Conditions for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity 
Analyte 
Temporary Withholding 
Permanent Discontinuation 
Total bilirubin 
> 3x ULN at any time 
> 2x ULN 
 
 
OR 
INR 
-- 
> 1.5 (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 8x ULN at any time 
 
> 5x ULN but < 8x ULN for ≥ 2 
weeks 
 
> 5x ULN but < 8x ULN and unable 
to adhere to enhanced monitoring 
schedule 
 
> 3x ULN with clinical signs or 
symptoms that are consistent with 
hepatitis (such as right upper 
quadrant pain/tenderness, fever, 
nausea, vomiting, jaundice) 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or total bilirubin 
values 
 
> 3x ULN (when baseline was 
< ULN) 
 
OR 
ALP 
> 8x ULN at any time 
-- 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
INR=international normalized ratio; ULN=upper limit of normal. 
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Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 28 of 73 
6.3.2 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then evolocumab/placebo should be 
permanently discontinued. Subjects who clearly meet the criteria for permanent 
discontinuation (as described in Section 6.3.1) should never be rechallenged. 
6.4 
Other Protocol-required Therapies 
Other protocol-required therapies are stable HIV therapy and stable dose of 
lipid-lowering therapy, if applicable, as defined in subject eligibility (Section 4.1). 
Other protocol-required therapies are not provided or reimbursed by Amgen (except if 
required by local regulation). The investigator will be responsible for obtaining 
commercially available supplies of these protocol-required therapies.  
Additional details regarding these protocol-required therapies are provided in the IPIM. 
6.5 
Concomitant Therapy 
Throughout the study, the investigator may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.8. 
6.6 
Medical Devices 
The AMD or prefilled AI/pen used in this study will be provided by Amgen. Additional 
details for the AMD or AI/pen are 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 
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), device(s), or combination 
products 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 
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Product:  Evolocumab 
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Date:  30 January 2017 
Page 29 of 73 
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 AI/pen); 
• 
missing labels, illegible labels, incorrect labels, and/or suspect labels;  
• 
change in IP appearance (eg, color change or visible presence of foreign material); 
• 
unexpected quantity or volume (eg, 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 complaint.  
Additional details regarding the identification and reporting of any product complaint(s) 
associated with an IP 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 
The following treatments are not permitted during the blinded portion of the study: 
• 
any lipid-lowering therapies not taken at the time of screening and enrollment 
(unless required in response to HIV worsening; see Section 9.1.2.1). 
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 30 of 73 
Please contact the Amgen medical monitor or designee if any of these therapies should 
be initiated during the blinded portion of the study. Note that a change in lipid-lowering 
therapy does not necessarily require ending IP administration. 
During the open-label period, adjustments to background lipid-lowering therapy due to 
results of the unblinded lipid panel (ie, asymptomatic LDL-C) will not be allowed. 
Changes to background lipid-lowering therapy for other reasons such as adverse events 
are allowed during the open-label period.  
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, HIV or 
hepatitis C virus (HCV) PI, antidepressant nefazodone and grapefruit juice in 
large quantities (> 1 quart daily [approximately 1 Liter]) should not be used during 
the study. See Table 2 for additional details. 
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 31 of 73 
Table 2.  Statin Interactions 
Statin 
Failure to Adjust Dosage for 
Concomitant Medications 
Use with Contraindicated Medication 
(Risk X) 
Atorvastatin 
Atorvastatin > 40 mg while taking 
boceprevir, simeprevir, or nelfinavir; 
atorvastatin > 20 mg while taking 
clarithromycin, telithromycin, 
itraconazole, fosamprenavir, or 
ritonavir-boosted darunavir, 
fosamprenavir, or saquinavir  
Concomitant use of atorvastatin with 
gemfibrozil, posaconazole, telaprevir, 
or tipranavir 
Fluvastatin 
Fluvastatin > 20 mg BID while taking 
fluconazole 
Concomitant use of fluvastatin with 
gemfibrozil 
Lovastatin 
Lovastatin > 20 mg daily while taking 
diltiazem or verapamil; lovastatin 
> 40 mg while taking amiodarone or 
niaspan 
Concomitant use of lovastatin with 
clarithromycin, erythromycin, 
telithromycin, itraconazole, 
nefazodone, posaconazole, 
voriconazole, HIV protease inhibitors, 
HCV protease inhibitors (bocepravir, 
telaprevir), cobicistat, or gemfibrozil 
Pitavastatin 
Pitavastatin > 1 mg daily with 
erythromycin or > 2 mg daily with 
rifampin 
Concomitant use of pitavastatin with 
gemfibrozil 
Pravastatin 
Pravastatin > 40 mg while taking 
clarithromycin 
Concomitant use of pravastatin with 
gemfibrozil 
Statin 
Failure to Adjust Dosage for 
Concomitant Medications 
Use with Contraindicated Medication 
(Risk X) 
Rosuvastatin 
Rosuvastatin > 10 mg while taking 
ritonavir-boosted atazanavir or 
lopinavir 
Concomitant use of rosuvastatin with 
gemfibrozil 
Simvastatin 
Simvastatin > 20 mg with amiodarone 
or amlodipine; simvastatin > 10 mg 
with diltiazem or verapamil; 
simvastatin > 40 mg with niaspan 
Concomitant use of simvastatin with 
clarithromycin, erythromycin, 
telithromycin, itraconazole, 
nefazodone, posaconazole, 
voriconazole, HIV protease inhibitors, 
HCV protease inhibitors (bocepravir, 
telapravir), cobicistat, or gemfibrozil 
BID=twice daily; HCV=hepatitis C virus; HIV=human immunodeficiency virus. 
7. 
STUDY PROCEDURES 
Screening assessments and study procedures outlined in this section and in Table 3 can 
only be performed after obtaining informed consent. 
All on-study visits and dosing should be scheduled from day 1 (randomization and first 
IP administration). For example, the week 4 visit 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 3. 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 
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Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 32 of 73 
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. 
7.1 
Schedule of Assessments  
Screening assessments and study procedures are outlined in this section and in Table 3 
(Schedule of Assessments). 
 
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Product:  Evolocumab 
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Date:  30 January 2017 
Page 33 of 73 
Table 3.  Schedule of Assessments 
 
 
Double-Blind Period 
Open-Label 
Period 
 
Study Day / Timepoint 
Screening 
4 (± 1) weeks 
Day 1 
Week 12 
± 3 days 
Week 20 
± 3 days 
Week 24 
± 3 daysa 
Week 36 
± 7 days 
EOS 
Week 52 
± 7 days 
General Procedures 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Vital signs  
X 
X 
X 
X 
X 
X 
X 
Safety data reportingb 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
 
 
X 
 
X 
Body weight, waist circumference 
X 
 
 
 
X 
 
X 
Body height 
X 
 
 
 
 
 
 
Screening placebo injectionc 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Central Laboratory 
 
 
 
 
 
 
 
Fasting lipids, ApoA1, ApoB, Lp(a) 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
HIV viral load and CD4 
X 
X 
X 
 
X 
X 
X 
Hepatitis C antibodies 
X 
 
 
 
 
 
 
Hepatitis C viral loadd 
X 
X 
X 
 
X 
X 
X 
Chemistry 
X 
X 
X 
 
X 
X 
X 
Page 1 of 2 
Footnotes defined on next page of this table 
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 34 of 73 
Table 3.  Schedule of Assessments 
 
 
Double-Blind Period 
Open-Label Period 
Study Day / Timepoint 
Screening 
4 (± 1) weeks 
Day 1 
Week 12 
± 3 days 
Week 20 
± 3 days 
Week 24 
± 3 daysa 
Week 36 
± 7 days 
EOS 
Week 52 
± 7 days 
Urinalysis 
X 
X 
X 
 
X 
X 
X 
Hematology 
X 
X 
X 
 
X 
X 
X 
Serum pregnancy,e urine pregnancy,e 
FSH/LH/estradiolf 
X 
X 
X 
X 
X 
X 
X 
HbA1c 
X 
 
X 
 
X 
X 
X 
Biomarkers (blood) 
 
X 
X 
 
X 
 
X 
Anti-evolocumab antibodies 
 
X 
X 
 
X 
X 
X 
Investigational Product 
 
 
 
 
 
 
 
IP dispensing 
 
X 
X 
 
X 
X 
 
IP reconciliation 
 
 
X 
X 
X 
X 
X 
IP administration (every 4 weeks)g 
 
X 
X 
X 
X 
X 
 
Page 2 of 2 
ApoA1=apolipoprotein A-I; ApoB=apolipoprotein B; CD4=cluster of differentiation 4; EOS=end of study; FSH=follicle-stimulating hormone; HbA1c=hemoglobin A1c; 
HIV=human immunodeficiency virus; IP=investigational product; LH=luteinizing hormone; Lp(a)=lipoprotein(a);
 
a At week 24, final double-blind period assessments will be conducted, and the first dose of open-label study drug will be administered. 
b Including review for adverse events/serious adverse events/disease-related events/adverse device effects. Adverse events possibly related to study procedures, 
adverse device effects and serious adverse events are reported from signing of the informed consent form. All other adverse events are reported from the 
time of randomization.   
c Placebo injection is to occur following determination of eligibility for all other screening parameters. 
d Hepatitis C viral load will be completed only in hepatitis C-positive subjects. 
e Pregnancy testing in females of childbearing potential. Serum pregnancy testing at screening. Urine pregnancy testing at day 1 and weeks 12, 20, 24, 36, and 
prior to IP administration and at EOS. Additional on-treatment pregnancy testing may be performed at the investigator’s discretion or as required by local laws and 
regulations. 
f FSH/LH/estradiol only at screening for menopausal women. 
g During the double-blind period, in addition to the in-clinic administration at day 1 and week 20, QM non-clinic IP is expected to be administered 4 times prior to the 
week 20 visit (ie, at weeks 4, 8,12, and 16). During the open-label period, in addition to the in-clinic administration at week 24, QM non-clinic evolocumab is expected 
to be administered 6 times prior to the week 52 visit at weeks 28, 32, 36, 40, 44, and 48. 
 
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Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 35 of 73 
7.2 
General Study Procedures  
The procedures performed at each study visit are outlined Table 3. Details regarding 
each type of procedure are provided in subsequent subsections.  
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 to be 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 sampling 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. 
Refer to the applicable supplemental central laboratory, IVRS/IWRS, IPIM, and study 
manuals for detailed collection and handling procedures. 
7.2.1 
Screening Enrollment and Randomization 
Subjects who are considered for entry into the study and have the risk and benefits of 
participating in the study explained will enter screening by signing and dating the ICF for 
this study. Informed consent must be obtained before completing any other screening 
procedure. 
After the subject signs the written informed consent, the site will screen the subject in 
order to assess eligibility for participation. Screening should be completed and the 
subject randomized or screen failed after 4 weeks (± 1 week) of signing the informed 
consent. 
Subjects will undergo SC placebo injection with device anticipated to be used during 
study (AMD or AI/pen) during screening.  
Subjects who tolerate the screening placebo injection, complete all screening 
procedures successfully, and meet all eligibility criteria at the end of screening will be 
randomized via IVRS/IWRS and will return to the study site for day 1 procedures while 
continuing their background HIV and lipid-lowering (if applicable) treatment. Subjects 
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Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 36 of 73 
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. 
7.2.2 
Rescreening 
Subjects who do not meet inclusion criterion 107 are considered screen failures and 
cannot be rescreened for this study. Suitable subjects who are ineligible at the initial 
screening for other reasons and have not been randomized can be reconsented and 
rescreened at a later time, unless they withdraw from screening, provided the study is 
still enrolling subjects. 
For subjects who are rescreened, data from the first screening period will not be used for 
the analysis. Rescreened subjects who are reconsented will repeat all screening 
procedures. Rescreened subjects will maintain the originally assigned subject 
identification number. 
7.2.3 
Double-blind Treatment Period 
Visits will occur per the Schedule of Assessments (Table 3) during the double-blind 
period from day 1 (week 1, baseline) through week 24. 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. 
If a subject withdraws from the study early, all efforts should be made to complete and 
report the observations as thoroughly as possible up to the date of withdrawal. If 
possible, the procedures of the week 24 visit should be completed at the time of 
withdrawal. 
7.2.4 
Open-label Period 
Subjects who receive a dose of IP at week 20 will continue in an open-label period. They 
will receive their first dose of open-label IP at the week 24 visit. Visits will then 
occur per the Schedule of Assessments (Table 3) at weeks 36 and 52. Visits during the 
open-label period must be completed within ± 7 days of the target visit date.  
7.2.5 
End of Study / Safety Follow-up 
At week 52 or 30 days after the last administration of IP, whichever is later, a safety 
follow-up is scheduled to occur. This safety follow-up can be an in-person visit to the 
study center or another contact with the subject. If the end-of-study visit is < 30 days 
after the last dose of IP, the subject will be contacted (eg, by phone) at 
30 (± 7) days after last IP for safety follow-up. 
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Product:  Evolocumab 
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Date:  30 January 2017 
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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. 
7.3.2 
Demographics 
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 history covering the period 
within 120 days prior to randomization. Additionally, a targeted cardiovascular and HIV 
history not limited to 120 days prior to randomization will be collected. Targeted 
cardiovascular history including, but not limited to, cardiovascular risk factors, history of 
CVD, revascularization procedures, family history, and potential familial 
hypercholesterolemia diagnostic criteria will be collected. Targeted HIV history including, 
but not limited to, duration, HIV complications, and occurrence of opportunistic infections 
or AIDS-defining illness from diagnosis will be collected. 
7.3.4 
Vital Signs 
The following measurements must be performed:  blood pressure and heart rate. The 
subject must be in a seated position in a rested and calm state for at least 5 minutes 
before blood pressure assessments are conducted. The appropriate size cuff should be 
used. The same arm and same position should be used throughout the study and 
documented on the vital sign CRF. 
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 
Safety Data Reporting 
Adverse events, serious adverse events, disease-related events, and adverse device 
effects observed by the investigator or reported by the subject will be collected at all 
study visits from randomization through EOS as detailed in Section 9. Adverse events 
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Product:  Evolocumab 
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Date:  30 January 2017 
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possibly related to study procedures, adverse device effects and serious adverse 
events are collected during screening. 
7.3.6 
Prior Therapies, Substance Use History, and Concomitant 
Medications 
Prior general and targeted therapies (eg, statins and HIV therapy) taken within 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. 
Concomitant therapies are to be collected from the signing of the informed consent 
through the EOS, 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. 
7.3.7 
Physical Examination 
A physical examination will be conducted as per standard of care. Physical examination 
findings should be recorded on the appropriate CRF (eg, height, weight, BMI, etc.) 
7.3.8 
Body Weight, Waist Circumference, and Height 
Body weight in kilograms and height in centimeters 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. 
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Product:  Evolocumab 
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Date:  30 January 2017 
Page 39 of 73 
7.4 
Laboratory Assessments 
All laboratory samples will be sent to the central laboratory, except for samples for 
urine pregnancy tests, which will be conducted by the local 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, urinalysis, hematology, and other labs to be 
conducted on blood and urine samples are shown in Table 4. Although not specifically 
listed, additional components, abnormal, and/or atypical cells will also be reported if 
present. 
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Product:  Evolocumab 
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Date:  30 January 2017 
Page 40 of 73 
Table 4.  Analyte Listing 
Chemistry  
Urinalysis 
Hematology 
Other Labs 
Sodium 
Potassium 
Chloride 
Bicarbonate  
Total protein 
Albumin 
Calcium 
Magnesium 
Phosphorus 
Fasting glucose 
Fasting insulin 
BUN or Urea 
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin 
CK 
ALP 
LDH 
AST 
ALT 
eGFR 
Specific gravity 
pH 
Blood 
Protein 
Glucose 
Bilirubin 
WBC 
RBC 
Epithelial cells 
Bacteria 
Casts 
Crystals 
Urine pregnancy 
test (females of 
childbearing 
potential) 
CD4 
Hemoglobin 
Hematocrit 
RBC 
RDW 
MCV  
MCH 
MCHC 
WBC 
Platelets 
Differential 
• Neutrophils 
• Bands 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes 
 
