Conditions: Heterozygous Familial Hypercholesterolemia
Keywords: Hypercholesterolemia Elevated Cholesterol High Cholesterol Heterozygous Familial Hypercholesterolemia PCSK9 mutations Paediatric pediatric Childhood Familial Hypercholesterolemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 158
Healthy volunteers: no

Brief summary:
A study to assess safety and efficacy of evolocumab (AMG-145) in paediatric subjects aged 10-17 years diagnosed with heterozygous familial hypercholesterolemia.

Detailed description:
A study to evaluate the effect of 24 weeks of subcutaneous (SC) evolocumab compared with placebo, when added to standard of care, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in pediatric subjects 10 to 17 years of age with heterozygous familial hypercholesterolemia (HeFH).

Arms:
arm 1: Matching subcutaneous injection every 4 weeks (QM) arm 2: Evolocumab subcutaneous injection QM

Interventions: intervention 1: Evolocumab intervention 2: Placebo
Intervention descriptions: intervention 1: Dose of subcutaneous evolocumab every 4 weeks intervention 2: Dose of subcutaneous placebo treatment every 4 weeks

Protocol document:
Prot_000.pdf: 
Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 1 of 84 
CONFIDENTIAL 
Title:  Double-blind, Randomized, Multicenter, Placebo-controlled, Parallel Group 
Study to Characterize the Efficacy, Safety, and Tolerability of 24 Weeks of 
Evolocumab for Low Density Lipoprotein-cholesterol (LDL-C) Reduction, as 
Add-on to Diet and Lipid-lowering Therapy, in Pediatric Subjects 10 to 17 Years of 
Age With Heterozygous Familial Hypercholesterolemia (HeFH) 
Evolocumab (AMG 145) 
Amgen Protocol Number (Evolocumab) 20120123 
EudraCT number 2014-002277-11 
Clinical Study Sponsor: 
Amgen Inc 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Phone: +1-805-447-1000 
Key Sponsor Contact(s): 
One Amgen Center Drive 
Mail Stop 27-1-F 
Thousand Oaks, CA 91320, USA 
Phone:
Fax:
Email:
Original, Date: 
09 December 2014 
Amendment 1, Date: 
20 May 2015 
Amendment 2, Date 
01 September 2015 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN, Canadian sites, 
1-866-50-AMGEN, all other countries call the local toll-free number, if provided, or call
+1-800-772-6436; Amgen’s general number in the US (1-805-447-1000).
NCT Number: NCT02392559
This NCT number has been applied to the document for 
purposes of posting on clinicaltrials.gov


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 2 of 84 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled “Double-blind, Randomized, Multicenter, 
Placebo-Controlled, Parallel Group Study to Characterize the Efficacy, Safety, and 
Tolerability of 24 Weeks of Evolocumab for Low Density Lipoprotein-Cholesterol (LDL-C) 
Reduction, as Add-On to Diet and Lipid-Lowering Therapy, in Pediatric Subjects 10 to 
17 Years of Age With Heterozygous Familial Hypercholesterolemia (HeFH)”, dated 
01 September 2015, and agree to abide by all provisions set forth therein.   
I agree to comply with the International Conference on Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines. 
I agree to ensure that Financial Disclosure Statements will be completed by: 
• 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
• 
my subinvestigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
at the start of the study and for up to one year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc. 
 
 
 
Signature 
 
 
Name of Investigator 
 
Date (DD Month YYYY) 
 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 3 of 84 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  Double-blind, Randomized, Multicenter, Placebo-controlled, Parallel Group Study to 
Characterize the Efficacy, Safety, and Tolerability of 24 Weeks of Evolocumab for Low Density 
Lipoprotein-cholesterol (LDL-C) Reduction, as Add-on to Diet and Lipid-lowering Therapy, in 
Pediatric Subjects 10 to 17 Years of Age With Heterozygous Familial Hypercholesterolemia 
(HeFH) 
Study Phase:  3b 
Indication:  Heterozygous familial hypercholesterolemia in pediatric subjects 
Primary Objective:  To evaluate the effect of 24 weeks of subcutaneous (SC) evolocumab 
compared with placebo, when added to standard of care, on percent change from baseline in 
low-density lipoprotein cholesterol (LDL-C) in pediatric subjects 10 to 17 years of age with HeFH. 
Secondary Efficacy Objectives:  to assess the effects of SC evolocumab compared with 
placebo, when added to standard of care, on mean percent change from baseline to weeks 22 
and 24 and change from baseline to week 24 in LDL-C, and on percent change from baseline to 
week 24 in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total 
cholesterol/HDL-C ratio, and ApoB/Apolipoprotein A-1 (ApoA1) ratio, in pediatric subjects 10 to 
17 years of age with HeFH 
Secondary Safety Objectives:  to evaluate the safety of SC evolocumab compared with 
placebo, when added to standard of care, in pediatric subjects 10 to 17 years of age with HeFH 
Secondary Pharmacokinetic Objective:  to characterize pharmacokinetic (PK) exposure 
Hypotheses:  The primary hypothesis is that SC evolocumab will be well tolerated and will result 
in greater reduction of LDL-C, defined as percent change from baseline to week 24, compared 
with placebo, when added to standard of care in pediatric subjects 10 to 17 years of age with 
HeFH. 
Primary Endpoint:  Percent change from baseline to week 24 in LDL-C 
Secondary Endpoints: 
• 
Mean percent change from baseline to weeks 22 and 24 in LDL-C 
• 
change from baseline to week 24 in LDL-C 
• 
percent change from baseline to week 24 in the following: 
− 
non-HDL-C 
− 
ApoB 
− 
total cholesterol/HDL-C ratio 
− 
ApoB/ApoA1 ratio 
Study Design: This is a randomized, multicenter, placebo-controlled, double-blind, parallel group 
study.  Subjects are eligible for screening if they are 10 to 17 years of age at time of 
randomization and have met the local applicable diagnostic criteria for HeFH.  Subjects 
considered for enrollment will undergo screening assessments, including laboratory screening by 
central laboratory.  Approximately 150 eligible subjects will be randomized in a 2:1 ratio to receive 
24 weeks of QM evolocumab or placebo.  Randomization will be stratified by screening LDL-C 
(< 160 mg/dL [4.1 mmol/L] vs ≥ 160 mg/dL) and age (< 14 years vs ≥ 14 years). 
The study includes collection of biomarker development samples.  Where permitted by local 
regulations, subjects will be invited to consent to pharmacogenetic analyses. 
After completion of Study 20120123, subjects will be offered to participate in an extension study 
where they will receive open-label evolocumab.  
Sample Size:  Approximately 150 subjects will be randomized. 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 4 of 84 
CONFIDENTIAL 
 
 
Summary of Subject Eligibility Criteria:  Males and females of 10 to 17 years of age with 
diagnosis of HeFH and receiving optimized standard of care lipid lowering therapy per locally 
applicable guidelines are eligible for this study. 
Subjects must have signed informed consent or subject assent for the study and appropriate 
parental/guardian consent must be available.  Subjects must be on a low-fat diet and must 
receive optimized background lipid-lowering therapy which includes a statin at optimal dose as 
determined by the managing physician not requiring uptitration in the opinion of the investigator.  
Lipid-lowering therapy must be stable for ≥ 4 weeks prior to screening.  Fasting LDL-C must be 
≥ 130 mg/dL (3.4 mmol/L) and fasting triglycerides must be ≤ 400 mg/dL (4.5 mmol/L) as 
determined by the central laboratory at screening. 
The following are the major exclusion criteria: homozygous familial hypercholesterolemia, 
type 1 diabetes or recently diagnosed (within 3 months of randomization) or poorly controlled 
(HbA1c > 8.5%) type 2 diabetes or newly diagnosed impaired glucose tolerance; thyroid 
stimulating hormone (TSH) < lower limit of normal (LLN) or TSH > 1.5x upper limit of normal 
(ULN) and free thyroxine (T4) levels that are outside normal range, estimated glomerular filtration 
rate (eGFR) < 30 ml/min/1.73m2, aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) > 2x ULN, creatine kinase (CK) > 3x ULN (all screening by central laboratory); known 
active infection, or major hematologic, renal, metabolic, gastrointestinal or endocrine dysfunction.  
Subjects are excluded if they have taken any cholesterylester transfer protein (CETP) inhibitor in 
the last 12 months, mipomersen or lomitapide in the last 5 months, lipid apheresis within the last 
12 weeks, or if they have previously received evolocumab or any other investigational therapy to 
inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9).  Subjects cannot be enrolled in 
another investigational device or drug study, receive other investigational agent(s) or procedures, 
or be within less than 30 days since ending another investigational device or drug study.  Female 
subjects of childbearing potential cannot be pregnant, planning to become pregnant, breast 
feeding or planning to breastfeed and must be willing to use acceptable method(s) of effective 
contraception  during treatment with IP (evolocumab or placebo) and for an additional 15 weeks 
after the end of treatment with IP (evolocumab or placebo). 
For a full list of eligibility criteria, please refer to Section 4.1.1 through Section 4.1.2.  
Investigational Product 
Amgen Investigational Product Dosage and Administration:  Evolocumab and placebo are 
Amgen investigational product (IP).  IP will be administered SC using a spring-based prefilled 
autoinjector/pen (prefilled AI/Pen).  Each prefilled AI/Pen will contain 1.0 mL deliverable volume, 
either 140 mg evolocumab or placebo. 
Non-Amgen Non-investigational Product Dosage and Administration:  Subjects will continue 
to use stable background lipid-lowering therapies as prescribed.  These therapies will not be 
provided by Amgen unless required by law. 
Procedures:  Subjects being considered for participation in this study, and who have signed 
informed consent or subject assent, will be assessed for inclusion and exclusion criteria.  Medical 
and medication history will be obtained.  Subjects will undergo screening assessments, including 
a SC administration of placebo to evaluate tolerability of the SC injection via the prefilled AI/pen.  
Lipid eligibility screening must be conducted after the subject has been on a low-fat diet and 
receiving lipid lowering therapy that includes an optimal dose of a statin not requiring uptitration in 
the opinion of the investigator and has been stable for ≥ 4 weeks.  Subjects should maintain their 
diet, lipid-lowering therapy, and exercise regimen unchanged throughout screening and all 
phases of study participation.  Eligible subjects will be randomized to receive IP (evolocumab or 
placebo), in addition to their background lipid lowering therapy.  An interactive voice response 
system and/or interactive web response system (IVRS/IWRS) will allocate subjects to 
administration of investigational product.  Day 1 is defined as the day of first administration of 
investigational product.  Subsequent study visits are at weeks 4, 12, 20, 22, and 24 (EOS, 
end-of-study).  Day 1 and week 24 visits must be scheduled at approximately the same time of 
day, and should be performed as close as possible to 8 am as the hormones measured have 
diurnal variation.  IP administration is every 4 weeks.  Administration at weeks 8 and 16 can be at 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 5 of 84 
CONFIDENTIAL 
 