Fasting lipids 
• Total cholesterol 
• HDL-C 
• LDL-C 
• Triglycerides 
• VLDL-C 
• Non-HDL-C 
ApoA1 
ApoB 
Lp(a) 
HbA1c 
Serum pregnancy test 
(females of childbearing 
potential) 
FSH/LH)/ Estradiol (if needed 
per exclusion 210) 
HCV antibody 
HCV viral load 
HIV viral load 
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 postscreening 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, Lp(a), 
and 
• 
Blinded to the site staff:  insulin,
 
. Analyses 
of 
 may not be completed until EOS so 
results are not expected to be available during the trial. 
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Product:  Evolocumab 
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Date:  30 January 2017 
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In addition, investigators should not perform non-protocol testing of these analytes 
during a subject’s study participation and until at least 12 weeks after the first dose of 
unblinded evolocumab at week 24 (ie, week 36 visit).  
The following central laboratory results during open-label period will be reported to the 
sites for the week 36 through week 52 visits:  lipid panel, ApoA1, ApoB, Lp(a).  
7.4.2 
Pregnancy Tests 
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, prior to administering the first dose of 
evolocumab/placebo. The central laboratory will provide the screening pregnancy tests. 
Urine pregnancy tests will be performed on day 1 and on weeks 12, 20, 24, and 36 
before IP administration and at EOS. 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required by local laws and regulations. 
7.5 
Antibody Testing Procedures 
Blood sample(s) for antibody testing are to be collected at the time points shown in 
Table 3 for the measurement of anti-evolocumab binding antibodies. Samples testing 
positive for binding antibodies will also be tested for neutralizing antibodies and may be 
further characterized for quantity/titer, isotype, affinity and presence of immune 
complexes. Additional blood samples may be obtained to rule out anti-evolocumab 
antibodies during the study. 
7.6 
Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
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. 
Blood samples are to be collected for biomarker development at day 1, week 12, 
week 24, and week 52. Refer to the laboratory manual for detailed collection and 
handling procedures for all biomarker development samples. 
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Product:  Evolocumab 
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Date:  30 January 2017 
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Biomarkers related to, but not limited to, 
 
 
 
 may be 
studied. 
7.7 
Pharmacogenetic Studies 
No additional blood will be collected for the pharmacogenetic analyses. If the subject 
consents to the optional pharmacogenetic portion of this study, deoxyribonucleic acid 
(DNA) analyses may be performed. These optional pharmacogenetic analyses focus on 
inherited genetic variations to evaluate their possible correlation to the disease and/or 
responsiveness to the therapies used in this study. The goals of the optional studies 
include the use of genetic markers to help in the investigation of cardiovascular disease, 
hyperlipidemia and other metabolic disorders and/or to identify subjects who may have 
positive or negative response to evolocumab. 
7.8 
Sample Storage and Destruction  
Any blood sample collected according to the Schedule of Assessments (Table 3) 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 
underlying inflammatory conditions, the dose response and/or prediction of response to 
evolocumab, and characterize aspects of the molecule (eg, mechanism of action/target, 
metabolites). Results from this analysis are to be documented and maintained, but are 
not necessarily reported as part of this study. Samples can be retained for up to 
20 years.  
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Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of pharmacogenetic, 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. 
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 3) and collection of data, including endpoints and adverse 
events. The investigator must document the change to the Schedule of Assessments 
(Table 3) and the level of follow-up that is agreed to by the subject (eg, in person, by 
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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, publicly available data 
can be included after withdrawal of consent. The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.  
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from IP and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
prior to study completion.  
Subjects may be eligible for continued treatment with Amgen 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: 
• 
subject request  
• 
subject request to end IP administration 
• 
safety concern (eg, due to an adverse event, pregnancy in a female subject)  
• 
death 
• 
lost to follow-up  
• 
administrative decision by Amgen (other than subject request, safety concern, or lost 
to follow-up) 
• 
decision by the primary investigator/physician 
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
• 
decision by Amgen  
• 
withdrawal of consent from study 
• 
death 
• 
lost to follow-up 
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9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
Disease-related Events 
Disease-related events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease. In this study, subjects are at risk for 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, MI, 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 adverse 
events or serious adverse events:  
• 
An event which is part of the normal course of disease under study (eg, disease 
progression in oncology or hospitalization due to disease progression) is to be 
reported as a disease-related event.  
• 
Death due to the disease under study is to be recorded on the Event CRF. 
A disease-related event that would qualify as an adverse event or serious adverse 
event is an event based on the underlying disease that is worse than expected as 
assessed by the investigator for the subject’s condition or an event for which the 
investigator believes there is a causal relationship between the investigational 
product(s)/study treatment/protocol required therapies and disease worsening. 
This must be reported as an adverse event or serious adverse event. 
9.1.2 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject. The event does not necessarily have a causal relationship with study treatment. 
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.  
The definition of adverse events includes worsening of a pre-existing medical condition. 
Worsening indicates that the pre-existing medical condition or underlying disease 
(eg, diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
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 
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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.  
The criteria for grade 4 in the Common Terminology Criteria for Adverse 
Events (CTCAE) grading scale differs from the regulatory criteria for serious adverse 
events. It is left to the Investigator’s judgment to report these grade 4 abnormalities as 
serious adverse events. 
9.1.2.1 
Worsening of HIV Disease 
HIV worsening will be captured as an adverse event. Because evolocumab is not 
expected to have any interaction with antiretroviral therapy or viral load or 
consequences of HIV infection, no specific actions with respect to study 
participation (including investigational product) are expected of the investigator. 
Should a subject’s viral load change or HIV infection worsen, the investigator is 
expected to manage HIV infection or any other concomitant illnesses per his or 
her clinical judgment. Background lipid-lowering therapy is expected to be stable. 
However, in the case of HIV worsening, because of potential drug–drug interaction 
between statins and antiretroviral therapy, changing background lipid-lowering 
therapy is left to the judgment of the investigator. 
9.1.3 
Adverse Device Effects 
An adverse device effect is any adverse event related to the use of a medical device. 
Adverse device effects include adverse events resulting from insufficient or inadequate 
instructions for use, adverse events resulting from any malfunction of the device, or 
adverse events resulting from use error or from intentional misuse of the device. 
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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 
provided 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 is to be reported as a serious adverse event if: 
• 
the subject’s pre-existing condition becomes worse than what the investigator would 
consider typical for a patient with the same underlying condition, or 
• 
 if the investigator believes a causal relationship exists between the 
IMP/protocol-required therapies and the event,  
• 
and the event meets at least 1 of the serious criteria above. 
An adverse event would meet the criterion of “requires hospitalization,” if the event 
necessitated an admission to a health care facility (eg, overnight stay).  
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event.” Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, DILI (see Appendix A for 
drug-induced liver injury reporting criteria), or events that necessitate an emergency 
room visit, outpatient surgery, or urgent intervention. 
9.2 
Safety Event Reporting Procedures  
9.2.1 
Reporting Procedures for Disease-related Events 
The investigator is responsible for ensuring that all disease-related events observed by 
the investigator or reported by the subject that occur after randomization through 
EOS/safety follow-up visit, or 30 days after the last administration of IP, whichever is 
later, are reported on the Event CRF as disease related.  
Disease-related events assessed by the investigator to be more severe than 
expected and/or related to the investigational medicinal product(s)/study 
treatment/protocol-required therapies and determined to be serious must be 
recorded on the event CRF as serious adverse events. Additionally, the 
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investigator is required to report a fatal disease-related event on the Event CRF as 
a disease-related event. 
9.2.2 
Adverse Events 
9.2.2.1 
Reporting Procedures for Adverse Events That Do Not Meet Serious 
Criteria 
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, or 30 days after the last administration of IP, whichever is 
later, are reported using the event CRF. Only adverse events possibly related to study 
procedures are to be collected during screening. 
The investigator must assign the following adverse event attributes: 
• 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
• 
Dates of onset and resolution (if resolved), 
• 
Severity, 
• 
Assessment of relatedness to IP, the AMD (or AI/pen), 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, the 
AMD (or AI/pen), or other protocol-required therapies. This relationship is indicated by a 
“yes” or “no” response to the question:  “Is there a reasonable possibility that the event 
may have been caused by the IP, the AMD (or AI/pen), or other protocol-required 
therapies?” Relatedness means that there are facts or reasons to support a 
relationship between investigational product and the event. 
The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity (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 (eg, administration of investigational 
product, protocol-required therapies, device[s]), and/or procedure?” Relatedness 
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means that there are facts or reasons to support a relationship between 
investigational product and the event. 
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 informed consent 
through EOS/safety follow-up visit, or 30 days after the last administration of IP, 
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.  
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 
summaries, medical records, or extracts from the medical record. Information provided 
about the serious adverse event must be consistent with that recorded on the Event 
CRF. 
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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. 
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 
studies where the first notification of a Serious Adverse Event is reported to Amgen via 
the Serious Adverse Event Contingency Report Form, the data must be entered into the 
EDC system when the system is again available. 
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. 
9.2.2.3 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after EOS. However, these serious adverse 
events can be reported to Amgen. In some countries (eg, European Union [EU] member 
states), investigators are required to report serious adverse events that they become 
aware of after 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. 
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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 HIV complications are anticipated to possibly occur in the 
enrolled subject population.  
The Amgen Safety Analysis team and medical team will review accumulating events on 
a regular basis. 
9.3 
Pregnancy and Lactation Reporting 
If a pregnancy occurs in a female subject, or a male subject fathers a child, while the 
subject is taking evolocumab/placebo, report the pregnancy to Amgen Global Patient 
Safety as specified below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur after the last dose of protocol-required therapies 
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 female subject becomes pregnant during the study, the investigator should 
attempt to obtain information regarding the birth outcome and health of the infant. 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly), the 
investigator will report the event as a serious adverse event. 
If a lactation case occurs while the female subject is taking protocol-required therapies 
report the lactation case to Amgen Global Patient Safety as specified below.  
In addition to reporting a lactation case during the study, investigators should report 
lactation cases that occur after the last dose of protocol-required therapies through 
15 weeks after the end of treatment with evolocumab/placebo. 
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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. 
If a male subject's female partner becomes pregnant, the investigator should 
discuss obtaining information regarding the birth outcome and health of the infant 
from the pregnant partner. 
10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoint 
• 
Percent change from baseline in LDL-C at week 24 
10.1.1.2 
Secondary Endpoints 
For week 24 the following secondary endpoints will be characterized: 
• 
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 
Safety Endpoints 
• 
Subject incidence of treatment emergent adverse events 
• 
Safety laboratory values and vital signs at each scheduled assessment 
• 
Incidence of anti-evolocumab antibody (binding and neutralizing) formation 
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10.1.1.4 
Exploratory Endpoints 
10.1.2 
Analysis Sets 
10.1.2.1 
Double-blind Treatment Period 
The full analysis set (FAS) includes all randomized subjects who receive at least one 
dose of IP in the double-blind treatment period. 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. 
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10.1.2.2 
Open-label Period 
The long-term analysis set (LAS) will include all subjects who received at least 1 dose of 
open-label IP in the open-label period. This analysis set will be used in all analyses for 
the open-label period. 
10.1.3 
Covariates and Subgroups 
 Baseline covariates include, but are not 
limited to: 
• 
Stratification factors in Double-blind Treatment Period: 
− 
Statin use at baseline (yes/no) 
− 
Hepatitis C status (yes/no) 
• 
Age:  <65 year, ≥ 65 years 
• 
Sex 
• 
Race 
• 
Study baseline LDL-C:  <median/≥median 
• 
Family history of premature coronary heart disease (yes/no) 
• 
 
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 450 total subjects. 
The primary analysis will require the 2-sided tests of the primary endpoint 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 primary endpoint. From the integrated efficacy analysis of completed 
phase 3 studies, 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% and -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%.  
In addition, 300 subjects in evolocumab 420 mg QM group will provide approximately 
95% probability of detecting adverse events that occur at a rate of 1%. 
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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 
10.4.1 
Primary Analysis 
To evaluate efficacy and safety of 24 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 related to the primary analyses of the study will be cleaned, processed and a 
snapshot will be taken; the study will also be unblinded.  
10.4.2 
Final Analysis  
The final analysis will be conducted when all subjects in the open-label period have 
either completed all the scheduled study visits in the open-label period or have early 
terminated from the study. At that time, the database will be cleaned, processed and a 
snapshot will be taken. The final analysis will be done to evaluate long-term safety and 
efficacy of evolocumab 420 mg QM. 
10.5 
Planned Methods of Analysis  
10.5.1 
General Considerations 
Based on the snapshot for the primary analysis, efficacy and safety analyses will be 
performed on FAS for the double-blind treatment period unless otherwise specified, and 
data will be summarized by randomized treatment group. Based on the snapshot for the 
final analysis, long-term efficacy and safety analyses will be performed on LAS and the 
analyses will be descriptive. 
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, standard deviation or standard error, minimum, 
and maximum. For categorical variables, the frequency and percentage will be given. 
Methods of handling missing data for efficacy endpoints will be described below. Missing 
data will not be imputed for safety endpoints. 
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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. 
Figure 1.  Multiplicity Adjustment Methods 
 
The following method will be used to preserve the family-wise error rate for the primary 
and secondary endpoints: 
1. If the treatment effect from the primary analysis of the primary endpoint is 
significant at a significance level of 0.05, statistical testing of the tier 1 secondary 
efficacy endpoints will follow the Hochberg procedure at a significance level of 
0.005 (Hochberg, 1988) 
2. If all tier 1 secondary efficacy endpoints are significant, the tier 2 secondary 
efficacy endpoints will be tested using the Hochberg procedure at a significance 
level of 0.05.  
3. If not all tier 1 secondary efficacy endpoints are significant, the tier 2 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. 
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10.5.2 
Primary Efficacy Endpoint 
To assess the primary endpoint of the mean percent change from baseline in LDL-C at 
week 24, a repeated measures linear effects model will be used on the FAS to compare 
the efficacy of evolocumab with placebo. The repeated measures model will include 
terms for treatment group, stratification factors, scheduled visit and the interaction of 
treatment with scheduled visit. Missing values will not be imputed 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. 
Subgroup Analysis 
If applicable, subgroup analyses on the primary endpoint will be conducted using the 
stratification factors or baseline covariates. 
10.5.3 
Secondary Efficacy Endpoints 
The statistical model and testing of the tier 1 secondary efficacy endpoints will be similar 
to the primary analysis of primary endpoints. The secondary endpoint of LDL-C 
response (50% reduction of LDL-C from baseline and achievement of target 
LDL-C < 70 mg/d Las defined in secondary endpoint section) will be analyzed using the 
Cochran-Mantel Haenszel test adjusted by the stratification factors. 
Analysis of the tier 2 secondary efficacy endpoints will use the same analysis model as 
the tier 1 endpoints. 
Multiplicity adjustment procedures are defined in Section 10.5.1.1. 
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 
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significant treatment-emergent adverse events will also be provided. Subject-level data 
may be provided instead of tables if the subject incidence is low. 
Subject incidence of all disease-related events and fatal disease-related events will be 
tabulated by system organ class and preferred term. 
10.5.5 
Exploratory Endpoints 
 
 
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 Clinical Study Manager to the investigator. The written 
informed consent document is to be prepared in the language(s) of the potential subject 
population. Amgen will require a copy of the site’s IRB/IEC informed consent. 
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 
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ICF to the subject and must allow for questions. Thereafter, both the subject and the 
witness must sign the ICF to attest that informed consent was freely given and 
understood.  
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed ICF, other written subject information, and any 
proposed advertising material must be submitted to the IRB/IEC for written approval. A 
copy of the written approval of the protocol and ICF must be received by Amgen before 
recruitment of subjects into the study and shipment of Amgen 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 renewal 
throughout the duration of the study. Copies of the investigator’s reports and the IRB/IEC 
continuance of approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen.  
• 
Subjects are to be identified by a unique subject identification number.  
• 
Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations.  
• 
On the CRF demographics page, in addition to the unique subject identification 
number, include the age at time of enrollment.  
• 
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 
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are important to the evaluation of the study. The investigator is obligated to inform and 
obtain the consent of the subject to permit such individuals to have access to his/her 
study-related records, including personal information. 
11.4 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of 
multi-center studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
• 
A recognized expert in the therapeutic area 
• 
An Investigator who provided significant contributions to either the design or 
interpretation of the study 
• 
An investigator contributing a high number of eligible subjects 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
If Amgen amends the protocol, agreement from the investigator must be obtained. The 
IRB/IEC must be informed of all amendments and give approval. The investigator must 
send a copy of the approval letter from the IRB/IEC to Amgen. 
Amgen reserves the right to terminate the study at any time. Both Amgen and the 
investigator reserve the right to terminate the investigator’s participation in the study 
according to the study contract. The investigator is to notify the IRB/IEC in writing of the 
study’s completion or early termination and send a copy of the notification to Amgen.  
Subjects may be eligible for continued treatment with Amgen 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. 
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In this study, the IVRS/IWRS system captures the following data points and these are 
considered source data:   
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.  
Elements 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 
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areas, laboratories) and review of study-related records will occur to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 
Data capture for this study is planned to be electronic: 
• 
All source documentation supporting entries into the CRFs must be maintained and 
readily available. 
• 
Updates to CRFs will be automatically documented through the software’s “audit 
trail”. 
• 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen. During this 
review, subject data are checked for consistency, omissions, and any apparent 
discrepancies. In addition, the data are reviewed for adherence to the protocol and 
GCP. To resolve any questions arising from the clinical data management review 
process, data queries are created in the EDC system database for site resolution 
and subsequently closed by the EDC system or by an Amgen reviewer. 
• 
The investigator signs only the Investigator Verification Form for this electronic data 
capture study or the investigator applies an electronic signature in the EDC system if 
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 3), 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.  
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12.5 
Language 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.  
12.6 
Publication Policy 
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 ICF 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. 
Boccara FM, Auclair A, Cohen C, et al. HIV protease inhibitors activate the adipocyte 
renin angiotensin system. Antivir Ther. 2010;15(3):363-375. 
Boccara F, Lang S, Meuleman C, et al. HIV and coronary heart disease:  time for a 
better understanding. J Am Coll Cardiol. 2013;61(5):511-523. 
Calmy A, Gayet-Ageron A, Montecucco F, et al; STACCATO Study Group. HIV 
increases markers of cardiovascular risk: results from a randomized, treatment 
interruption trial. AIDS. 2009;23(8):92-939. 
Capeau J, From lipodystrophy and insulin resistance to metabolic syndrome:  HIV 
infection, treatment and aging. Curr Opin HIV AIDS. 2007;2(4):  247-252. 
Carballo D, Delhumeau C, Carballo S, et al; Swiss HIV Cohort Study and AMIS registry. 
Increased mortality after a first myocardial infarction in human immunodeficiency virus-
infected patients; a nested cohort study. AIDS Res Ther. 2015;22(12):4. 
Caron-Debarle M, Boccara F, Lagathu C, et al. Adipose Tissue as a Target of HIV-1 
Antiretroviral Drugs. Potential Consequences on Metabolic Regulations. Curr Pharm 
Des. 2010. 
Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet. 2000;356(9239):  
1423-1430. 
Carr A, Samaras K, Thorisdottir A, et al. Diagnosis, prediction, and natural course of 
HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes 
mellitus:  a cohort study. Lancet. 1999;353(9170):  2093-2099. 
Chow FC, Regan S, Feske S, et al. Comparison of ischemic stroke incidence in 
HIV-infected and non-HIV-infected patients in a US health care system. J Acquir 
Immune Defic Syndr. 2012;60(4):  351-358. 
Freiberg MS, Chang CC, Kuller LH, et al. HIV infection and the risk of acute myocardial 
infarction. JAMA Intern Med. 2013;173(8):  614-622. 
Grinspoon SK. Metabolic syndrome and cardiovascular disease in patients with human 
immunodeficiency virus. Am J Med. 2005;118(suppl)2:23S-28S. 
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. 
Biometrika. 1988;75:800-802. 
Johns KW, Bennett MT, Bondy GP. Are HIV-positive patients resistant to statin therapy? 
Lipids Health Dis. 2007;6:27. 
Kohli P, Giugliano RP. Low-density lipoprotein lowering in 2013 by nonstatin agents:  the 
discovery and development of promising novel targeted therapies. J Cardiovasc 
Pharmacol Ther. 2013;18(3):199-210. 
Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and 
mortality in patients with HIV infection. PLoS Med. 2008;5(10):e203. 
Neuhaus J, Jacobs Jr DR, Baker JV, et al. Markers of inflammation, coagulation, and 
renal function are elevated in adults with HIV infection. J Infect Dis. 
2010;201(12):1788-1795. 
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Periard D, Telenti A, Sudre P, et al. Atherogenic dyslipidemia in HIV-infected individuals 
treated with protease inhibitors. The Swiss HIV Cohort Study. Circulation. 
1999;100(7):700-705. 
Rasmussen LD, Kronborg G, Larsen CS, et al. Statin therapy and mortality in 
HIV-infected individuals; a Danish nationwide population-based cohort study. PLoS One. 
2013;8(3):e52828. 
Silverberg MJ, Leyden W, Hurley L, et al. Response to newly prescribed lipid-lowering 
therapy in patients with and without HIV infection. Ann Intern Med. 2009;150(5):301-313. 
El-Sadr WM, Lundgren J, Neaton JD, et al. Strategies for Management of Antiretroviral 
Therapy Study. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 
2006;355(22):2283-2296. 
Triant VA., Lee H, Hadigan C. Increased acute myocardial infarction rates and 
cardiovascular risk factors among patients with human immunodeficiency virus disease. 
J Clin Endocrinol Metab. 2007;92(7):2506-2512. 
Wiens BL. A fixed sequence Bonferroni procedure for testing multiple endpoints. 
Pharmaceut Statist. 2003;2:211–215. 
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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. The CTCAE is available at the following link: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
Drug-induced Liver Injury Reporting & Additional Assessments  
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL according to the criteria specified in Section 6.3 require the following: 
• 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
• 
The appropriate 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 6.3.1 and 6.3.2 or 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 24 hours  
• 
In cases of TBL > 2x ULN, retesting of liver tests, and bilirubin (total and direct) is to 
be performed every 24 hours until laboratory abnormalities improve 
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Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the 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 IgG, Anti-nuclear antibody (ANA), Anti 
Smooth Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to 
assess for autoimmune hepatitis 
− 
Obtain serum acetaminophen (paracetamol) levels 
− 
Obtain a more detailed history of:   
• 
Prior and/or concurrent diseases or illness 
• 
Exposure to environmental and/or industrial chemical agents  
• 
Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting, and fever 
• 
Prior and/or concurrent use of alcohol, recreational drugs and special diets 
• 
Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
− 
Obtain viral serologies 
− 
Obtain CPK, haptoglobin, lactate dehydrogenase, 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 eSerious Adverse Event Contingency Report Form 
 
 
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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 
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Amendment 1 
Protocol Title:  A Double Blind, Randomized, Placebo Controlled, Multicenter 
Study to Evaluate Safety, Tolerability, and Efficacy on LDL-C of Evolocumab 
(AMG 145) in Subjects With HIV and With Hyperlipidemia and/or Mixed 
Dyslipidemia 
 
Amgen Protocol Number EVO 20130286 
BEIJERINCK: evolocumaB Effect on LDL-C lowerIng in subJEcts with human 
immunodeficiency viRus and INcreased Cardiovascular risK 
 