 
the study site (optional visit) or at a location other than the study site.  Last administration of IP is 
at week 20.  Subjects who discontinue IP early for any reason will be asked to continue to return 
for all other study procedures and measurements until the end of the study. 
Assessments and procedures include vital signs, adverse events/serious adverse 
events/adverse device effects (ADE)/disease related events(DRE)/cardiovascular (CV) 
events, and concomitant therapy, dietary instruction, physical exam including neurologic 
examination and assessment of waist circumference, body height and weight, 12-lead 
electrocardiograms (ECGs), fasting lipids, chemistry, hematology, anti-evolocumab antibodies, 
biomarker sample collection, serum pregnancy testing (females of childbearing potential), 
urinalysis, assessment of growth and pubertal development (Tanner staging), Cogstate 
neurocognitive assessment, carotid intima-media thickness (cIMT), and IP administration.  In 
addition, specific laboratory assessments will be performed, including estradiol for girls, 
testosterone for boys, creatinine phosphokinase, follicle-stimulating hormone, luteinizing 
hormone, adenocorticotropic hormone, dehydroepiandrosterone, and cortisol.  If the subject 
consented to pharmacogenetics analyses, DNA will be extracted from some of the blood 
samples.  IP administration by SC injection, if applicable, will be done after all other procedures 
have been completed.  
For a full description of procedures, please refer to Section 7. 
Statistical Considerations:   
General Considerations 
Efficacy and safety analyses will be performed on the full analysis set (FAS), which includes all 
randomized subjects who have received at least 1 dose of IP. 
The superiority of evolocumab to placebo will be assessed for all efficacy endpoints. 
Methods of adjusting for multiplicity due to multiple endpoints are provided in Section 10.5.1 
Events of death, myocardial infarction (MI), hospitalization for unstable angina, coronary 
revascularization, stroke, transient ischemic attack (TIA), and hospitalization for heart failure will 
be adjudicated by an independent Clinical Events Committee (CEC). Subject incidence of 
exploratory endpoint events will be summarized for each treatment group. 
Analysis of Primary Efficacy Endpoint 
To assess the primary endpoint of percent change from baseline in LDL-C at week 24, a repeated 
measures linear mixed effects model will be used to compare the efficacy of evolocumab with 
placebo. Missing values will not be imputed when the repeated measures linear mixed effects 
model is used.   
Analyses of Secondary Efficacy Endpoints 
The statistical model for the secondary efficacy endpoints will be similar to the primary endpoint. 
Safety Analyses 
Safety summaries will include the subject incidence of adverse events, summaries of laboratory 
parameters, vital signs, and anti-evolocumab antibodies.   
An independent data monitoring committee (DMC) will formally review the accumulating data 
from this and other completed and ongoing studies with evolocumab to ensure there is no 
avoidable increased risk for harm to subjects.  Analyses for the DMC will be provided by a group 
which is external to Amgen. 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen 
Data Element Standards 
Version(s)/Date(s):  
Version 4.1 / 20 June 2014 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 6 of 84 
CONFIDENTIAL 
 
 
Study Design and Treatment Schema 
 
QM = dosed monthly; IP = investigational product  


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 7 of 84 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ADE 
Adverse device effect 
ADHD 
attention deficit hyperactivity disorder 
AE 
Adverse event 
AI/Pen 
Autoinjector pen 
ALP 
Alkaline phosphatase 
ALT (SGPT) 
Alanine aminotransferase (serum glutamic-pyruvic transaminase) 
AMD 
Automated mini doser 
ApoA1 
Apolipoprotein A-1 
ApoB 
Apolipoprotein B 
AST (SGOT) 
Aspartate aminotransferase (serum glutamic-oxaloacetic 
transaminase) 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CAD 
Coronary artery disease 
CAS 
Completer analysis set 
CEC 
Clinical events committee 
CETP 
Cholesterylester transfer protein 
CHD 
Coronary heart disease 
CK 
Creatine kinase 
CTCAE 
Common Terminology Criteria for Adverse Events 
DET 
Detection (Test) 
DHEA-S 
Dehydroepiandrosterone sulfate 
DILI 
Drug-induced liver injury 
DMC 
Data monitoring committee (Efficacy and Safety Evaluation 
Committee) 
DNA 
Deoxyribonucleic acid 
DRE 
Disease related event 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR  
Estimated glomerular filtration rate; eGFR will be calculated by the 
central laboratory and provided to the investigator. 
Electronic Source Data 
(eSource)  
Source data captured initially into a permanent electronic record 
used for the reconstruction and evaluation of a trial. 
End of Follow-up 
Defined as when the last subject completes the last 
protocol-specified assessment in the study 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 8 of 84 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
End of Study (end of trial) Defined as when the last subject is assessed or receives an 
intervention for evaluation in the study; if the study includes multiple 
parts (eg, safety follow-up or survival assessment), the end of study 
would include these additional parts 
End of Study (primary 
completion) 
The end of the study (primary completion) is defined as the last day 
on which a randomized subject in this study completes the 
end-of-study visit (week 24) or terminates the study early 
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 
EOS 
End-of-study (for the individual subject) 
eSAE contingency report 
form 
Electronic serious adverse event contingency report form 
FAS 
Full analysis set 
FH 
Familial hypercholesterolemia 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GMLT 
Groton Maze Learning Task  
HCV 
Hepatitis C virus 
HDL-C 
High density lipoprotein cholesterol 
HeFH 
Heterozygous familial hypercholesterolemia 
HoFH 
Homozygous familial hypercholesterolemia 
HR 
Heart Rate 
hsCRP 
High sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
IBG 
Independent Biostatistical Group 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IDN 
Identification (Test) 
IEC 
Independent ethics committee 
IFU 
Instructions for Use 
IP 
Investigational product (evolocumab or placebo, administered with 
the medical device used in this study – the prefilled autoinjector/pen 
[AI/pen]) 
INR 
International normalized ratio 
Interactive Voice 
Response (IVR) 
Telecommunication technology that is linked to a central computer in 
real time as an interface to collect and process information.  


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 9 of 84 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
Interactive Web 
Response (IWR) 
Web based technology that is linked to a central computer in real 
time as an interface to collect and process information.  
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Board 
IVRS/IWRS 
Interactive Voice Response System / Interactive Web Response 
System 
LDH 
Lactate dehydrogenase 
LDL-C 
Low-density lipoprotein cholesterol 
LDLR 
Low-density lipoprotein receptor 
LLN 
Lower limit of normal 
LOF 
Loss-of-function 
Lp(a) 
Lipoprotein(a) 
Monthly 
Defined as every 4 weeks with a window of ± 3 days.  For practical 
considerations, study visits are scheduled based on a weekly 
calendar with a window of +/- 3 days for each visit, thus dosing 
intervals are allowed to be up to 31 days for the QM regimen. 
NASH 
Nonalcoholic steatohepatitis 
NCI 
National Cancer Institute 
OCL 
One Card Learning (Test) 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PD 
Pharmacodynamic 
PFS 
Pre-filled syringe 
PI 
Principal investigator 
PK 
Pharmacokinetic(s) 
Q2W 
Q2W is defined as every 2 weeks with a window of ± 3 days for each 
visit, thus dosing intervals are allowed to be up to 17 days for the 
Q2W regimen. Note: Day 1 and week 24 visits must be scheduled at 
approximately the same time of day, and should be performed as 
close as possible to 8 am as the hormones measured have diurnal 
variation. 
QM 
QM is defined as every 4 weeks with a window of ± 3 days for each 
visit, thus dosing intervals are allowed to be up to 31 days for the 
QM regimen. Note: Day 1 and week 24 visits must be scheduled at 
approximately the same time of day, and should be performed as 
close as possible to 8 am as the hormones measured have diurnal 
variation. 
RBC 
Red blood cells 
SAE 
Serious adverse event 
SC 
Subcutaneous 
SoC 
Standard of care 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 10 of 84 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
Source Data 
Information from an original record or certified copy of the original 
record containing patient information for use in clinical research.  
The information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained 
in source documents (original records or certified copies). (ICH 
Guideline (E6)).  Examples of source data include Subject 
identification, Randomization identification, and Stratification Value. 
Study Day 1 
Defined as the first day that protocol-specified investigational 
product is administered to the subject 
TBL 
Total bilirubin 
TIA 
Transient ischemic attack 
TNF 
Tumor necrosis factor 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper limit of normal 
VLDL-C 
Very low-density lipoprotein cholesterol 
WBC 
White blood cell 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 11 of 84 
CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................ 3 
Study Design and Treatment Schema ............................................................................. 6 
Study Glossary ................................................................................................................ 7 
1. 
OBJECTIVES ....................................................................................................... 15 
1.1 
Primary ..................................................................................................... 15 
1.2 
Secondary Efficacy ................................................................................... 15 
1.3 
Secondary Safety ...................................................................................... 15 
1.4 
Secondary Pharmacokinetic ...................................................................... 15 
1.5 
Tertiary ...................................................................................................... 15 
1.6 
Exploratory ................................................................................................ 15 
2. 
BACKGROUND AND RATIONALE ...................................................................... 16 
2.1 
Hypercholesterolemia and the Pediatric Population .................................. 16 
2.2 
Amgen Investigational Product .................................................................. 17 
2.2.1 
Background and Nonclinical Studies ......................................... 17 
2.2.2 
Clinical Studies .......................................................................... 18 
2.3 
Pediatric Risk Assessment ........................................................................ 20 
2.4 
Rationale ................................................................................................... 22 
2.5 
Clinical Hypotheses ................................................................................... 23 
3. 
EXPERIMENTAL PLAN ........................................................................................ 23 
3.1 
Study Design ............................................................................................. 23 
3.2 
Number of Sites ........................................................................................ 24 
3.3 
Number of Subjects ................................................................................... 24 
3.4 
Replacement of Subjects .......................................................................... 24 
3.5 
Estimated Study Duration .......................................................................... 24 
3.5.1 
Study Duration for Subjects ....................................................... 24 
3.5.2 
End of Study .............................................................................. 24 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 25 
4.1 
Inclusion and Exclusion Criteria ................................................................ 25 
4.1.1 
Inclusion Criteria ........................................................................ 25 
4.1.2 
Exclusion Criteria ...................................................................... 25 
5. 
SUBJECT ENROLLMENT .................................................................................... 27 
5.1 
Randomization/Treatment Assignment ...................................................... 28 
5.2 
Site Personnel Access to Individual Treatment Assignments .................... 28 
6. 
TREATMENT PROCEDURES .............................................................................. 28 
6.1 
Classification of Products and Medical Devices......................................... 28 
6.2 
Amgen Investigational Product Evolocumab and Placebo ......................... 29 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 12 of 84 
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6.2.1 
Dosage, Administration, and Schedule ...................................... 29 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 30 
6.3 
Other Protocol-required Therapies ............................................................ 30 
6.4 
Withholding of Amgen Investigational Product or Statin 
Background Therapy due to Elevation of Creatine Kinase (CK) ................ 31 
6.5 
Hepatotoxicity Stopping and Rechallenge Rules ....................................... 31 
6.5.1 
Criteria for Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ................................. 31 
6.5.2 
Criteria for Conditional Withholding of Amgen 
Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ................................. 32 
6.5.3 
Criteria for Rechallenge of Amgen Investigational 
Product and Other Protocol-required Therapies After 
Potential Hepatotoxicity ............................................................. 33 
6.6 
Concomitant Therapy ................................................................................ 33 
6.7 
Medical Devices ........................................................................................ 33 
6.8 
Product Complaints ................................................................................... 34 
6.9 
Excluded Treatments and/or Procedures During Study Period .................. 35 
7. 
STUDY PROCEDURES ....................................................................................... 35 
7.1 
Schedule of Assessments ......................................................................... 35 
7.2 
General Study Procedures ........................................................................ 38 
7.2.1 
Screening Enrollment and Randomization ................................. 40 
7.2.1.1 
Screening Placebo Administration ........................... 40 
7.2.1.2 
Screening ................................................................ 40 
7.2.1.3 
Randomization ........................................................ 41 
7.2.1.4 
Retesting ................................................................. 42 
7.2.1.5 
Rescreening ............................................................ 42 
7.2.1.6 
Screen Fail .............................................................. 42 
7.2.2 
Treatment and End of Study ...................................................... 42 
7.3 
Antibody Testing Procedures .................................................................... 44 
7.4 
Biomarker Development ............................................................................ 44 
7.5 
Pharmacogenetic Studies ......................................................................... 45 
7.6 
Sample Storage and Destruction ............................................................... 45 
7.7 
Standardization of Study Procedures ........................................................ 46 
7.7.1 
Measurement of Vital Signs ....................................................... 46 
7.7.2 
Height, Weight, and Waist Circumference ................................. 47 
7.7.3 
Tanner Staging (Sexual Maturity Ratings) ................................. 48 
7.7.4 
Carotid Intima-Media Thickness (cIMT) ..................................... 48 
7.7.5 
Electrocardiograms.................................................................... 48 
7.7.6 
Lipid Measurements .................................................................. 49 
7.7.7 
Neurocognitive Assessments .................................................... 49 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 13 of 84 
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7.7.8 
Neurologic Examination ............................................................. 50 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 51 
8.1 
Subjects’ Decision to Withdraw ................................................................. 51 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 51 
8.3 
Reasons for Removal From Screening, Treatment, or Study..................... 52 
8.3.1 
Reasons for Removal From Screening ...................................... 52 
8.3.2 
Reasons for Removal From Treatment ...................................... 52 
8.3.3 
Reasons for Removal From Study ............................................. 52 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 52 
9.1 
Adverse Events ......................................................................................... 52 
9.1.1 
Definition of Adverse Events ...................................................... 52 
9.1.2 
Definition of Serious Adverse Events ......................................... 53 
9.1.3 
Definition of Disease-related Events .......................................... 54 
9.2 
Reporting of Adverse Events ..................................................................... 54 
9.2.1 
Reporting Procedures for Adverse Events That do not 
Meet Serious Criteria ................................................................. 54 
9.2.2 
Reporting Procedures for Serious Adverse Events .................... 56 
9.2.3 
Reporting Procedures for Disease-related Events ..................... 58 
9.3 
Pregnancy and Lactation Reporting .......................................................... 58 
10. 
STATISTICAL CONSIDERATIONS ...................................................................... 59 
10.1 
Study Endpoints, Analysis Sets, and Covariates ....................................... 59 
10.1.1 
Study Endpoints ........................................................................ 59 
10.1.1.1 
Primary Efficacy Endpoint ....................................... 59 
10.1.1.2 
Secondary Efficacy Endpoints ................................. 59 
10.1.1.3 
Tertiary Efficacy Endpoints ...................................... 59 
10.1.1.4 
Exploratory Endpoints ............................................. 60 
10.1.1.5 
Secondary Safety Endpoints ................................... 60 
10.1.1.6 
Secondary Pharmacokinetics Endpoints ................. 60 
10.1.1.7 
Other Safety Endpoints ........................................... 60 
10.1.2 
Analysis Sets ............................................................................. 61 
10.1.3 
Baseline Covariates and Subgroups .......................................... 61 
10.2 
Sample Size Considerations ..................................................................... 61 
10.3 
Access to Individual Subject Treatment Assignments by Amgen 
or Designees ............................................................................................. 62 
10.4 
Planned Analyses ..................................................................................... 62 
10.4.1 
Data Monitoring Committee (DMC) ............................................ 62 
10.4.2 
Primary Analysis ........................................................................ 62 
10.5 
Planned Methods of Analysis .................................................................... 62 
10.5.1 
General Considerations ............................................................. 62 
10.5.2 
Primary Efficacy Endpoint Analyses .......................................... 63 