Amendment Date: 
30 January 2017 
Rationale: 
Regulatory agencies had expressed concerns that HIV-positive subjects without clinical 
atherosclerotic cardiovascular disease (ASCVD) with LDL ≥ 70 mg/dL but ≤ 100 mg/dL 
would be eligible to this study. The protocol was amended to address the regulators’ 
concerns. Per this amendment, subjects with clinical ASCVD disease with LDL 
≥ 70 mg/dL are eligible for this study. For subjects without clinical ASCVD, LDL must be 
≥ 100 mg/dL. 
Additionally, regulators suggested that a subpopulation of subjects not on statin 
background therapy be included in this study. They also inquired about a prespecified 
size for that subpopulation that would allow for generalizability of the study results. 
Feasibility analysis suggest that such a population is very small in clinical practice. For 
this study, per amendment, we will aim to enroll a subpopulation of subjects needing 
lipid-lowering therapy but not on statin therapy, congruent with the reality of clinical 
practice. We anticipate this subpopulation not on statin therapy to be about 10%. In the 
protocol, a size for this subpopulation is not prespecified, but text was added regarding 
stratification of randomization by statin treatment to include the expected percentage of 
subjects on statin treatment. The European Medicines Agency did not mandate a cap or 
subgroup size.  
This amendment also clarifies the definition of statin intolerance in inclusion 
criterion 106. 
Sections of the protocol concerning temporary withholding and permanent 
discontinuation of investigational product in response to hepatotoxicity, pregnancy and 
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lactation reporting, and disease-related event reporting were updated to reflect current 
Amgen guidelines. The electronic Serious Adverse Event Contingency form 
(Appendix B) was replaced with the current version of the form. 
Further, to address how HIV worsening will be classified, a section was added to clarify 
that HIV worsening will be recorded as an adverse event. In the case of HIV worsening, 
because of potential drug–drug interaction between statins and antiretroviral therapy, 
changing background lipid-lowering therapy is left to the judgment of the investigator. 
In addition to these changes, the pregnancy test schedule was revised to address 
regulatory agency concerns, and details were provided to clarify when serum and urine 
pregnancy tests will be performed.  
Minor administrative and typographical changes were made throughout the protocol.  
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Description of Changes: 
Section:  Global 
Change: Minor corrections throughout (eg, typographical, punctuation, and spelling 
errors; revision of dates); administrative changes on page 1 (added short title of protocol; 
updated name and added contact information for Global Clinical Trial Manager); addition 
of terms to Study Glossary. 
Section:  Synopsis 
Summary of Subject Eligibility Criteria 
Replace: 
The study will enroll adult subjects (≥ 18 years of age) with known HIV infection, on 
maximally tolerated statin therapy (maximally tolerated statin can include no type or 
dose of statin in those diagnosed as statin intolerant) who have received HIV therapy 
that has been stable for ≥ 6 months prior to randomization and that is not expected to 
change during the duration of study participation, and who have fasting LDL-C of 
≥ 70 mg/dL (1.8 mmol/L) or non-HDL-C ≥ 100 mg/dL (2.6 mmol/L) and fasting 
triglycerides ≤ 600 mg/dL (6.8 mmol/L). Subjects who are receiving lipid-lowering 
therapy must have been on a stable dose for ≥ 4 weeks prior to randomization. 
With: 
The study will enroll adult subjects (≥ 18 years of age) with known HIV infection, who 
have received stable HIV therapy for ≥ 6 months prior to randomization and that is 
not expected to change during the duration of study participation. Subjects must 
be on stable doses of lipid-lowering therapy for ≥ 4 weeks prior to randomization 
and not expected to change during the duration of study participation. Subjects 
should be on maximally tolerated dose of statins. For some subjects, “maximally 
tolerated” may indicate no statin at all due to statin intolerance or contraindication 
to statin therapy. A statin-intolerant subject must meet the criteria described in 
Section 4.1.1, criterion 106. Statin intolerance or contraindication must be 
documented. Subjects without known clinical atherosclerotic CVD (ASCVD) must 
have fasting LDL-C of ≥ 100 mg/dL (2.6 mmol/L) or non-HDL-C of ≥ 130 mg/dL 
(3.4 mmol/L) as determined by the central laboratory at screening. Subjects with 
known clinical ASCVD must have fasting LDL-C of ≥ 70 mg/dL (1.8 mmol/L) or 
non-HDL-C of ≥ 100mg/dL (2.6 mmol/L) as determined by the central laboratory. 
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Clinical ASCVD 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. 
Subjects must also have fasting triglycerides ≤ 600 mg/dL (6.8 mmol/L). 
Amgen Investigational Product 
Replace: 
The Amgen investigational product (IP) is the IMP plus the device (AMD or AI/pen). 
With: 
The Amgen investigational product (IP) is the IMP plus the device (AMD [called an 
“on-body infuser prefilled cartridge” in the United States] or AI/pen). 
Double-blind Treatment Period 
Replace: 
The IP is expected to be delivered by AMD but may be achieved by 3 injections with 
AI/pen if AMD not available. 
With: 
The IP may be delivered by AMD or by 3 injections with AI/pen. 
Procedures: 
First paragraph 
Replace: 
Subjects will undergo SC placebo injection with device to be used during study (AMD, or 
AI/Pen) during screening. 
With: 
Subjects will undergo SC placebo injection with the device anticipated to be used 
during study (AMD or AI/pen) during screening. 
Second and third paragraphs 
Replace: 
Laboratory tests will be conducted at day 1 (fasting lipids, apolipoprotein A-1 (ApoA1), 
ApoB, Lp(a), 
 
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 HIV viral load and cluster of differentiation 4 (CD4), hepatitis C virus (HCV) 
viral load, (if applicable) chemistry, urinalysis, hematology HbA1c biomarkers [blood], 
and anti-evolocumab antibodies) and week 12 (fasting lipids, ApoA1, ApoB, Lp(a), 
, HIV viral load and CD4, HCV viral load, [if applicable] 
chemistry, urinalysis, hematology, HbA1c, biomarkers [blood], and anti-evolocumab 
antibodies). Vital signs, safety data reporting, and concomitant therapy will be recorded 
at each visit. At the end of the double-blind treatment period at week 24, laboratory tests 
(fasting lipids, ApoA1, ApoB, Lp(a),
, HIV viral load and 
CD4, HCV viral load, [if applicable] chemistry, urinalysis, hematology, serum pregnancy 
[follicle-stimulating hormone/luteinizing hormone (FSH/LH)/estradiol] [if applicable], 
hemoglobin A1c (HbA1c), biomarkers [blood], and anti-evolocumab antibodies) will be 
conducted and vital signs, safety data reporting, concomitant therapy, physical 
examination, and body weight/waist circumference will be recorded. 
Following the double-blind treatment period, subjects who received a dose of IP at 
week 20 will continue to a 52-week open-label period in which all subjects will be treated 
with QM evolocumab at weeks 28, 32, 36, 40, 44, and 48. Laboratory tests will be 
conducted at week 36 (fasting lipids, ApoA1, ApoB, Lp(a), 
 
, HIV viral load and CD4, HCV viral load [if applicable] chemistry, urinalysis, 
hematology, HbA1c, and anti-evolocumab antibodies) and week 52 (fasting lipids, 
ApoA1, ApoB, Lp(a), 
, HIV viral load and CD4, HCV viral 
load, (if applicable) chemistry, urinalysis, hematology, serum pregnancy 
[FSH/LH/estradiol] [if applicable], HbA1c, biomarkers [blood], and anti-evolocumab 
antibodies). Vital signs, safety data reporting, and concomitant therapy will be recorded 
at week 36. At end of study week 52, vital signs, safety data reporting, concomitant 
therapy, physical examination, body weight, and waist circumference will be recorded. 
With: 
Laboratory tests will be conducted at day 1 and week 12. Vital signs, safety data 
reporting, urine pregnancy testing (as applicable), and concomitant therapy will be 
recorded at each visit. At the end of the double-blind treatment period at week 24, 
laboratory tests will be conducted, and vital signs, safety data reporting, urine 
pregnancy testing (as applicable) concomitant therapy, physical examination, and 
body weight/waist circumference will be recorded. 
Following the double-blind treatment period, subjects who received a dose of IP at 
week 20 will continue to a 24-week open-label period in which all subjects will be treated 
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 6 of 20 
with QM evolocumab at weeks 24, 28, 32, 36, 40, 44, and 48. Laboratory tests will be 
conducted at week 36 and week 52. Vital signs, safety data reporting, urine pregnancy 
testing (as applicable), and concomitant therapy will be recorded at week 36. At end of 
study week 52, vital signs, safety data reporting, urine pregnancy testing (as 
applicable), concomitant therapy, physical examination, body weight, and waist 
circumference will be recorded. 
Section: 2.3, Rationale 
Replace: 
It is anticipated that evolocumab may be used in HIV-infected individuals who cannot 
achieve optimal LDL-C despite the use of maximally tolerated statin therapy or who are 
intolerant to statin. 
With: 
It is anticipated that evolocumab may be used in HIV-infected individuals who cannot 
achieve optimal LDL-C despite the use of maximally tolerated statin therapy or who are 
intolerant to statin or for whom statin is contraindicated. 
Section:  3.1, Study Design 
Replace: 
Randomization will be stratified by entry statin treatment (yes/no) and hepatitis C status 
(yes/no). 
The double-blind treatment period will be 24 weeks, after which subjects who received a 
dose of investigational product (IP) at week 20 will continue in an open-label period 
during which all subjects will be treated with QM evolocumab. 
With: 
Randomization will be stratified by entry statin treatment (yes/no) and by hepatitis C 
status (yes/no). The size of the subgroup not on statin therapy is expected to be 
approximately 10% and no more than 20% of the subjects. This enrollment 
projection is expected to be reflective of clinical practice. 
The double-blind period will be 24 weeks, after which subjects who received a dose of 
investigational product (IP) at week 20 will continue in an open-label period during which 
all subjects will be treated with QM evolocumab. 
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 7 of 20 
Last paragraph 
Replace: 
SC evolocumab and placebo will be administered QM at the study site or appropriate 
non-investigator site settings (eg, at the subject’s home) by automated mini-doser (AMD) 
or by spring-based prefilled autoinjector/pen (AI/Pen) if AMD is not available. 
With: 
SC evolocumab and placebo will be administered QM at the study site or appropriate 
non-investigator site settings (eg, at the subject’s home) by automated mini-doser (AMD; 
referred to in the United States as an “on-body infuser prefilled cartridge”) or by 
spring-based prefilled autoinjector/pen (AI/pen). 
Section:  3.2 Number of Sites 
Replace: 
Approximately 70 sites globally will participate in this study. 
With: 
Approximately 75 sites globally will participate in this study. 
Section:  4.1.1 Inclusion Criteria 
Replace: 
106 
Subject on stable dose of maximally tolerated statin therapy for ≥ 4 weeks prior 
to randomization. For subjects whose maximally tolerated dose of statin is no 
type or dose (ie, determined to be statin intolerant by primary investigator), 
background lipid-lowering therapy is not required 
With: 
101 
106 
Subject on stable lipid-lowering therapy for ≥ 4 weeks prior to 
randomization and not expected to change during the duration of study 
participation. Subjects should be on maximally tolerated dose of statins. For 
some subjects, “maximally tolerated” may indicate no statin at all due to 
statin intolerance or contraindication to statin therapy. Statin intolerance or 
contraindication must be documented. A subject with statin intolerance 
must be evidenced by the following: 
a. Must have tried at least 2 statins with failure to at least 1 of the statins 
at an average daily dose at or below the following doses due to 
intolerable myopathy (ie, myalgia [muscle pain, ache, or weakness 
without creatine kinase elevation]), myositis (muscle symptoms with 
increased creatine kinase levels), or rhabdomyolysis (muscle 
symptoms with marked creatine elevation, as defined under “b”):  
CONFIDENTIAL 
 
 


Product:  Evolocumab
Protocol Number:  20130286
Date:  30 January 2017
Page 8 of 20
CONFIDENTIAL

atorvastatin: 10 mg 

simvastatin: 10 mg 

pravastatin: 40 mg 

rosuvastatin: 5 mg 

lovastatin: 20 mg 

fluvastatin: 40 mg

pitavastatin: 2 mg
AND
b. Symptoms resolved or improved when statin dose was decreased or 
discontinued 
For subjects that developed rhabdomyolysis, defined as creatine kinase > 10 × 
upper limit of normal (ULN), failure of only 1 statin at any dose is acceptable. 
Replace:
107
Fasting LDL-C of ≥70 mg/dL (1.8 mmol/L) or non-HDL-C ≥100 mg/dL 
(2.6 mmol/L) as determined by central laboratory during screening
With:
107
Subject without known clinical atherosclerotic CVD (ASCVD): fasting 
LDL-C of ≥100 mg/dL (2.6 mmol/L) or non-HDL-C of ≥130 mg/dL 
(3.4 mmol/L) as determined by the central laboratory at screening. Subject 
with known clinical ASCVD: fasting LDL-C of ≥70 mg/dL (1.8 mmol/L) or 
non-HDL-C of ≥100 mg/dL (2.6 mmol/L) as determined by the central laboratory.
Clinical ASCVD 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.
Section: 5 Subject Enrollment
Replace:
Subjects who are unable to complete or meet eligibility on initial screening will be 
permitted to re-screen except for subjects with LDL-C <70 mg/dL and non-HDL-C 
< 100 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, except for subjects who do not meet inclusion criterion 107
(see Section 7.2.2).


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 9 of 20 
Section:  5.1 Randomization/Treatment Assignment 
Last paragraph 
Replace: 
The randomization date is to be documented in the subject’s medical record and on the 
enrollment CRF. 
With: 
The randomization date (study day 1) is to be documented in the subject’s medical 
record and on the enrollment CRF. 
Section:  6.1 Classification of Product(s) or Medical Devices(s) 
Second paragraph 
Replace: 
The investigational medical device is the AMD, or the spring based prefilled AI/Pen if 
AMD is not available. 
With: 
The investigational medical device is the AMD, or the spring based prefilled AI/pen. 
Section:  6.2.1.2 Double-blind Treatment Period 
Second paragraph, add: 
See Table 3 for the schedule of in-clinic visits. 
Section:  6.2.1.3 Open-label Period 
Replace: 
Dosing at week 24 is expected to be in-clinic while dosing for weeks 28, 32, 36, 40, 44, 
and 48 is expected to be in an appropriate non-clinic setting (eg, at the subject’s home). 
Subjects who do not wish to self-inject at home may return to the clinic for injection. 
With: 
Dosing at week 24 is expected to be in-clinic while dosing for weeks 28, 32, 36, 40, 44, 
and 48 is expected to be in an appropriate non-clinic setting (eg, at the subject’s home, 
even on weeks with in-clinic visits); however, subjects who do not wish to self-inject 
at home may return to the clinic for injection. 
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 10 of 20 
Section:  6.3 Hepatotoxicity Stopping and Rechallenge Rules 
Replace: 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], AST, 
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 (DILI): Premarketing Clinical Evaluation (July 2009). 
With: 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], AST, 
ALT, total bilirubin [TBL]) and/or international normalized ratio (INR) and/or 
signs/symptoms of hepatitis (as described below) may meet the criteria for withholding 
or permanent discontinuation of Amgen IP or other protocol-required therapies as 
specified in the Guidance for Industry Drug-Induced Liver Injury (DILI): Premarketing 
Clinical Evaluation (July 2009). 
Section:  6.3.1 Criteria for Permanent Discontinuation of Amgen Investigational Product 
and Other Protocol-required Therapies Due to Potential Hepatotoxicity 
Delete  
• 
TBL ≥ 2x ULN 
• 
AND increased AST or ALT ≥ 3x ULN from a baseline value were less than the ULN  
• 
AND ALP < 2x ULN 
• 
AND no other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT and/or 
TBL values include, but are not limited to: 
Add: 
6.3.1 Criteria for Withholding or Permanent Discontinuation of Amgen Investigational 
Product and Other Protocol-required Therapies Due to Potential Hepatotoxicity 
The following stopping and/or withholding rules (Table 1) apply to subjects for 
whom another cause of their changes in liver biomarkers (TBL, INR and 
transaminases) has not been identified.  
Important alternative causes for elevated AST/ALT and/or TBL values include, but 
are not limited to: 
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 11 of 20 
Table 1.  Conditions for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity 
Analyte 
Temporary Withholding 
Permanent Discontinuation 
Total bilirubin 
> 3x ULN at any time 
> 2x ULN 
 
 
OR 
INR 
-- 
> 1.5 (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 8x ULN at any time 
 
> 5x ULN but < 8x ULN for ≥ 2 
weeks 
 
> 5x ULN but < 8x ULN and unable 
to adhere to enhanced monitoring 
schedule 
 
> 3x ULN with clinical signs or 
symptoms that are consistent with 
hepatitis (such as right upper 
quadrant pain/tenderness, fever, 
nausea, vomiting, jaundice) 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or total bilirubin 
values 
 
> 3x ULN (when baseline was 
< ULN) 
 
OR 
ALP 
> 8x ULN at any time 
-- 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
INR=international normalized ratio; ULN=upper limit of normal. 
Move from original Section 6.3.3 to Section 6.3.1: 
Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL, is discovered and the laboratory abnormalities resolve 
to normal or baseline (Section 6.3.2). 
Section:  6.3.2 Criteria for Conditional Withholding of Amgen Investigational Product and 
Other Protocol-required Therapies Due to Potential Hepatotoxicity 
Delete entire section 
Section:  6.7 Product Complaints 
Replace: 
A product complaint is defined by Amgen as any written, electronic or oral 
communication that alleges deficiencies related to the identity, quality, durability, 
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 12 of 20 
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. 
With: 
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), device(s), or combination 
products after it is released for distribution to market or clinic by either Amgen or by 
distributors and partners for whom Amgen manufactures the material. 
Section:  6.8 Excluded Treatments, Medical Devices, and/or Procedures During Study 
Period 
Add: 
• 
any lipid-lowering therapies not taken at the time of screening and enrollment 
(unless required in response to HIV worsening; see Section 9.1.2.1). 
Section:  7 Study Procedures 
Replace: 
All on-study visits and dosing should be scheduled from day 1 (first IP administration).  
With: 
All on-study visits and dosing should be scheduled from day 1 (randomization and first 
IP administration). 
Section:  7.1 Table 3  Schedule of Assessments 
Table body 
Add: 
Hepatitis C viral load assessment at screening 
Urine pregnancye test at Day 1, Weeks 12, 20, 24, and 36 
IP administration (every 4 weeks); Week 12 and Week 36 timepoints added 
Footnote a to column header “Week 24 ± 3 days”; re-letter remaining footnotes in table 
Footnote a: At week 24, final double-blind period assessments will be conducted, 
and the first dose of open-label study drug will be administered. 
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 13 of 20 
Footnote b 
Replace: 
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: 
Including review for adverse events/serious adverse events/disease-related 
events/adverse device effects. Adverse events possibly related to study procedures, 
adverse device effects and serious adverse events are reported from signing of 
the informed consent form. All other adverse events are reported from the time of 
randomization. 
Footnote e 
Add: 
Serum pregnancy testing at screening. Urine pregnancy testing at day 1 and 
weeks 12, 20, 24, 36, and prior to IP administration and at EOS. 
Footnote f 
Replace: 
FSH/LH/estradiol only at screening if applicable. 
With: 
FSH/LH/estradiol only at screening for menopausal women. 
Footnote g 
Replace: 
During the double-blind treatment period, in addition to the in-clinic administration at day 
1 and week 20, 
With: 
During the double-blind period, in addition to the in-clinic administration at day 1 and 
week 20, 
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 14 of 20 
Section:  7.2.2 Rescreening 
Replace: 
Subjects with LDL-C <70 mg/dL and non-HDL-C < 100 mg/dL by central lab result during 
screening are considered screen failures and cannot be rescreened for this study. 
With: 
Subjects who do not meet inclusion criterion 107 are considered screen failures and 
cannot be rescreened for this study. 
Section:  7.2.3 Double-blind Treatment Period 
Replace: 
Visits will occur per the Schedule of Assessments (Table 2) during the treatment period 
from day 1 (week 1, baseline) through week 24. 
With: 
Visits will occur per the Schedule of Assessments (Table 3) during the double-blind 
period from day 1 (week 1, baseline) through week 24. 
Section:  7.2.4 Open-label Period 
Replace: 
Subjects who receive a dose of IP at week 20 will continue in an open-label period. 
Visits will occur per the Schedule of Assessments (Table 2) at weeks 36 and 52. Visits 
during the open-label period must be completed within ± 7 days of the target visit date.  
With: 
Subjects who receive a dose of IP at week 20 will continue in an open-label period. They 
will receive their first dose of open-label IP at the week 24 visit. Visits will then 
occur per the Schedule of Assessments (Table 3) at weeks 36 and 52. Visits during the 
open-label period must be completed within ± 7 days of the target visit date.  
Section:  7.2.5 End of Study / Safety Follow-up 
Add: 
At week 52 or 30 days after the last administration of IP, whichever is later, a safety 
follow-up is scheduled to occur. This safety follow-up can be an in-person visit to the 
study center or another contact with the subject. If the end-of-study visit is < 30 days 
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 15 of 20 
after the last dose of IP, the subject will be contacted (eg, by phone) at 
30 (± 7 days) after last IP for safety follow-up. 
Section:  7.3.4 Vital Signs 
Replace: 
The position should be the same that is used throughout the study and documented on 
the vital sign CRF. 
With: 
The same arm and same position should be used throughout the study and 
documented on the vital sign CRF. 
Section:  7.3.5 Safety Data Reporting 
Replace: 
Adverse events, serious adverse events, disease-related events, and adverse device 
effects observed by the investigator or reported by the subject will be collected at all 
study visits from the signing of the informed consent through EOS as detailed in 
Section 9. Only adverse events or adverse device effects possibly related to study 
procedures and serious adverse events are collected during screening. 
With: 
Adverse events, serious adverse events, disease-related events, and adverse device 
effects observed by the investigator or reported by the subject will be collected at all 
study visits from randomization through EOS as detailed in Section 9. Adverse events 
possibly related to study procedures, adverse device effects and serious adverse 
events are collected during screening. 
Section:  7.4 Laboratory Assessments  
Replace: 
All laboratory samples will be sent to the central laboratory. 
Specific analytes for serum chemistry, coagulation, urinalysis, hematology, and other 
labs to be conducted on blood and urine samples are shown in Table 3. 
CONFIDENTIAL 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 16 of 20 
With: 
All laboratory samples will be sent to the central laboratory, except for samples for 
urine pregnancy tests, which will be conducted by the local laboratory. 
Specific analytes for serum chemistry, urinalysis, hematology, and other labs to be 
conducted on blood and urine samples are shown in Table 4. 
Section :  Table 4  Analyte Listing 
Delete: Coagulation (column heading) 
 
PT/INR (table text) 
Add: 
Urine pregnancy test (females of childbearing potential) in Urinalysis column 
Section:  7.4.2 Serum Pregnancy Test  
Replace: 
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 baseline, prior to administering the first dose of 
evolocumab/placebo. The central laboratory will provide the baseline pregnancy tests. 
With: 
Section:  7.4.2 Pregnancy Tests 
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, prior to administering the first dose of 
evolocumab/placebo. The central laboratory will provide the screening pregnancy tests. 
Urine pregnancy tests will be performed on day 1 and on weeks 12, 20, 24, and 36 
before IP administration and at EOS. 
Section:  9.1.1 Disease-related Events 
Replace: 
Disease-related events and/or disease related outcomes that do not qualify as serious 
adverse events:  
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 17 of 20 
With: 
Disease-related events and/or disease related outcomes that do not qualify as adverse 
events or serious adverse events:  
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: 
A disease-related event that would qualify as an adverse event or serious adverse 
event is an event based on the underlying disease that is worse than expected as 
assessed by the investigator for the subject’s condition or an event for which the 
investigator believes there is a causal relationship between the investigational 
product(s)/study treatment/protocol required therapies and disease worsening. 
This must be reported as an adverse event or serious adverse event. 
Section:  9.1.2 Adverse Events 
Add:  
Section 9.1.2.1, Worsening of HIV Disease 
HIV worsening will be captured as an adverse event. Because evolocumab is not 
expected to have any interaction with antiretroviral therapy or viral load or 
consequences of HIV infection, no specific actions with respect to study 
participation (including investigational product) are expected of the investigator. 
Should a subject’s viral load change or HIV infection worsen, the investigator is 
expected to manage HIV infection or any other concomitant illnesses per his or 
her clinical judgment. Background lipid-lowering therapy is expected to be stable. 
However, in the case of HIV worsening, because of potential drug–drug interaction 
between statins and antiretroviral therapy, changing background lipid-lowering 
therapy is left to the judgment of the investigator. 
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 18 of 20 
Section:  9.2.1 Reporting Procedures for Disease-related Events 
Replace: 
The investigator is responsible for ensuring that all disease-related events observed by 
the investigator or reported by the subject that occur after randomization through 
EOS/safety follow-up visit, or 30 days after the last administration of IP, whichever is 
later. Disease-related events are reported using the Event CRF, and additionally, the 
investigator is required to report a fatal Disease Related Event on the Event CRF.  
Events assessed by the investigator to be serious, require reporting of the event on the 
Event CRF. 
Events assessed by the investigator to be related to the investigational medicinal 
product(s)/study treatment/protocol-required therapies, and determined to be serious, 
require reporting of the event on the Event CRF.  
Events assessed by the investigator to be related to the IP/protocol-required therapies, 
and determined to be serious, require reporting of the event on 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 after randomization through 
EOS/safety follow-up visit, or 30 days after the last administration of IP, whichever is 
later are reported on the Event CRF as disease related.  
Disease-related events assessed by the investigator to be more severe than 
expected and/or related to the investigational medicinal product(s)/study 
treatment/protocol-required therapies and determined to be serious must be 
recorded on the event CRF as serious adverse events. Additionally, the 
investigator is required to report a fatal disease-related event on the Event CRF as 
a disease-related event. 
Section:  9.2.2.1 Reporting Procedures for Adverse Events That Do Not Meet Serious 
Criteria 
First paragraph, add: 
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. 
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 19 of 20 
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 EOS/safety 
follow-up, 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 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, or 30 days after the last 
administration of IP, whichever is later, are reported using the event CRF. 
Fourth and fifth paragraphs, add last sentence: 
Relatedness means that there are facts or reasons to support a relationship 
between investigational product and the event. 
Section:  9.2.2.2 Reporting Procedures for Serious Adverse Events 
Third paragraph, replace: 
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. 
With: 
The investigator may be asked to provide additional follow-up information, which may 
include a discharge summaries, medical records, or extracts from the medical record. 
Information provided about the serious adverse event must be consistent with that 
recorded on the Event CRF. 
Section:  9.3 Pregnancy and Lactation Reporting 
Replace: 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking protocol-required therapies report the pregnancy to Amgen as 
specified below. 
CONFIDENTIAL 
 
 


Product:  Evolocumab 
Protocol Number:  20130286 
Date:  30 January 2017 
Page 20 of 20 
With: 
If a pregnancy occurs in a female subject, or a male subject fathers a child, while the 
subject is taking evolocumab/placebo, report the pregnancy to Amgen Global Patient 
Safety as specified below. 
Add fourth paragraph: 
If a female subject becomes pregnant during the study, the investigator should 
attempt to obtain information regarding the birth outcome and health of the infant. 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly), the 
investigator will report the event as a serious adverse event. 
Sixth paragraph, replace: 
In addition to reporting a lactation case during the study, investigators should monitor 
lactation cases that occur after the last dose of protocol-required therapies through 
15 weeks after the end of treatment with evolocumab/placebo. 
With: 
In addition to reporting a lactation case during the study, investigators should report 
lactation cases that occur after the last dose of protocol-required therapies through 
15 weeks after the end of treatment with evolocumab/placebo. 
Add eighth paragraph: 
If a male subject's female partner becomes pregnant, the investigator should 
discuss obtaining information regarding the birth outcome and health of the infant 
from the pregnant partner. 
Section:  10.1.3 Covariates and Subgroups 
Add: 
 
Section:  Appendix B, Sample eSerious Adverse Event Contingency Report Form 
Replaced form with current version 
CONFIDENTIAL 
 
 

SAP_001.pdf: 
Product:  Evolocumab 
Statistical Analysis Plan:  20130286 
Date:  20 January 2019 
Page 1 of 35 
CONFIDENTIAL 
Statistical Analysis Plan 
A Double Blind, Randomized, Placebo Controlled, Multicenter Study to Evaluate 
Safety, Tolerability, and Efficacy on LDL-C of Evolocumab (AMG 145) in Subjects 
with HIV and with Hyperlipidemia and/or Mixed Dyslipidemia 
BEIJERINCK: evolocumaB Effect on LDL-C lowerIng in subJEcts with human 
immunodeficiency viRus and INcreased Cardiovascular risK 
Protocol Number: 
20130286 
Version: 
1.0 
Date: 
20 January 2019 
Authors: 
 
NCT Number: NCT02833844 
This NCT number has been applied to the document for 
purposes of posting on clinicaltrials.gov 


Product:  Evolocumab 
Statistical Analysis Plan:  20130286 
Date:  20 January 2019 
Page 2 of 35 
CONFIDENTIAL 
 