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10.5.3 
Secondary Efficacy Endpoints Analyses .................................... 64 
10.5.4 
Tertiary Efficacy Endpoint Analyses .......................................... 64 
10.5.5 
Secondary Safety and Pharmacokinetic Endpoint 
Analyses ................................................................................... 64 
10.5.6 
Other Safety Endpoint Analyses ................................................ 65 
10.5.7 
Exploratory Endpoint Analyses .................................................. 65 
11. 
REGULATORY OBLIGATIONS ............................................................................ 66 
11.1 
Informed Consent ...................................................................................... 66 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 67 
11.3 
Subject Confidentiality ............................................................................... 67 
11.4 
Investigator Signatory Obligations ............................................................. 68 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................. 68 
12.1 
Protocol Amendments and Study Termination .......................................... 68 
12.2 
Study Documentation and Archive ............................................................ 69 
12.3 
Study Monitoring and Data Collection ....................................................... 70 
12.4 
Investigator Responsibilities for Data Collection ........................................ 71 
12.5 
Language .................................................................................................. 71 
12.6 
Publication Policy ...................................................................................... 71 
12.7 
Compensation ........................................................................................... 72 
13. 
REFERENCES ..................................................................................................... 73 
14. 
APPENDICES ...................................................................................................... 76 
List of Tables 
Table 1.  Schedule of Assessments ............................................................................... 36 
Table 2.  Analyte Listing1 ............................................................................................... 39 
List of Appendices 
Appendix A.  Additional Safety Assessment Information ................................................ 77 
Appendix B.  Sample Electronic Serious Adverse Event (eSAE) Contingency 
Report Form ........................................................................................... 79 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................... 82 
Appendix D.  Tanner Stages (Sexual Maturity Ratings) ................................................. 84 


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1. 
OBJECTIVES 
1.1 
Primary 
To evaluate the effect of 24 weeks of subcutaneous (SC) evolocumab compared with 
placebo, when added to standard of care, on percent change from baseline in 
low-density lipoprotein cholesterol (LDL-C) in pediatric subjects 10 to 17 years of age 
with heterozygous familial hypercholesterolemia (HeFH). 
1.2 
Secondary Efficacy 
• 
to assess the effects of SC evolocumab compared with placebo, when added to 
standard of care, on mean percent change from baseline to weeks 22 and 24 and 
change from baseline to week 24 in LDL-C, and on percent change from baseline to 
week 24 in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B 
(ApoB), total cholesterol/HDL-C ratio, and ApoB/Apolipoprotein A-1 (ApoA1) ratio, in 
pediatric subjects 10 to 17 years of age with HeFH 
1.3 
Secondary Safety 
• 
to evaluate the safety of SC evolocumab compared with placebo, when added to 
standard of care, in pediatric subjects 10 to 17 years of age with HeFH 
1.4 
Secondary Pharmacokinetic 
• 
to characterize pharmacokinetic (PK) exposure 
1.5 
Tertiary 
• 
to assess the effects of SC evolocumab compared with placebo, when added to 
standard of care, on percent change from baseline to week 24 in total cholesterol, 
very low-density lipoprotein cholesterol (VLDL-C), HDL-C, ApoA1, triglycerides, and 
lipoprotein(a) [Lp(a)], in pediatric subjects 10 to 17 years of age with HeFH 
• 
to assess the effects of SC evolocumab compared with placebo, when added to 
standard of care, on mean percent change from baseline to weeks 22 and 24 in 
non-HDL-C, ApoB, total cholesterol/HDL-C ratio, ApoB/ApoA1 ratio, total cholesterol, 
very low-density lipoprotein cholesterol (VLDL-C), HDL-C, ApoA1, triglycerides, and 
Lp(a), in pediatric subjects 10 to 17 years of age with HeFH 
1.6 
Exploratory 


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2. 
BACKGROUND AND RATIONALE 
2.1 
Hypercholesterolemia and the Pediatric Population 
Hypercholesterolemia (elevated serum low-density lipoprotein cholesterol [LDL-C]) is an 
established risk factor for coronary heart disease (CHD) in humans (Grundy et al, 2004), 
and more  than 50 million patients are treated for hypercholesterolemia in the United 
States and Europe (Kuklina et al, 2011; Kotseva et al, 2009; Tolonen et al, 2005).  
Cholesterol elevations requiring pharmacologic therapy are uncommon in children.  
However, patients with familial hypercholesterolemia (FH), an almost exclusively 
autosomal dominant condition most often resulting from deficient or defective LDLR 
function (Rader et al, 2003), have elevated LDL-C beginning in childhood.  Since FH is a 
genetic condition, the prevalence among children is very similar to the prevalence 
among younger adults. 
In the pediatric population, FH may be identified by the combination of elevated LDL-C 
and a positive family history of hypercholesterolemia and/or premature cardiovascular 
disease.  HeFH affects approximately one out of every 200 to 500 people worldwide 
(National Collaborating Centre, 2008; Nordestgaard et al, 2013; Rader et al, 2003).  By 
comparison, homozygous FH (HoFH) is present in approximately 1 in 1,000,000 
individuals (Goldstein et al, 2001).  Without treatment, these patients have severe 
hypercholesterolemia, develop premature coronary artery disease, and are at increased 
risk for premature cardiovascular death (Rader et al, 2003). 
In the adult population, hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase 
inhibitors (statins) are currently the treatment of choice for both heterozygous FH 
patients and homozygous FH patients (Grundy et al, 2004), as statins inhibit 
endogenous cholesterol biosynthesis and upregulate LDLR expression (increasing the 
activity of functional LDLR) (Rader et al, 2003).  Although statins reduce mortality in this 
patient population (Raal et al, 2011), cholesterol levels may remain elevated in FH 
patients despite therapy with diet, exercise, and medications.  
Pediatric guidelines in the United States (Daniels and Greer, 2008;  
McCrindle et al, 2007; Kavey et al, 2006) recommend considering pharmacologic 


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treatment after initial treatment with lifestyle modification has failed in patients ≥ 10 years 
of age with LDL-C that is: 
 ≥ 130 mg/dL (3.4 mmol/L) for the highest risk (eg, diabetes mellitus) 
 ≥ 160 mg/dL (4.1 mmol/L) for intermediate risk (eg, ≥ 2 other CHD risk factors, 
family history of premature coronary artery disease [CAD]) 
 ≥ 190 mg/dL (4.9 mmol/L) for the lowest risk (no cardiovascular risk factors) 
Similarly, treatment guidelines from the European Society of Cardiology and European 
Atherosclerosis Society (ESC/EAS; Reiner et al, 2011) and from the National Institute for 
Health and Clinical Excellence (NICE; National Collaborating Centre, 2008) recommend 
statin treatment in patients who are ≥ 10 years of age and have HeFH or HoFH, and 
consider pharmacologic treatment for subjects with HoFH at earlier ages 
(Reiner et al, 2011).  When a child with FH has exceptionally high LDL-C and/or 
cardiovascular risk, bile acid sequestrants and ezetimibe are also indicated and may be 
used in combination. 
Thus, while currently available therapies can reduce LDL-C levels, novel therapies that 
can be used alone or in combination with existing agents to more effectively reduce 
LDL-C would be valuable for both adults and pediatric patients with severely elevated 
cholesterol levels.  
2.2 
Amgen Investigational Product  
2.2.1 
Background and Nonclinical Studies 
Recycling of the hepatic cell surface low-density lipoprotein receptor (LDLR) plays a 
critical role in regulating serum LDL-C levels.  Proprotein convertase subtilisin/kexin 
type 9 (PCSK9) binds to the LDLR and down regulates hepatic cell surface LDLR, 
which, in turn, leads to increased levels of circulating LDL-C.  Humans with PCSK9 
loss-of-function mutations have cholesterol levels lower than normal and reduced 
incidence of CHD (Abifadel et al, 2009).  Evolocumab (formerly referred to as AMG 145) 
is a fully human monoclonal immunoglobulin G2 (IgG2), 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. 
Evolocumab binds to human, cynomolgus monkey, and hamster PCSK9 with a similar 
high affinity (dissociation equilibrium constant [KD] = 16, 8, and 14 pM, respectively) and 