 
Table of Contents 
Table of Contents .............................................................................................................. 2 
1. 
Introduction .............................................................................................................. 7 
2. 
Objectives ................................................................................................................ 7 
2.1 
Primary ......................................................................................................... 7 
2.2 
Secondary .................................................................................................... 7 
2.3 
Safety ........................................................................................................... 7 
2.4 
Exploratory ................................................................................................... 7 
3. 
Study Overview ........................................................................................................ 8 
3.1 
Study Design ................................................................................................ 8 
3.2 
Sample Size ................................................................................................. 9 
4. 
Study Endpoints and Covariates .............................................................................. 9 
4.1 
Study Endpoints ........................................................................................... 9 
4.1.1 
Primary efficacy endpoint ............................................................. 9 
4.1.2 
Secondary efficacy endpoints ....................................................... 9 
4.1.3 
Safety endpoints ......................................................................... 10 
4.1.4 
Exploratory endpoints ................................................................. 10 
4.2 
Planned Covariates .................................................................................... 11 
5. 
Hypotheses and/or Estimations .............................................................................. 11 
6. 
Definitions .............................................................................................................. 11 
6.1 
Study Time Points ...................................................................................... 11 
6.2 
Demographics and Baseline Related Definitions ....................................... 12 
6.3 
Other Study Related Definitions ................................................................. 15 
7. 
Analysis Subsets .................................................................................................... 16 
7.1 
Full Analysis Set ......................................................................................... 16 
7.2 
Completers Analysis Set ............................................................................ 16 
7.3 
Long-term Analysis Set .............................................................................. 17 
7.4 
Subgroup Analyses .................................................................................... 17 
8. 
Interim Analysis and Early Stopping Guidelines ..................................................... 17 
9. 
Data Screening and Acceptance ............................................................................ 17 
9.1 
General Principles ...................................................................................... 17 
9.2 
Data Handling and Electronic Transfer of Data .......................................... 18 
9.3 
Handling of Missing and Incomplete Data .................................................. 18 
9.3.1 
Patterns of Missing Data ............................................................ 18 
9.3.2 
Missing Lipid Measurements ...................................................... 18 
9.3.3 
Handling of Incomplete Dates .................................................... 18 
9.4 
Detection of Bias ........................................................................................ 19 


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9.5 
Outliers ....................................................................................................... 19 
9.6 
Distributional Characteristics ...................................................................... 20 
9.7 
Validation of Statistical Analyses ................................................................ 20 
10. 
Statistical Methods of Analysis ............................................................................... 20 
10.1 
General Principles ...................................................................................... 20 
10.2 
Subject Accountability ................................................................................ 22 
10.3 
Important Protocol Deviations .................................................................... 22 
10.4 
Demographic and Baseline Characteristics ................................................ 23 
10.5 
Efficacy Analyses ....................................................................................... 24 
10.5.1 
Analyses of Primary Efficacy Endpoint ....................................... 26 
10.5.1.1 
Primary Analysis of Primary Endpoint ...................... 26 
10.5.1.2 
Sensitivity Analyses of Primary Endpoint ................. 26 
10.5.1.3 
Covariate and Subgroup Analyses of 
Primary Endpoints .................................................... 26 
10.5.2 
Analyses of Secondary Efficacy Endpoints ................................ 27 
10.5.3 
Analyses of Exploratory Endpoints ............................................. 27 
10.6 
Safety Analyses .......................................................................................... 27 
10.6.1 
Adverse Events .......................................................................... 27 
10.6.2 
Laboratory Test Results ............................................................. 28 
10.6.3 
Vital Signs ................................................................................... 28 
10.6.4 
Antibody Formation .................................................................... 28 
10.6.5 
Exposure to Investigational Product ........................................... 28 
10.6.6 
Exposure to Other Protocol-specified Treatment ....................... 29 
11. 
Changes From Protocol-specified Analyses .......................................................... 29 
12. 
Literature Citations / References ............................................................................ 30 
13. 
Appendices ............................................................................................................ 31 
List of Tables 
Table 1.  Imputation Rules for Incomplete Dates ............................................................ 19 
Table 2.  Key Efficacy Analyses Summary Table ........................................................... 24 
List of Figures 
Figure 1.  Multiplicity Adjustment Methods ...................................................................... 21 
List of Appendices 
Appendix A.  Analytical Study week Assignments .......................................................... 32 
Appendix B.  Common Terminology Criteria for AEs (CTCAE) ....................................... 33 
Appendix C.  Framingham Risk Score (FRS) ................................................................. 34 


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Table of Abbreviations 
Abbreviation or Term 
Definition/Explanation 
ACC 
American College of Cardiology 
AE 
Adverse event  
AHA 
American Heart Association 
AI 
Autoinjector 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AMD 
Automated mini-doser 
ApoA1 
Apolipoprotein A-I 
ApoB 
Apolipoprotein B 
AST 
Aspartate aminotransferase 
BP 
Blood pressure 
CAS 
Completer analysis set 
CD4 
Cluster of differentiation 4 
CHD 
Coronary heart disease 
CK 
Creatine kinase 
CMH 
Cochran Mantel-Haenszel 
CRF 
Case report form 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
DQR 
Data Quality Review 
eCRF 
Electronic Case Report Form 
EOIP 
End of Investigational Product  
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 (Primary 
completion) 
The date when the last subject has completed the assessments for 
week 24 
End of Study for 
Individual Subject 
Defined as the last day that protocol-specified procedures are 
conducted for an individual subject 
End of Treatment 
Defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject 


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Abbreviation or Term 
Definition/Explanation 
EOS 
End of study 
FAS 
FRS 
Full analysis set 
Framingham Risk Score 
GSO-DM 
Global Study Operations-Data Management 
HbA1c 
Hemoglobin A1c 
HCV 
Hepatitis C virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IP 
Investigational product 
IPDs 
Important Protocol Deviations 
IVRS 
Telecommunication technology that is linked to a central computer in 
real time as an interface to collect and process information.  
LAS 
Long-term analysis set 
LDL-C 
Low-density lipoprotein cholesterol 
LDLR 
Low-density lipoprotein receptor 
LFT 
Liver function test 
LH 
Luteinizing hormone 
Lp(a) 
Lipoprotein(a) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
PI 
Protease inhibitor 
QM 
Once monthly 
SC 
Subcutaneous 
SD 
Standard deviation 
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 
TEAE 
Treatment Emergent Adverse Event 
ULN 
Upper limit of normal 


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Abbreviation or Term 
Definition/Explanation 
VLDL-C 
Very low-density lipoprotein cholesterol 
WHODRUG 
World Health Organization Drug 
 


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1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol amendment 1 for Evolocumab 
Study 20130286 dated 30 January 2017.  The scope of this plan includes the primary 
analysis and final analysis that are planned and will be executed by the Biostatistics 
department unless otherwise specified. 
2. 
Objectives 
2.1 
Primary 
To evaluate the effect of 24 weeks of subcutaneous (SC) evolocumab administered 
every month (QM) compared with placebo QM on percent change from baseline in 
low-density lipoprotein cholesterol (LDL-C) in human immunodeficiency virus 
(HIV)-positive subjects with hyperlipidemia or mixed dyslipidemia 
2.2 
Secondary 
• 
To assess the effects of 24 weeks of SC evolocumab QM compared with placebo 
QM on change from baseline in LDL-C, and percent change from baseline in 
 non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total 
cholesterol (TC), lipoprotein(a) [Lp(a)], triglycerides, HDL-C, and very low-density 
lipoprotein cholesterol (VLDL-C), in HIV-positive subjects with hyperlipidemia or 
mixed dyslipidemia 
• 
To assess the effects of 24 weeks of SC evolocumab QM compared with placebo 
QM on percent of subjects attaining LDL-C < 70 mg/dL (1.8 mmol/L) in HIV-positive 
subjects with hyperlipidemia or mixed dyslipidemia 
• 
To assess the effects of 24 weeks of SC evolocumab QM compared with placebo 
QM on percent of subjects attaining a 50% reduction in LDL-C from baseline in 
HIV-positive subjects with hyperlipidemia or mixed dyslipidemia 
2.3 
Safety 
To evaluate the safety and tolerability of SC evolocumab QM compared with placebo 
QM in HIV-positive subjects with hyperlipidemia or mixed dyslipidemia 
2.4 
Exploratory 


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3. 
Study Overview 
3.1 
Study Design 
This is a phase 3b, multicenter, double-blind, randomized, placebo-controlled study with 
an open-label extension period designed to assess the efficacy and safety of 
evolocumab in HIV-positive subjects with hyperlipidemia and/or mixed dyslipidemia. 
Treatment with baseline HIV and lipid-lowering (if applicable) medications being taken at 
randomization will continue throughout the clinical study. The study consists of 
3 periods: 
• 
Screening (to ensure tolerance of SC injections, includes a placebo injection) 
• 
Double-blind treatment period 
• 
Open-label extension period 
Subjects will undergo screening procedures, including laboratory assessments and a 
screening placebo injection, before being randomized 2:1 into the following treatment 
groups for the double-blind treatment period: 
• 
SC evolocumab 420 mg QM 
• 
SC placebo QM 
The overall sample size will be approximately 450 subjects, with approximately 
300 subjects in the evolocumab group. Randomization will be stratified by entry statin 
treatment (yes/no) and hepatitis C status (yes/no).  The size of the subgroup not on 
statin therapy is expected to be approximately 10% and no more than 20% of the 
subjects. This enrollment projection is expected to be reflective of clinical practice. 
The double-blind treatment period will be 24 weeks, after which subjects who received a 
dose of investigational product (IP) at week 20 will continue in an open-label period 
during which all subjects will be treated with QM evolocumab. The open-label period will 
continue up through the end of study (EOS) visit at week 52. 
SC evolocumab and placebo will be administered QM at the study site or appropriate 
non-investigator site settings (eg, at the subject’s home) by automated mini-doser (AMD) 
or by spring-based prefilled autoinjector/pen (AI/Pen). 


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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 450 total subjects. 
The primary analysis will require the 2-sided tests of the primary endpoint 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 primary endpoint. From the integrated efficacy analysis of completed phase 3 
studies, the treatment effect of evolocumab 420 mg QM compared to placebo and the 
corresponding 95% confidence interval at the mean of weeks 10 and 12 was -64.98% 
[-69.51%, -60.45%], with treatment effect ranges between -55.1% and -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%. 
In addition, 300 subjects in the evolocumab 420 mg QM group will provide approximately 
95% probability of detecting adverse events that occur at a rate of 1%. 
It is expected that the proportion of subjects assigned to the no statin use at baseline 
stratum will be approximately 10%.  In this stratum, 30 subjects in the evolocumab 
420 mg QM group will provide approximately 79% probability of detecting adverse 
events that occur at a rate of 5%.  
4. 
Study Endpoints and Covariates 
4.1 
Study Endpoints 
4.1.1 
Primary efficacy endpoint 
Percent change from baseline in LDL-C at week 24 
4.1.2 
Secondary efficacy endpoints 
For week 24 the following secondary endpoints will be characterized: 
• 
Tier 1 
o Change from baseline in LDL-C 
o Percent change from baseline in non-HDL-C 
o Percent change from baseline in ApoB 
o Percent change from baseline in TC 


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o Achievement of target LDL-C <70 mg/dL (1.8 mmol/L) 
o LDL-C response (50% reduction of LDL-C from baseline) 
• 
Tier 2 
o Percent change from baseline in Lp(a) 
o Percent change from baseline in triglycerides 
o Percent change from baseline in HDL-C 
o Percent change from baseline in VLDL-C 
4.1.3 
Safety endpoints 
• 
Subject incidence of treatment emergent adverse events 
• 
Safety laboratory values and vital signs at each scheduled assessment 
• 
Incidence of anti-evolocumab antibody (binding and neutralizing) formation 
4.1.4 
Exploratory endpoints 


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4.2 
Planned Covariates 
Baseline covariates include: 
• 
Stratification factors in Double-blind Treatment Period: 
o Statin use at baseline (yes/no) 
o Hepatitis C status (yes/no) 
• 
Age 
• 
Sex 
• 
Race (black, white, and other) 
• 
LDL-C 
• 
Family history of premature coronary heart disease (yes/no) 
• 
 
• 
Region (North America, Europe, other) 
• 
Body Mass Index (BMI) 
• 
Glucose tolerance status (type 2 diabetes mellitus, metabolic syndrome, neither 
type 2 diabetes mellitus nor metabolic syndrome) 
• 
Hypertension (yes, no) 
• 
Current smoker (yes, no) 
• 
Baseline CHD risk factors ≥ 2 (yes, no) 
• 
Triglycerides 
• 
NCEP high risk (yes, no) 
• 
Statin intensity (High/Moderate/Low intensity as per ACC/AHA guidelines) 
• 
Lipid entry target (above both non-HDL-C and LDL-C entry criteria thresholds, above 
non-HDL-C entry criteria threshold only, and above LDL-C criteria threshold only) 
• 
Protease inhibitor use 
5. 
Hypotheses and/or Estimations 
The null hypothesis is that there is no mean difference in the mean percent change from 
baseline at week 24 in LDL-C between evolocumab 420 mg QM and placebo, and the 
alternative hypothesis is that a mean difference does exist. 
6. 
Definitions 
6.1 
Study Time Points 
Enrollment Date  
Enrollment Date is the same as randomization date (ie, the date a subject is randomized 
in the interactive voice response system (IVRS) as recorded on the eCRF).  


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Study Day 1  
For each subject, Study Day 1 is defined as the first day of investigational product 
administration (SC evolocumab 420 mg QM or SC placebo QM). If a subject enrolled but 
never received IP, Study Day 1 is defined as the enrollment day. 
Study Day  
For each subject, and for a given date of interest, study day is defined as the number of 
days since Study Day 1:  
Study day = (date of interest – Study Day 1 date) + 1.  
If the date of interest is prior to the Study Day 1:  
Study day = (date of interest – Study Day 1 date), so that the day prior to Study Day 1 is 
study day -1.  
First Dose Date of SC IP (TR01SDTM) 
For each subject, the first dose date of SC IP is defined as the first date of 
investigational product administration, equivalent to study day 1. 
First Dose Date of SC IP in the Open-label period (TR02SDTM) 
For each subject, the first dose date of SC IP in the open-label period is defined as the 
first date of open-label investigational product administration.  
Last dose date of Double-blind Investigational Product 
For each subject, the last dose date of double-blind investigational product is defined as 
the date of the last administration of double-blind investigational product. 
End of Investigational Product (EOIP) Date  
For each subject, the end of investigational product date is defined as the date of 
decision to end investigational product.   
End of Study (EOS) Date  
For each subject, the End of Study Date is the date recorded on the End of Study eCRF.  
6.2 
Demographics and Baseline Related Definitions 
Age  
Subject age at enrollment will be collected in years in the clinical database. 