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is pharmacologically active in both animal species.  Evolocumab exhibited nonlinear PK 
consistent with target-mediated elimination and a low volume of distribution (Vss/F) 
indicating limited tissue distribution.  A concentration-response relationship was 
observed between serum unbound evolocumab, free PCSK9, and LDL-C. 
Evolocumab-related effects were limited to expected pharmacology (serum LDL-C and 
total cholesterol lowering).  Toxicological assessments included repeated dose studies in 
the hamster and cynomolgus monkey (up to 3- and 6-months, respectively) at 
evolocumab dose levels up to 300 mg/kg, a 3-month repeated dose study in the 
cynomolgus monkey in which evolocumab was dosed in combination with rosuvastatin, 
a hamster carcinogenicity study, a hamster fertility study, and an enhanced pre-post 
natal development study in the cynomolgus monkey.  No evolocumab-related adverse 
effect was observed in any study. 
Refer to the specific sections of the AMG 145 Investigators Brochure for additional 
information related to the physical, chemical, and pharmaceutical properties of 
evolocumab. 
2.2.2 
Clinical Studies 
Evolocumab is intended for long-term use and has been evaluated in approximately 
6800 subjects in 26 clinical studies to date.  Regulatory submissions have been filed in 
several jurisdictions, including to the Food and Drug Administration (FDA) in the United 
States and to the European Medicines Agency (EMA) in Europe.  The submissions are 
based on a phase 3 program which evaluated evolocumab administered every two 
weeks and monthly in various treatment settings (ie, in combination with statins, 
statin-intolerant, heterozygous familial hypercholesterolemia [HeFH] or as an adjunct to 
diet [monotherapy]).  Additional studies with evolocumab are ongoing or planned, 
including studies to provide additional long-term safety and efficacy data, studies to 
determine the effect of evolocumab on coronary atherosclerosis, and studies to evaluate 
the effects of evolocumab on lipoprotein metabolism.  The FOURIER trial is a large 
cardiovascular outcomes trial that is ongoing. 
The combined PK data including phase 1, 2 and 3 studies have consistently shown that 
evolocumab displays approximately dose-proportional increases in exposure for 
repeated dose regimens ≥ 140 mg SC. 
Pharmacodynamic (PD) studies explored LDL-C and unbound PCSK9 responses after 
administration of a wide range of SC doses and dosing frequencies.  With the 140 mg 


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once every 2 weeks (Q2W) and 420 mg QM (once monthly) regimens, maximal LDL-C 
reduction was observed at 1 week or 2 weeks following administration, respectively, and 
returned towards baseline at the end of the dosing interval. 
A side-by-side analysis of efficacy across the individual phase 3 primary hyperlipidemia 
and mixed dyslipidemia studies demonstrated the following for evolocumab administered 
140 mg Q2W and 420 mg QM: 
• 
Evolocumab was superior to placebo in reducing LDL-C (approximately 55% to 75% 
compared with placebo), total cholesterol, apolipoprotein B (ApoB), non-high density 
lipoprotein cholesterol (non-HDL-C), total cholesterol/high-density lipoprotein 
cholesterol (HDL-C), and ApoB/apolipoprotein A1(ApoA1) very low-density 
lipoprotein cholesterol (VLDL-C), triglycerides, lipoprotein(a) (Lp[a]), and increasing 
HDL-C and ApoA1. 
• 
Evolocumab reduced LDL-C as early as week 1 following administration, generally 
achieved maximal response within 1 to 2 weeks after dosing with 140 mg Q2W and 
420 mg QM, respectively, and maintained efficacy with long-term use. 
• 
Reductions in LDL-C and improvements in other lipid parameters were reversible 
upon cessation of treatment, with no evidence of rebound. 
• 
Evolocumab 140 mg Q2W and 420 mg QM dosing regimens were clinically 
equivalent; no clinically meaningful differences, with respect to reductions in LDL-C 
and improvements in other lipid parameters, were noted between the 2 doses. 
• 
Evolocumab 140 mg Q2W and 420 mg QM dosing regimens were effective in all 
subgroups relative to placebo and ezetimibe with no notable differences observed 
among subgroups (ie, age, race, gender, region, body mass index, current smoking 
status, baseline CHD risk factors, family history of premature CHD, glucose 
tolerance status [diabetes mellitus type 2, metabolic syndrome, or neither], 
hypertension, unbound baseline PCSK9, baseline LDL-C, baseline triglycerides, and 
National Cholesterol Education Program [NCEP], 2002 high risk status). 
• 
Administration of evolocumab with the prefilled autoinjector/pen (AI/pen) was shown 
to be safe and effective for its intended use and the conditions of use, including 
self-administration in the home-use setting. 
The results of the analyses conducted in the primary hyperlipidemia (heterozygous 
familial and nonfamilial) and mixed dyslipidemia integrated safety analysis set for 
evolocumab demonstrated the following with respect to safety:  
• 
In the integrated parent studies, the most common (≥ 2%) adverse events in the 
combined evolocumab group or control group were nasopharyngitis, upper 
respiratory tract infection, headache, back pain, and myalgia.  Common adverse 
events in the year 1 standard of care (SoC)-controlled period did not include 
headache and myalgia; otherwise, common adverse events were the same as 
integrated parent studies with the addition of arthralgia and hypertension.  There 
were no additional common adverse events during the year 2+ open-label extension 
(OLE) period. 


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• 
The types and incidence of adverse events were consistent across studies where 
evolocumab was given as monotherapy, in combination therapy with statins (with or 
without ezetimibe) or in subjects with statin intolerance. 
• 
Most adverse events were grade 1 or 2. 
• 
Serious adverse events, deaths, positively adjudicated clinical events, and adverse 
events leading to discontinuation of investigational product (IP) were infrequently 
reported and similar across treatment groups. 
• 
No safety issues were detected for adverse events of interest associated with other 
lipid-lowering therapies (ie, diabetes adverse events, liver-related adverse events, 
muscle-related adverse events, neurocognitive adverse events) and those that could 
theoretically be associated with PCSK9 inhibition/LDL-C receptor upregulation (ie, 
hepatitis C events).  No cognitive adverse events have been reported among 
adolescents in the completed Study 20110233 or in the ongoing open-label 
evolocumab-only Study 20110271. 
• 
The device-related adverse events from the 3 SC presentations (ie, pre-filled syringe 
[PFS], prefilled AI/pen, and automated mini doser [AMD]) were uncommon, mostly 
grade 1, and generally limited to injection site reactions. 
• 
An evaluation of vitamin E data showed that long-term evolocumab exposure 
(52 weeks) did not change normalized vitamin E levels, regardless of LDL-C 
concentration.  Similarly, long-term evolocumab exposure (52 weeks) did not affect 
steroid hormone levels (cortisol, adrenocorticotropic hormone, follicle-stimulating 
hormone, luteinizing hormone, testosterone, or estradiol), regardless of LDL-C 
concentration. 
• 
The type and incidence of adverse events observed in subjects with LDL-C 
concentrations < 25 mg/dL (< 0.6 mmol/L) and < 40 mg/dL (< 1.0 mmol/L) were 
similar to those observed in subjects with LDL-C concentrations ≥ 40 mg/dL 
(≥ 1.0 mmol/L).  In particular, no safety signal was identified for neurocognitive 
adverse events, vitamin E levels, or steroid analytes based on LDL-C concentrations. 
• 
Presence of anti-evolocumab antibodies was infrequent, non-neutralizing, and not 
associated with clinically relevant adverse events. 
Refer to the AMG 145 Investigators Brochure for additional information regarding the 
clinical experience with evolocumab. 
2.3 
Pediatric Risk Assessment 
Loss-of-function (LOF) mutations of the PCSK9 gene are associated with low serum 
LDL-C levels (≤ 100 mg/dL [2.6 mmol/L]) (Cohen et al, 2005).  Subjects with 
heterozygous PCSK9 LOF mutations exhibit lower serum PCSK9 levels and as much as 
88% reduction in the incidence of CHD over a 15-year period compared with noncarriers 
of the mutations (Cohen et al, 2006).  Importantly, despite complete loss of PCSK9 and 
associated very low serum LDL-C levels (< 20 mg/dL [0.5 mmol/L]), 2 subjects with 
LOF mutations in both PCSK9 alleles appear healthy (Hooper et al, 2007; Zhao 2006). 


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The subjects in this study are a pediatric population.  In Amgen’s development program 
for evolocumab, 2 studies to date have included pediatric subjects along with adults.  
The completed Study 20110233 was a phase 2/3 study of subjects 12 to 80 years of age 
with HoFH; Part A of Study 20110233 was an open-label pilot study in 8 subjects and 
Part B of Study 20110233 was a randomized, double-blind, placebo-controlled study of 
49 subjects (Raal et al., 2014).  The ongoing Study 20110271 is a phase 2/3, 
multicenter, open-label study of evolocumab in approximately 310 subjects 12 to 
80 years of age with severe FH. 
To date, 15 subjects < 18 years of age and with HoFH or compound HeFH have been 
enrolled in Studies 20110233 and 20110271; 10 participated in both studies, 
4 participated only in Study 20110271, and 1 participated only in Study 20110233.  
Based on the most recent data cut off of 01 July 2014, all adolescent subjects in 
Study 20110271 have HoFH.  Per protocol, the non-apheresis subjects (n=10) began 
the study on 420 mg QM, while the apheresis subjects (n=4) began the study on 420 mg 
Q2W.  In general, no differences in the safety profile have been seen in pediatric 
subjects relative to adults.  In Study 20110271, the subject incidences of treatment 
emergent adverse events and serious adverse events were 71% and 14% among 
adolescents, compared to 68% and 10% among all subjects with HoFH.  Average 
exposure to evolocumab was longer among adolescents, median 11.4 months vs 
7.5 months in adults with HoFH.  Among pediatric subjects, a total of 28 adverse events 
have been reported in Study 20110271.  All but 2 of these events were deemed 
non-serious and were Common Terminology Criteria for Adverse Events (CTCAE) 
grade 1 or 2.  The 2 serious adverse events (worsening of chest pain and occlusive 
coronary artery disease) were both CTCAE grade 3 and unrelated to IP, and are both 
known cardiovascular consequences of the subjects’ underlying FH.  No serious adverse 
events were deemed by the investigator to be related to evolocumab. 
The dose of 420 mg evolocumab SC was selected based on pharmacokinetic modeling 
for this pediatric age group (Section 2.4) and is supported by the current safety 
experience with the same dosing in pediatric subjects in Studies 20110233 and 
20110271. 
As in studies with adult subject, the subjects in this study will be monitored for the 
development of anti-evolocumab antibodies.  To date, the overall immunogenicity rate is 
< 1% and the formation of neutralizing anti-evolocumab antibodies has not been 
observed. 