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Baseline Lipid and Lipid-related Parameters  
Baseline values for fasting lipids (total cholesterol, HDL-C, LDL-C, VLDL-C and 
triglycerides), ApoA1, ApoB, Lp(a) and their derived parameters (eg, ratio between 
them) are defined as the mean of the two most recent non-missing fasting 
concentrations measured through central lab prior to or on Study Day 1. If for any reason 
only 1 value is available, then that value will be used as baseline. 
Other Baseline Values  
The baseline value is defined as the last non-missing value collected prior to or on Study 
Day 1. 
Change (absolute change) from Baseline  
The arithmetic difference between a post-baseline value and baseline for a given time 
point:  
Change (absolute change) from baseline = (post-baseline value – baseline value) 
Percent Change from Baseline  
The percent change from baseline for a given variable at a given time point is defined 
as:  
100 x [(value at given time point – baseline value) / baseline value] 
Baseline Metabolic Syndrome  
For each subject without type 2 diabetes mellitus, metabolic syndrome is identified by 
the presence of 3 or more of the components listed below (modified AHA/NHLBI 
criteria). Subjects with type 2 diabetes cannot be categorized as having metabolic 
syndrome. 
Risk Factor 
Defining Level 
Elevated waist circumference: 
Non-Asian: 
  Men 
  Women 
Asian: 
  Men 
  Women 
 
 
≥ 102 cm 
≥ 88 cm 
 
≥ 90 cm 
≥ 80 cm 
Triglycerides 
≥ 150 mg/dL 
HDL cholesterol 
  Men 
  Women 
 
< 40 mg/dL 
< 50 mg/dL 
Blood Pressure 
SBP ≥ 130 mmHg or DBP ≥ 85 mmHg 
OR Hypertension checked ‘yes’ on 
Cardiovascular Medical History eCRF 
Fasting glucose 
≥ 100 mg/dL 


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Baseline CHD Risk Factors  
A subject will be categorized as having 2 or more CHD Risk Factors (Y/N) from the list of 
the modified NCEP ATP III risk factors:  
• 
current cigarette smoking  
• 
hypertension  
• 
type II diabetes mellitus 
• 
family history of premature CHD as recorded on the Cardiac Risk Factors eCRF  
• 
low HDL-C defined as baseline HDL-C < 40 mg/dL in men and < 50 mg/dL in 
women. 
Baseline National Cholesterol Education Program (NCEP) Risk Categories  
Risk Factor 
Defining Level 
High Risk: CHD or CHD Risk 
Equivalent 
 
Coronary Artery Disease OR  
Cerebrovascular or Peripheral Vascular Disease OR  
Type 2 Diabetes Mellitus OR  
2 or more Risk Factors (see below) AND FRS > 20% 
(see Appendix C for FRS calculation) 
Moderately High Risk 
NOT High Risk AND 
2 or more Risk Factors AND 
FRS ≥ 10% AND ≤ 20% 
Moderate Risk 
NOT High Risk AND 
2 or more Risk Factors AND 
FRS < 10%  
Lower Risk 
NOT High Risk AND 
0 to 1 Risk Factor  
Risk Factors for NCEP Risk Categories: 
Risk factors are: current cigarette smoking, hypertension or (baseline SBP ≥ 140 or DBP 
≥ 90 mmHg), family history of premature CHD as recorded in the Cardiac Risk Factors 
eCRF form, low HDL-C cholesterol defined as baseline HDL-C < 40 mg/dL, 
age ≥ 45 years in men or ≥ 55 years in women. 
Systematic Coronary Risk Estimation (SCORE) Categories  
The SCORE system estimates the 10-year risk of a first fatal atherosclerotic event, 
whether heart attack, stroke, or other occlusive arterial disease, including sudden 
cardiac death (ESC/EAS 2011). The SCORE risk estimates will be computed from the 


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high and low risk region tables based on sex and baseline smoking status, systolic blood 
pressure, total cholesterol and age. 
6.3 
Other Study Related Definitions 
Analytical Study Week Assignments  
Analytical windows will be used to assign parameter measurements to study weeks. The 
algorithm is provided in Appendix A. 
Actual Treatment Group  
A subject’s actual treatment group is the randomized treatment group, unless the subject 
receives treatment throughout the double-blind period that is different from the 
randomized treatment group assignment, in which case the actual treatment group is the 
treatment received.   
Investigational Product (IP)  
Double-blind period IP: evolocumab SC 420 mg QM and corresponding SC placebo. 
Open-label period IP: evolocumab SC 420 mg QM 
Double-blind IP Exposure Period in Months  
For each subject:  
Double-blind IP Exposure Period = [min (TR01EDT 
-1, EOIP + 28 days, EOS Date) - Study day 1 + 1]/ 365.25 * 12 
Open-label IP Exposure Period in Months  
For each subject receiving at least one dose of open-label IP: 
Open-label IP Exposure Period = [min (EOIP + 28 days, EOS Date) - TR02SDT + 1]/ 
365.25 * 12 
Study Exposure Period in Months  
For each randomized subject, Study Exposure Period = (EOS date – Enrollment Date + 
1) / 365.25 * 12 
Treatment Emergent Adverse Event (TEAE)  
Events categorized as Adverse Events (AEs) starting on or after first dose of 
investigational product as determined by the flag indicating if the adverse event started 
before the first dose on the Events eCRF and up to and including EOS.  Double-blind 
TEAEs are those that start before the earlier of last dose date of double blind 


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IP + 28 days and first dose date of open-label IP.  Open-label TEAEs are those that start 
on or after the date of first dose of open-label IP and start before the earlier of last dose 
date of open-label IP + 28 days and EOS. 
Serious Adverse Event (SAE) 
Treatment-emergent adverse events (as defined above) that are indicated as serious on 
the Events eCRF. 
LDL-C Reflexive Approach  
For all analyses related to LDL-C, unless specified otherwise, a LDL-C reflexive 
approach will be used. When calculated LDL-C is less than 40 mg/dL or triglycerides are 
> 400 mg/dL, the UC LDL-C value from the same blood sample will be used instead, if 
available. 
Achievement of target LDL-C < 70 mg/dL  
A subject has achievement of LDL-C < 70 mg/dL if the week 24 LDL-C value is less than 
70 mg/dL. If the value is missing, the subject is considered without the achievement.  
LDL-C response (50% reduction from baseline) 
A subject has a response of 50% reduction from baseline in LDL-C if the week 24 LDL-C 
percent change from baseline value is less than or equal to -50%. If the value is missing, 
the subject is considered without the response. 
7. 
Analysis Subsets 
7.1 
Full Analysis Set 
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 analyses, subjects will be grouped according to their 
actual treatment group (as defined in Section 6.3). 
7.2 
Completers Analysis Set 
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 an observed value 
for the primary endpoint.  Subjects who did not adhere are identified as those who have 
an EOIP reason other than completed and EOIP date not after first dose of open-label 
IP. 


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7.3 
Long-term Analysis Set 
The long-term analysis set (LAS) will include all subjects who received at least 1 dose of 
open-label IP in the open-label period. This analysis set will be used in all analyses for 
the open-label period. 
7.4 
Subgroup Analyses 
Subgroup by stratification factor 
• 
Statin use at baseline (yes/no) 
• 
Hepatitis C Status (yes/no) 
Subgroup by baseline characteristics 
• 
Age: < 65 years, ≥ 65 years 
• 
Sex 
• 
Race (black, white, and other) 
• 
LDL-C: (< baseline median, ≥ baseline median) 
• 
Family history of premature CHD (yes, no) 
• 
 
• 
Region (North America, Europe, other) 
• 
BMI (<25, 25-30, ≥30) 
• 
Hypertension (yes, no) 
• 
Current smoker (yes, no) 
• 
Baseline CHD risk factors ≥ 2 (yes, no)  
• 
Triglicerides (< baseline median, ≥ baseline median) 
• 
NCEP high risk (yes, no) 
• 
Statin intensity (High/Moderate/Low intensity as per ACC/AHA guidelines) 
• 
Lipid entry target (above both non-HDL-C and LDL-C entry criteria thresholds, above 
non-HDL-C entry criteria threshold only, and above LDL-C criteria threshold only) 
• 
Glucose tolerance status (type 2 diabetes mellitus, metabolic syndrome, neither 
type 2 diabetes mellitus nor metabolic syndrome) 
• 
Protease inhibitor use 
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. 


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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 
issue identification and resolution (DIIR) process, queries will be made to the sites to 
distinguish true missing values from other unknown values (eg, 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 uses a repeated measures linear 
effects model, missing lipid measurements will not be imputed. The handling of missing 
LDL-C response (50% reduction of week 24 LDL-C from baseline) and achievement of 
target week 24 LDL-C < 70 mg/dL is provided in Section 6.3. Sensitivity analysis will be 
performed on the primary endpoint 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.  
9.3.3 
Handling of Incomplete Dates  
Adverse events can be flagged as treatment emergent using valid answers to the 
question “Did event start before first dose of investigational product?” on the eCRF 
regardless of the AE onset date being complete or not.  
Adverse events and concomitant medication ([eg, lipid regulatory medication] collected 
start date data) with completely or partially missing start dates will be queried. After the 


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issue is queried, if the date is still incomplete with year only or year and month only, the 
start date will be imputed as described in Table 1 below. 
Table 1.  Imputation Rules for Incomplete Dates 
Start date (AE and 
concomitant 
medication) 
Missing 
Imputation 
Exception 
Day 
1 
Default to Study Day 1 if an event starts 
the same year and month as Study Day 
1 
Day / Month 
1-Jan 
Default to Study Day 1 if an event 
started the same year as Study Day 1 
9.4 
Detection of Bias  
This study has been designed to minimize potential bias by the use of randomization of 
subjects into treatment groups and the use of blinding. Other factors that may bias the 
results of the study include:  
• 
major protocol deviations likely to impact the analysis and interpretation of the 
efficacy endpoints  
• 
subject level unblinding before final database lock and formal unblinding  
• 
DMC related analyses  
Important protocol deviations likely to impact the analysis and interpretation of the 
efficacy endpoints will be tabulated in the Clinical Study Report (CSR).  
Any unblinding of individual subjects prior to formal unblinding of the study will be 
documented in the CSR. The impact of such unblinding on the results observed will be 
assessed. Data from subjects whose treatment assignments are unblinded prior to 
formal unblinding will be listed. The timing and reason for unblinding will be included in 
these listings.  
Additional sensitivity analyses may be included to assess the impact of potential biases 
on the primary endpoint. If any sensitivity analyses are required to evaluate potential 
biases in the study’s conclusions, then the sources of the potential biases and results of 
the sensitivity analyses will be documented in the CSR. 
9.5 
Outliers 
Various methods, including univariate summaries, histograms, scatter plots, box plots, 
and line graphs, may be used to identify outliers in key safety and efficacy variables. 
Extreme data points will be identified during the blinded review of the data prior to 
database lock. Such data points will be reviewed with clinical data management to 


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ensure accuracy. The primary analyses will include outliers in the data. Sensitivity 
analyses may be undertaken if extreme outliers for a variable are observed. 
9.6 
Distributional Characteristics 
Distributional assumptions for the primary and secondary co-endpoints will be assessed. 
If the assumptions are not met, then alternative methods will be utilized. The use of 
alternative methods will be fully justified in the CSR. 
9.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.   
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.2 or 
later.   
10. 
Statistical Methods of Analysis 
10.1 
General Principles 
To evaluate efficacy and safety of 24 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. Data will be 
locked at each clean snapshot (the primary analysis and final analysis). 
Based on the locked snapshot for the primary analysis, efficacy and safety analyses will 
be performed on FAS unless otherwise specified, and data will be summarized by 
randomized treatment group. Data occuring after the first dose of open-label 
evolocumab will be excluded from the primary analysis dataset. 
The final analysis will be performed when all subjects have completed all scheduled 
study visits in the open-label period or have early terminated from the study.  Based on 
the final locked snapshot for the final analysis, long-term efficacy and safety analyses 
will be performed on LAS and the analyses will be descriptive.  Safety endpoints and 
exploratory endpoints will be evaluated for the open-label period and summarized overall 
and by treatment in the double-blind period.  


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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, standard deviation or standard error, minimum, 
and maximum. For categorical variables, the frequency and percentage will be given.  
Methods of handling missing data for efficacy endpoints are 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 
 


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The following method will be used to preserve the family-wise error rate for the primary 
and secondary endpoints: 
1. If the treatment effect from the primary analysis of the primary endpoint is 
significant at a significance level of 0.05, statistical testing of the tier 1 secondary 
efficacy endpoints will follow the Hochberg procedure at a significance level of 
0.005 (Hochberg, 1988) 
2. If all tier 1 secondary efficacy endpoints are significant, the tier 2 secondary 
efficacy endpoints will be tested using the Hochberg procedure at a significance 
level of 0.05. 
3. If not all tier 1 secondary efficacy endpoints are significant, the tier 2 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 treatment 
period, discontinued study and reasons for discontinuing will be summarized by 
treatment group. 
Key study dates for the first subject enrolled, last subject enrolled and last subject’s end 
of double-blind IP, last subject’s end of open-label 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. 


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10.4 
Demographic and Baseline Characteristics 
Demographic (ie, age, age group [< 65, >= 65], sex, race, ethnicity) and baseline 
disease characteristics (cardiovascular medical history, HIV medical history, laboratory 
parameters, antiretroviral therapy 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. 
 