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Volumes of blood withdrawn for analysis will be minimized as appropriate for this 
pediatric population. 
2.4 
Rationale 
FH is a genetic disorder which typically requires lifelong treatment, sometimes beginning 
in childhood.  It is therefore important to study the safety and efficacy of potential 
treatments for FH in children and adolescents.  Because developmental processes that 
are complete in adults are ongoing in children and adolescents, additional safety 
assessments (eg, biochemical and clinical assessments of puberty, carotid intimal 
medial thickness, and cognition) are also appropriate.  Data from a dedicated 
randomized placebo-controlled study of evolocumab and adolescents will support the 
existing data from nonclinical studies in ages corresponding to human adolescence and 
clinical data from adolescent subjects participating in the TESLA and TAUSSIG studies.  
The safety and efficacy of evolocumab 420 mg SC QM in adults have been extensively 
studied in phase 2 and phase 3 clinical trials.  Additionally, in the two studies that have 
included pediatric subjects (TESLA and TAUSSIG), evolocumab lowered LDL-C and 
other lipid parameters in subjects aged 12-17 years.  The percent change from baseline 
in LDL-C has been chosen as the primary assessment for this study because of the 
extensive body of data from interventional studies and epidemiological evidence 
demonstrating a strong causal relationship between serum LDL cholesterol, and the risk 
of CHD.  These data also support the relationship with other clinical manifestations of 
atherosclerosis such as cerebrovascular disease (stroke) or peripheral vascular disease.  
These relationships are present over a broad range of LDL-C levels.  Additionally, 
current guidelines focus on LDL-C as a target for therapy. 
Non-HDL cholesterol (non-HDL-C), ApoB, the ratio of total cholesterol/HDL-C, the ratio 
of ApoB/ApoA1, and Lp(a) have been included as secondary efficacy endpoints because 
these markers are known as useful markers of cardiovascular risk under certain 
circumstances and because they may be employed as future targets for lipid lowering 
therapy. 
Additional endpoints include triglycerides and HDL-C because data in adults 
demonstrates lowering of triglycerides and raising of HDL-C with evolocumab.  In 
addition, triglycerides and HDL-C are independent risk factors for cardiovascular disease 
(Austin et al, 1998; Sarwar et al, 2007). 


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Pharmacokinetic data from the 2 studies with evolocumab that included adults as well as 
pediatric subjects age 12 years and older (Studies 20110233 and 20110271) show that 
exposure among pediatric subjects is comparable to that seen in adults of similar weight.  
Further pharmacokinetic modeling to predict the optimal dosing regimen for pediatric 
subjects 10 to 17 years of age shows that the exposure with monthly administration of 
420 mg evolocumab SC in these subjects is expected to fall within in the range observed 
to date in the evolocumab development program. 
2.5 
Clinical Hypotheses 
The primary hypothesis is that SC evolocumab will be well tolerated and will result in 
greater reduction of LDL-C, defined as percent change from baseline to week 24, 
compared with placebo, when added to standard of care in pediatric subjects 10 to 
17 years of age with HeFH 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a randomized, placebo-controlled, double-blind, parallel group, multicenter study. 
Subjects are eligible for screening if they are 10 to 17 years of age at time of 
randomization and have met the local applicable diagnostic criteria for HeFH.  Subjects 
considered for enrollment will undergo screening assessments, including laboratory 
screening by central laboratory.  Approximately 150 eligible subjects will be randomized 
in a 2:1 ratio to receive 24 weeks of QM evolocumab or placebo.  Randomization will be 
stratified by screening LDL-C (< 160 mg/dL [4.1 mmol/L] vs ≥ 160 mg/dL) and age 
(< 14 years vs ≥ 14 years) at randomization. 
The study includes collection of biomarker development samples.  Where permitted by 
local regulations, subjects will be invited to consent to pharmacogenetic analyses. 
Events of death, myocardial infarction (MI), hospitalization for unstable angina, coronary 
revascularization, stroke, transient ischemic attack (TIA), and hospitalization for heart 
failure will be adjudicated by an independent Clinical Events Committee (CEC). Subject 
incidence of exploratory endpoint events will be summarized for each treatment group.  
Processes of event identification and submission to the CEC are described in a CEC 
Endpoint Reporting Manual. 
An independent data monitoring committee (DMC) will formally review the accumulating 
data from this and other completed and ongoing studies with evolocumab to ensure 


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there is no avoidable increased risk for harm to subjects.  Analyses for the DMC will be 
provided by a group which is external to Amgen. 
After completion of Study 20120123, subjects will be offered participation in an extension 
study where they will receive open-label evolocumab. 
The overall study design is described by a study schema at the end of the protocol 
synopsis section. 
The study endpoints are defined in Section 10.1.1. 
3.2 
Number of Sites 
This study will include approximately 30 sites in North America, Latin America, Europe, 
Australia, and New Zealand, and may include sites in Middle East.  Additional sites may 
be added if necessary to achieve the enrollment goal within the planned time. 
Sites that do not randomize subjects within 3 months of being open for enrollment may 
be closed. 
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”. 
There will be approximately 150 subjects randomized in this study.  Justification for the 
sample size can be found in Section 10.2 Sample Size Considerations. 
3.4 
Replacement of Subjects 
There will be no replacement for randomized subjects. 
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
After signing the informed consent or subject assent, subjects should be randomized 
within 8 weeks.  Including the screening, study treatment, and follow-up, the maximal 
total duration of study participation for a subject will be 32 weeks or approximately 
8 months. 
3.5.2 
End of Study 
The end of the study (primary completion) is defined as the last day on which a 
randomized subject in this study completes the end-of-study visit (week 24) or 
terminates the study early. 


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4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).  This log may be completed and updated via an Interactive Voice Response 
system (IVRS)/Interactive Web Response system (IWRS). 
Before any study-specific activities/procedure, the appropriate written informed consent 
(and assent, when applicable) must be obtained (see Section 11.1).  In addition to 
written informed consent from a legally acceptable representative, the assent of the child 
also must be obtained, as appropriate if requested by the institutional review 
board/independent ethics committee (IRB/IEC). 
4.1 
Inclusion and Exclusion Criteria 
4.1.1 
Inclusion Criteria 
101 
Subject has provided written informed consent or subject assent prior to 
initiation of any study-specific activities/procedures. 
and/or  
102 
Subject’s legally acceptable representative has provided informed consent when 
the subject is legally too young to provide informed consent and the subject has 
provided written subject assent based on local regulations and/or guidelines prior 
to any study-specific activities/procedures being initiated. 
103 
Male or female, ≥ 10 to ≤ 17 years of age at time of randomization (includes the 
year after the subject completes the 17th year after birth but not the day of 
completing the 18th year after birth). 
104 
Diagnosis of heterozygous familial hypercholesterolemia by local applicable 
diagnostic criteria for HeFH (ie, criteria outlined by the Simon Broome Register 
Group [Scientific Steering Committee, 1991], the Dutch Lipid Clinic Network 
[World Health Organization, 1999], MEDPED [Williams et al, 1993]),  or by 
genetic testing. 
105 
On an approved statin with stable dose for ≥ 4 weeks before LDL-C screening 
and, in the opinion of the investigator, not requiring up-titration. 
106 
Subject must be on a low-fat diet, and if taking any other lipid-lowering therapy 
(eg, ezetimibe, bile-acid sequestering resin, omega 3 fatty acids or niacin), this 
therapy must be unchanged for ≥ 4 weeks prior to LDL-C screening; fibrates 
must be stable for at least 6 weeks prior to screening. 
107 
Fasting LDL-C at screening ≥ 130 mg/dL (3.4 mmol/L) as determined by central 
laboratory. 
108 
Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) by central laboratory at screening. 
4.1.2 
Exclusion Criteria 
201 
Homozygous familial hypercholesterolemia 
202 
Lipid apheresis within the last 12 weeks prior to screening 