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10.5 
Efficacy Analyses  
The following table summarizes the key efficacy analyses that will be conducted for the primary analysis 
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 
Primary Endpoint 
• 
Percent change from 
baseline at week 24 in 
LDL-C  
 
Repeated measures 
model  
 
P1  
 
P1 compare to α = 0.05  
 
• 
Non-parametric analyses 
will be performed 
• 
Multiple imputation for 
subjects who discontinue 
evolocumab and are 
missing primary endpoint 
data. 
Secondary Endpoints (Tier 1) 
• 
LDL-C achievement at 
week 24  
• 
LDL-C response at 
week 24  
 
Cochran Mantel-Haenszel  
(CMH) test  
 
P2a 
 
If P1 < 0.05,  
 P2a for each tier 
1 endpoint will be tested 
through Hochberg method 
with α = 0.005  
 
Else (ie, primary endpoint is 
not significant)  
 No further testing  
 
• 
Change from baseline at 
week 24 in LDL-C 
• 
Percent change from 
baseline at week 24 in: 
• 
non-HDL-C 
• 
ApoB 
• 
total cholesterol  
Repeated measures 
model  
 
P2a 
 
Page 1 of 2 
Footnotes are defined on next page of the table 
 


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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 
Secondary Endpoints (Tier 2) 
• 
Percent change from 
baseline at week 24 in: 
• 
Lp(a) 
• 
Triglycerides 
• 
HDL-C 
• 
VLDL-C 
 
Repeated measures 
model 
P2b  
If all P2a values are 
significant through Hochberg 
method,  
 all P2b values will be 
tested through Hochberg 
method with α = 0.05  
 
Else (ie, not all tier 1 
endpoints are significant),  
 all P2b values will be 
tested through Hochberg 
method with α = 0.045  
 
 
Page 2 of 2 
Supportive analysis: the primary analysis will be repeated using the CAS. 
 


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10.5.1 
Analyses of Primary Efficacy Endpoint 
10.5.1.1 
Primary Analysis of Primary Endpoint 
To assess the primary endpoint of the percent change from baseline in LDL-C at week 
24, a repeated measures linear effects model will be used on the FAS to compare the 
efficacy of evolocumab with placebo. The repeated measures model will include terms 
for treatment group, stratification factors, scheduled visit and the interaction of treatment 
with scheduled visit.  All LDL-C values observed will be used irrespective of whether a 
subject remained on IP, and missing values will not be imputed for primary analysis. If 
there are fewer than 5 subjects in one stratum, then the Hepatitis C status stratification 
factor will not be included in the repeated measures model.  To account for the repeated 
LDL-C measurements within a subject across the visits, the repeated measures linear 
effects model will use an unstructured covariance.  
Multiplicity adjustment procedures are defined in Section 10.1. 
10.5.1.2 
Sensitivity Analyses of Primary Endpoint 
To evaluate the robustness of the analysis results, sensitivity analyses will be performed 
as follows: 
• 
Non-parametric analyses will be performed 
• 
Multiple imputation for subjects who discontinue IP with missing endpoint data  
• 
It will be assumed that the missing percent change values will be normally 
distributed with a mean 0 and a variance-covariance matrix the same as the 
observed variance-covariance matrix from subjects in the placebo group who did 
not discontinue IP. 
• 
If there are at least 25 subjects who discontinue evolocumab but have 
 non-missing week 24 endpoint data, an additional multiple imputation will be 
carried out utilizing the information from these subjects (mean and variance) to 
impute the missing data for subjects who discontinue evolocumab and have 
missing endpoint data 
10.5.1.3 
Covariate and Subgroup Analyses of Primary Endpoints 
As a supportive analysis, the primary analysis will be repeated using the CAS to 
estimate the on-treatment treatment effect.   
In addition to the primary analysis specified in Section 10.5.1.1, covariate-adjusted 
analyses of the primary efficacy endpoint will be performed as supportive analyses using 
the baseline covariates in Section 4.2 in their original format, one at a time, in the 
primary model used in the primary analyses as appropriate.  


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Subgroup analyses on the primary efficacy endpoint will be conducted using the 
subgroups specified in Section 7.3. Depending on the distribution of baseline LDL-C, 
analyses using different subgroups of baseline LDL-C will be performed if applicable. 
Treatment effect differences among subgroups, which represent subgroup by treatment 
interactions, will be estimated and tested based on statistics from the subgroup repeated 
measures models.  
For covariate and subgroup analyses, the stratification factors from the eCRF will be 
used. Differences in stratum assignment between data collection via IVRS and eCRF will 
be tabulated. 
10.5.2 
Analyses of Secondary Efficacy Endpoints 
The statistical model and testing of the secondary efficacy endpoints (change from 
baseline and percent change from baseline) will be similar to the primary analysis of the 
primary endpoint. The secondary endpoints of achievement of target LDL-C < 70 mg/dL 
at week 24 and LDL-C response of 50% reduction of week 24 LDL-C from baseline will 
be analyzed using the Cochran-Mantel Haenszel test adjusted by the stratification 
factors. 
Multiplicity adjustment procedures are defined in Section 10.1. 
10.5.3 
Analyses of Exploratory Endpoints 
 
 
 
 
10.6 
Safety Analyses 
10.6.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 19.0 or later will be 
used to code all events categorized as adverse events (AEs) to a system organ class 
and a preferred term.  Severity of TEAEs will be graded using the CTCAE (Appendix B) 
and recorded on the Events eCRF. All adverse event tables will be summarized by 
actual treatment group. Double-blind period TEAEs will be summarized in the primary 
analysis; open-label period TEAEs will be summarized in the final analysis.  
Subject incidence of all TEAEs, serious TEAEs, TEAEs leading to withdrawal of 
investigational product, and fatal TEAEs will be tabulated by system organ class, high 
level group term and preferred term in descending order of frequency.  Additionally, the 


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subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class, high level group term and preferred term in descending order of frequency 
for each baseline statin use stratum.   
Summaries of treatment-emergent, serious TEAEs and target IP TEAEs occurring in at 
least 1% of the subjects by preferred term in any treatment arm will be provided in 
descending order of frequency.   
Subject incidence of treatment-emergent adverse events related to a device will be 
tabulated by preferred term in descending order of frequency by treatment group.  
10.6.2 
Laboratory Test Results 
Descriptive statistics will be provided for actual values and changes from baseline in 
select laboratory parameters at each protocol-specified scheduled visit. Laboratory 
analytes are provided in the protocol Table 3. Lab shift tables using the CTCAE v4.03 or 
later grading will be used for the select analytes of interest, when applicable. 
In addition, CK and liver function test (LFT) abnormalities will be assessed by the 
incidence overall and by visits of the following categories:  
• 
CK > 5 x ULN  
• 
CK > 10 x ULN  
• 
ALT or AST ≥ 3 x ULN  
• 
ALT or AST ≥ 5 x ULN  
• 
Total bilirubin ≥ 2 x ULN  
• 
(ALT or AST ≥ 3 x ULN) and (Total bilirubin ≥ 2 x ULN and ALP < 2 x ULN)  
10.6.3 
Vital Signs 
Systolic and diastolic blood pressure and heart rate will be summarized for each 
treatment group using descriptive statistics at each scheduled visit. 
10.6.4 
Antibody Formation  
The incidence and percentages of subjects who develop anti-evolocumab antibodies 
(binding and if positive, neutralizing) at anytime will be tabulated. 
10.6.5 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the patient-month exposure to 
double-blind or open-label investigational product and the categorical representation of 
dose received.  
Exposure definitions are provided in Section 6.3. 


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10.6.6 
Exposure to Other Protocol-specified Treatment  
The number and proportion of subjects receiving selected lipid-lowering medications 
captured on Other Protocol Required Therapy (Lipid Lowering Therapy) eCRF will be 
summarized by category and preferred term for each treatment group as coded by the 
World Health Organization Drug (WHODRUG) dictionary. Summaries will be provided 
for baseline use and use during each study period. The use of antiretroviral therapies 
captured on the Other Protocol Required Therapy (Antiretroviral Therapy) eCRF will be 
summarized similarly.  In addition, the reasons for a change in Antiretroviral Therapy will 
be summarized.   
11. 
Changes From Protocol-specified Analyses 
 
   


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12. 
Literature Citations / References 
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. 
Biometrika 1988;75:800-802.  
Wiens BL. A fixed sequence Bonferroni procedure for testing multiple endpoints. 
Pharmaceut. Statist. 2003; 2:211-215. 
The Task Force for the management of dyslipidaemias of the European Society of 
Cardiology (ESC) and the European Atherosclerosis Society (EAS). ESC/EAS 
Guidelines for the management of dyslipidaemias. European Heart Journal. 2011; 
32:1769–1818. 
Stone N, Robinson J, Lichtenstein A et al. 2013 ACC/AHA guideline on the treatment of 
blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the 
American College of Cardiology/American Heart Association Task Force on Practice 
Guidelines. Circulation 2014;129(25 Suppl 2): S1-45.  
 


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13. 
Appendices  


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Appendix A.  Analytical Study week Assignments 
Selected endpoints will be summarized by scheduled study visits in descriptive analyses. 
Since the actual visits may not exactly coincide with their scheduled visit day, the actual 
visit day is mapped to the study visit generally by non-overlapping consecutive intervals 
covering the entire time continuum. The mapping intervals for all distinct schedules are 
summarized in the following table: 
 
Handling multiple records assigned to an analytical study week:  
If there is more than one record in a study week interval, the analytical record for that 
specific study week will be defined as the record closest to the scheduled visit day of 
that specific study week (7 x study week + 1). If two records are equidistant from the 
scheduled day, then the earlier record will be chosen. If there are multiple records on the 
same day, the last record will be used. 
 
Double-Blind Period 
Open-Label Period 
Analytical Study Week  
Week 12 
Week 20 
Week 24 
Week 36 
Week 52 
Scheduled Visit Day  
85 
141  
169  
253 
365 
Vital Signs 
(1, 112] 
(112, 154] 
(154, 210] 
(210, 308] 
(308, 378] 
Body Weight, Waist 
circumference 
 
 
(1, 210] 
 
(210, 378] 
Fasting Lipids, ApoA1, ApoB, 
Lp(a), 
 HIV viral load, 
CD4, Hepatitis C viral load, 
chemistry, 
 
, urinalysis, 
hematology, HbA1c 
(1, 126] 
 
(126, 210] 
(210, 308] 
(308, 371] 


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Appendix B.  Common Terminology Criteria for AEs (CTCAE) 
Refer to the NCI Common Terminology Criteria for AEs (CTCAE) for AEs and lab shift 
grading and information. The CTCAE is available at the following link:  
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 


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Appendix C.  Framingham Risk Score (FRS) 
Method to calculate the Framingham Risk Score (FRS): 
The β coefficients given in the two tables below are used to compute a linear function. 
The latter is corrected for the averages of the participants’ risk factors (mean) from the 
Framingham study, and the subsequent result is exponentiated and used to calculate a 
10-year probability of HCHD after insertion into a survival function (Wilson et al). 
The calculation is different for men and women and use the following coefficients βi, 
where i represents each of the independent variables.  The values below are from the 
Framingham heart study (http://www.framinghamheartstudy.org/risk/hrdcoronary.html).   
t_chol = total cholesterol, hdl = HDL-C, sbp = systolic blood pressure, trt_htn = treatment 
for hypertension (if sbp > 120), smoker = current smoker 
Men 
 
 
 
 
 
 
 
 
 
 
 
 
 
Women 
Independent 
variable 
Coefficient 
βi 
mean 
Independent 
variable 
Coefficient 
βi 
mean 
ln(age) 
52.00961 
3.8926095 
ln(age) 
31.764001 
3.9213204 
ln(t_chol) 
20.014077 
5.3441475 
ln(t_chol) 
22.465206 
5.3628984 
ln(hdl) 
-0.905964 
3.7731132 
ln(hdl) 
-1.187731 
4.0146369 
ln(sbp) 
1.305784 
4.8618212 
ln(sbp) 
2.552905 
4.8376494 
trt_htn 
(spb>120) 
0.241549 
0.1180474 
trt_htn 
(spb>120) 
0.420251 
0.142802 
smoker 
12.096316 
0.335602 
smoker 
13.07543 
0.3236202 
ln(age)* 
ln(t_chol) 
-4.605038 
20.811156
2 
ln(age)* 
ln(t_chol) 
-5.060998 
21.0557746 
ln(age)*smoker1 
-2.84367 
1.2890301 
ln(age)*smoker2 
-2.996945 
1.2519882 
ln(age)*ln(age) 
-2.93323 
15.214496
5 
 
 
 
1 if age>70 then ln(70)*smoker 
2 if age>78 then ln(78)*smoker 
The steps to determine the FRS is the same for men and women. 
Men 
For each subject: 
1. Calculate Lmen = βln(age)*ln(age) + βln(t_chol)*ln(t_chol) + βln(hdl) *ln(hdl) + 
βln(sbp)*ln(sbp) + βtrt_htn*(if trt_htn) + βsmoker*(if smoker) + β 
ln(age)*ln(t_chol)*ln(age)*ln(t_chol) + βln(age)*smoker*ln(age)*(if smoker)  + 
βln(age)*ln(age)*ln(age)*ln(age) 
2. Calculate Amen = Lmen - 172.300168 (note: the value of 172.300168 was 
derived based on the mean columns in above table) 
3. Calculate Bmen = exp (Amen) 


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4. Calculate Pmen = 1 – 0.9402^Bmen   
5. FRSmen = Pmen*100 (rounded to nearest integer) 
Women 
For each subject: 
1. Calculate Lwomen = βln(age)*ln(age) + βln(t_chol)*ln(t_chol) + βln(hdl) *ln(hdl) + 
βln(sbp)*ln(sbp) + βtrt_htn*(if trt_htn) + βsmoker*(if smoker) + β 
ln(age)*ln(t_chol)*ln(age)*ln(t_chol) + βln(age)*smoker*ln(age)*(if smoker)   
2. Calculate Awomen = Lwomen – 146.5933061 (note: the value of 146.5933061 was 
derived based on the mean columns in above table) 
3. Calculate Bwomen = exp (Awomen) 
4. Calculate Pwomen = 1 – 0.98767^Bwomen   
5. FRSwomen = Pwomen*100 (rounded to nearest integer) 
Notes 
• 
For men, if subject is > age 70, then use ln(70)*smoker 
• 
For women, if subject is > age 78, then use ln(78)*smoker 
• 
For dichotomous variables trt_htn and smoker use 1/0 to represent yes/no 
respectively 
o If a subject has sbp ≤ 120 mmHg, then trt_htn is no 
Calculated scores should match the interactive calculator 
http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=prof