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203 
Type 1 diabetes or newly diagnosed (within 3 months of randomization) type 2 
diabetes, or poorly controlled type 2 diabetes (HbA1c > 8.5%) or newly 
diagnosed impaired glucose tolerance (within 3 months of randomization). 
204 
Untreated or inadequately treated hyperthyroidism or hypothyroidism as defined 
by thyroid stimulating hormone (TSH) < lower limit of normal (LLN) or > 1.5 times 
the upper limit of normal (ULN), respectively, and free thyroxine (T4) levels that 
are outside normal range at screening. 
205 
Moderate to severe renal dysfunction, defined as an estimated glomerular 
filtration rate (eGFR) < 30 ml/min/1.73m2 at screening, confirmed by a repeat 
measurement at least 1 week apart. 
206 
Persistent active liver disease or hepatic dysfunction, defined as aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) > 2 times the ULN as 
determined by central laboratory analysis at screening, confirmed by a repeat 
measurement at least 1 week apart. 
207 
Creatine kinase (CK) > 3 times the ULN at screening, confirmed by a repeat 
measurement at least 1 week apart. 
208 
Known active infection or major hematologic, renal, metabolic, gastrointestinal or 
endocrine dysfunction in the judgment of the investigator. 
209 
Unreliability as a study participant based on the investigator's (or designee’s) 
knowledge of the subject (eg, alcohol or other drug abuse in the past year, 
inability or unwillingness to adhere to the protocol, or psychosis). 
210 
Subject has taken a cholesterylester transfer protein (CETP) inhibitor such as 
anacetrapib, dalcetrapib or evacetrapib in the last 12 months, or mipomersen or 
lomitapide in the last 5 months prior to LDL-C screening. 
211 
Subject has previously received evolocumab or any other investigational therapy 
to inhibit PCSK9. 
212 
Currently receiving treatment in another investigational device or drug study, or 
less than 30 days since ending treatment on another investigational device or 
drug study(s).  Other investigational procedures or treatments while participating 
in this study are excluded. 
213 
Female subject who has experienced menarche and unwilling to use acceptable 
method(s) of effective birth control during treatment with IP (evolocumab or 
placebo) and for an additional 15 weeks after the end of treatment with IP 
(evolocumab or placebo). A female who has experienced menarche is 
considered of childbearing potential. 
• 
Acceptable methods of preventing pregnancy include: true sexual 
abstinence when this is in line with the preferred and usual lifestyle of the 
subject (periodic abstinence [eg, calendar, ovulation, symptothermal, 
post-ovulation methods], declaration of abstinence for the duration of the 
study, and withdrawal are not acceptable methods of contraception), or 
use of hormonal birth control methods (oral, implantable, injectable, 
transdermal, intravaginal), intrauterine devices (IUDs), intrauterine 
hormonal-releasing system (IUS), or two (2) barrier methods (one by 
each partner and at least one of the barrier methods must include 
spermicide, unless spermicide is not approved in the country or 
region - the male must use a condom and the female must choose either 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 27 of 84 
CONFIDENTIAL 
 
 
a diaphragm OR cervical cap, OR contraceptive sponge.  Note: a male 
and female condom cannot be used together due to the risk of tearing.)  
Note:  If additional medications are given during treatment which may 
alter the contraceptive requirements (these additional medications may 
require an increase in the number of contraceptive methods and/or length 
of time that contraception is to be utilized or length of time 
breastfeeding is to be avoided after the last dose of protocol-required 
therapies) the investigator is to discuss these changes with the study 
subject.   
214 
Female subject with a positive pregnancy test 
215 
Female subject is pregnant or breast feeding, or planning to become pregnant or 
planning to breastfeed during screening, during treatment with IP (evolocumab or 
placebo), and within 15 weeks after the end of treatment with IP (evolocumab or 
placebo). 
216 
Known sensitivity to any of the active substances or their excipients to be 
administered during dosing, eg, carboxymethylcellulose. 
217 
Subject will not be available for protocol-required study visits or procedures, to 
the best of the subject and investigator’s knowledge (Note: Day 1 and week 24 
visits must be scheduled at approximately the same time of day, and should be 
performed as close as possible to 8 am as the hormones measured have diurnal 
variation). 
218 
History or evidence of any other clinically significant disorder, condition or 
disease, or planned or expected procedure 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 IRB/IEC approval of the protocol, 
AMG 145 Investigator’s Brochure (IB), informed consent form (ICF), and all other subject 
information and/or recruitment material, if applicable (see Section 11.2).  All subjects or 
parents/legally acceptable representatives must personally sign and date the informed 
consent form or subject assent form before commencement of study-specific 
activities/procedures. 
Each subject who enters into the screening period for the study receives a unique 
subject identification number before any study-related activities/procedures are 
performed.  The subject identification number will be assigned by the IVRS/IWRS.  The 
investigator or designee must contact the IVRS/IWRS to register subjects once the 
informed consent, and subject assent if applicable, is signed to obtain the unique subject 
identification number.  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. 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 28 of 84 
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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. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria. The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment CRF. 
5.1 
Randomization/Treatment Assignment 
Assignment to the 2 treatment arms (Section 3.1) will be based on a 
computer-generated randomization schedule prepared by Amgen before the start of the 
study. 
Each subject will receive a unique randomization number and each randomization 
number will only be assigned to 1 subject.  Randomization will be stratified by screening 
LDL-C (< 160 mg/dL [4.1 mmol/L] vs ≥ 160 mg/dL) and age (< 14 years vs ≥ 14 years) at 
time of randomization. 
Once the investigator decides that a subject has met all eligibility criteria, a site 
representative will make the randomization call to the IVRS/IWRS to assign a 
randomization number to the subject.  The randomization call to the IVRS/IWRS is 
accomplished by entering the pertinent information as detailed in the IVRS/IWRS user 
manual.  A confirmation fax or email will be sent to the site to verify that the correct 
information has been entered and to confirm the assignment of a randomization number. 
The randomization date is to be documented in the subject’s medical record and on the 
enrollment electronic case report form (eCRF). 
5.2 
Site Personnel Access to Individual Treatment Assignments 
A subject’s treatment assignment should only be unblinded when knowledge of the 
treatment is essential for the further management of the subject on this study.  
Unblinding at the study site for any other reason will be considered a protocol deviation.  
The investigator is strongly encouraged to contact the 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 Products and Medical Devices 
The Amgen investigational medicinal products used in this study include: evolocumab 
and matching placebo. 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 29 of 84 
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The medical device used in this study is the prefilled autoinjector/pen (AI/Pen). 
An Investigational Product Instruction Manual (IPIM) and the Instructions For Use (IFU), 
documents external to this protocol, contain detailed information regarding the storage, 
preparation, destruction, and administration of investigational product. 
6.2 
Amgen Investigational Product Evolocumab and Placebo 
Evolocumab and placebo will be manufactured and packaged by Amgen Inc. and 
distributed using Amgen clinical IP distribution procedures.  Evolocumab will be 
presented as a sterile, preservative-free solution in a single use, disposable, handheld 
mechanical (spring-based) prefilled autoinjector/pen (AI/Pen) for fixed dose, 
SC injection.  The prefilled AI/Pen contains a 1.0 mL deliverable volume of 140 mg/mL 
evolocumab or 1.0 mL deliverable volume of placebo. 
IP (evolocumab or placebo) should be stored refrigerated and protected from light 
according to the storage and expiration information provided on the label (where 
required).  IP should be handled per the instructions provided in the IPIM and the 
Instructions for Use (IFU) for the prefilled AI/Pen. 
The prefilled AI/Pen should be inspected for IP quality, expiry, and damage before 
using.  Damaged, expired, or degraded product should not be used and any issues with 
the prefilled AI/Pen should be reported to Amgen.  Further details are provided in the 
IPIM and IFU. 
6.2.1 
Dosage, Administration, and Schedule 
IP (evolocumab or matching placebo) will be administered SC in accordance with 
instructions in the IPIM and IFU.  IP administration by SC injection if performed during a 
study visit must occur after vital signs, electrocardiogram (ECG), and blood draw 
procedures, if applicable.  After IP administration at the first dosing visit, subjects will be 
held for observation for at least 30 minutes before being discharged. 
Each QM administration of IP will consist of 3 injections of 140 mg evolocumab or 
placebo in 1.0 mL (administration by prefilled AI/Pen) for a total of 3.0 mL (placebo or 
420 mg evolocumab) administered. 
In this study, subjects have the option of self-administration, defined as 
SC administration of IP by the subject, designee or a qualified health care professional in 
a non-investigator site setting (eg, at home).  The subject (or designee, if not a qualified 
healthcare professional) must have demonstrated competency at administration of 
SC injections before self-administration is permitted.  The first self-administered dose by 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 30 of 84 
CONFIDENTIAL 
 
 
the subject (or designee, if not a healthcare professional) must be administered at the 
site under the supervision of a healthcare provider. 
Details of preparing IP and the injection procedures are included in the IPIM and IFU 
provided by Amgen prior to the start of the study.  The dosing schedule is described by a 
schema in the protocol synopsis. 
When IP is mandated to be administered at the study site, the date and completion time 
of administration, the body location of the injection, and whether the injection was fully or 
partially administered are to be recorded on each subject’s CRF. 
When IP can be administered at a non-investigator site location, at a minimum, the dates 
the devices were dispensed and the used devices returned, and for each device whether 
it was returned fully or partially used are to be recorded on each subject’s CRF. 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation  
There will be no dose adjustments in this study.  If, in the opinion of the investigator, 
a subject is unable to tolerate a specific dose of IP, that subject will discontinue IP but 
will continue to return for all other study procedures and measurements until the end of 
the study. 
If a subject is late for administration of IP, administration should occur as soon as 
possible.  A full QM dose of IP should not be administered within less than 7 days of a 
previous dose.  If a subject arrives for a visit with IP administration and IP was 
administered within the prior 7 days, the dose should not be administered but all other 
study procedures should be conducted.  Administration of IP should occur as soon as 
possible but at least 7 days after the previous administration. 
Subjects who completely miss a dose of IP will continue in the study and receive the 
next dose of IP per their schedule of administration. 
6.3 
Other Protocol-required Therapies 
All lipid-lowering drugs that are allowed per protocol and that the subject may be taking, 
must be commercially available and are not provided or reimbursed by Amgen (except if 
required by local regulation).  The investigator will be responsible for obtaining supplies 
of these drugs.  All such therapy needs to be stable and unchanged during the entire 
time of screening and study participation unless a change is clinically necessary. 


Product:  Evolocumab 
Protocol Number:  20120123 
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Page 31 of 84 
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6.4 
Withholding of Amgen Investigational Product or Statin Background 
Therapy due to Elevation of Creatine Kinase (CK) 
If CK is > 5x ULN, CK must be retested before IP is administered.  In addition, 
investigators will ask study subjects to promptly report muscle pain, cramps, or 
weakness especially if accompanied by malaise or fever.  If such symptoms occur, the 
subject’s CK levels should be measured and if CK is > 5x ULN, the subject should be 
instructed to discontinue statin background therapy and IP.  CK must be retested before 
any statin or IP is administered. 
The following rules apply: 
CK at prior visit 
CK on retest 
Amgen Investigational Product and Non-Amgen 
Statin Background Therapy Administration 
> 5x ULN 
> 10x ULN 
Discontinue statin and IPa.  Contact Amgen 
Medical Monitor 
> 5x to ≤ 10x ULN 
Discontinue statin and retest CK before statin 
administration.  Consider continuing IP if 
alternative explanation  
≤ 5x ULN 
Consider continuing IP and statin 
a CK elevations >10x ULN that have been confirmed to be secondary to myocardial infarction do not require 
discontinuation of Amgen IP or non-Amgen statin background therapy. 
If muscular symptoms are severe and cause daily discomfort, even if the CK levels are 
elevated to ≤ 5x ULN, in consultation with the Amgen medical monitor, discontinuation of 
statin, or introduction of an alternative statin may be considered at the lowest dose and 
with close monitoring. 
6.5 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio [INR] and/or signs/symptoms of hepatitis 
(as described below) may meet the criteria for withholding or permanent discontinuation 
of Amgen investigational product or other protocol-required therapies as specified in the 
FDA Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, 
July 2009. 
6.5.1 
Criteria for Permanent Discontinuation of Amgen Investigational 
Product and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity 
Statin and investigational product should be discontinued permanently and the subject 
should be followed according to the recommendations in Appendix A (Additional Safety 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 32 of 84 
CONFIDENTIAL 
 
 
Assessment Information) for possible drug-induced liver injury (DILI), if ALL of the 
criteria below are met:  
• 
TBL > 2x ULN or INR > 1.5 (testing determined per Appendix A) 
AND  
• 
AST or ALT > 3x ULN  
AND  
• 
no other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT and/or 
TBL values include, but are not limited to: 
− 
hepatobiliary tract disease 
− 
viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus, cytomegalovirus, 
herpes simplex virus, varicella, toxoplasmosis, and parvovirus) 
− 
right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia.   
− 
exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants and mushrooms   
− 
heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation 
(eg, indinavir, atazanavir) 
− 
alpha-one antitrypsin deficiency 
− 
alcoholic hepatitis 
− 
autoimmune hepatitis  
− 
Wilson’s disease and hemochromatosis 
− 
nonalcoholic fatty liver disease including steatohepatitis (NASH)  
− 
Non-hepatic causes (eg, rhabdomyolysis, hemolysis) 
6.5.2 
Criteria for Conditional Withholding of Amgen Investigational 
Product and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity 
For subjects who do not meet the criteria for permanent discontinuation of Amgen 
investigational product outlined above and have no underlying liver disease, and 
eligibility criteria requiring normal transaminases and TBL at baseline or subjects with 
underlying liver disease and baseline abnormal transaminases, the following rules are to 
be followed for withholding of Amgen investigational product and other protocol-required 
therapies:  
• 
AST or ALT > 8x ULN at any time 
• 
AST or ALT > 5x ULN but < 8x ULN for ≥ 2 weeks (or subject unable to adhere to 
enhanced monitoring schedule) 


Product:  Evolocumab 
Protocol Number:  20120123 
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Page 33 of 84 
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• 
ALT or AST > 3x ULN with clinical signs or symptoms that are, in the opinion of the 
investigator, consistent with hepatitis (such as right upper quadrant pain/tenderness, 
fever, nausea, vomiting, jaundice, rash or eosinophilia > 5%) 
• 
TBL > 3x ULN at any time 
• 
ALP > 8x ULN at any time 
Both statin and investigational product should be withheld pending investigation into 
alternative causes of DILI.  If statin or investigational product is withheld, the subject is to 
be followed according to recommendations in Appendix A for possible DILI.  
Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL, is discovered and the laboratory abnormalities resolve 
to normal or baseline (Section 6.5.3). 
6.5.3 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then investigational product should be 
permanently discontinued.  Subjects who clearly meet the criteria for permanent 
discontinuation (as described in Section 6.5.1) should never be rechallenged. 
6.6 
Concomitant Therapy  
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.9. 
All concomitant therapies are to be collected from start of screening through the 
end-of-study (EOS), including medications being taken at the time of enrollment.  This 
includes all lipid-regulating medications (eg, statin, ezetimibe, fibrates, cholesterol 
absorption inhibitors, and bile acid sequestrants).  Therapy name, indication, dose, unit, 
frequency, route, start date and stop date will be collected. 
6.7 
Medical Devices 
IP (evolocumab and placebo) will be provided by prefilled AI/pen (Section 6.2).  The 
prefilled AI/pen is a modified version of the SureClick™ autoinjector, a device that is 
commercially available for the administration of Aranesp® or Enbrel® drug product by 
patients or caregivers in a non-healthcare environment, or by healthcare professionals in 
the clinic environment in the United States (Enbrel® only) and in Europe. 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
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CONFIDENTIAL 
 
 
Ancillary medical devices (eg, sterile needles, alcohol prep pads), that are commercially 
available are not usually provided or reimbursed by Amgen (except, for example, if 
required by local regulation).  The investigator will be responsible for obtaining supplies 
of these devices. 
6.8 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug or device after it is released for distribution to market or clinic by 
either Amgen or by distributors and partners for whom Amgen manufactures the 
material.  This includes any drug(s) or device(s) provisioned and/or 
repackaged/modified by Amgen. Drug(s) or device(s) includes investigational 
product.  
Any product complaints associated with the medicinal product, prefilled AI/Pen or other 
Amgen provided, protocol-required product in this study must be reported to Amgen 
within 24 hours of discovery or notification of the complaint.  Please do not use the 
device or product that is subject of a complaint until Amgen confirms that it is permissible 
to do so. 
Examples of product complaints that need to be reported to Amgen include, but are not 
limited to: 
• 
broken or cracked cartridges 
• 
subject or healthcare provider cannot appropriately use the product despite training 
(eg, due to malfunction of the AI/Pen) 
• 
missing labels, illegible labels, incorrect labels, and/or suspect labels  
• 
change in IP appearance, for example color change or visible presence of foreign 
material 
• 
unexpected quantity or volume, for example number of tablets or amount of fluid in 
the prefilled AI/Pen 
• 
evidence of tampering or stolen material 
If possible, please have the device or medicinal product associated with the complaint 
available for examination when reporting a product complaint.  Maintain device or other 
Amgen provided protocol-required suspect product at appropriate storage conditions 
until further instructions are received from Amgen. 
The investigator is responsible for ensuring that all product complaints observed by the 
investigator or reported by the subject that occur after signing of the informed consent 


Product:  Evolocumab 
Protocol Number:  20120123 
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Page 35 of 84 
CONFIDENTIAL 
 
 
through 30 days after the last dose of IP or EOS, whichever is later, are reported to 
Amgen within 24 hours of discovery or notification of the product complaint. 
For more details regarding the identification and reporting of product and device 
complaints, refer to the IPIM and the IFU. 
6.9 
Excluded Treatments and/or Procedures During Study Period  
The following treatments are not permitted during the study, including screening: 
• 
lipid apheresis 
• 
treatments for inhibition of PCSK9 or any investigational therapies other than study 
provided investigational product 
• 
mipomersen or lomitapide 
• 
red yeast rice 
• 
other drugs (besides those mentioned above) that significantly affect lipid 
metabolism (eg, systemic cyclosporine, systemic steroids [intravenous, 
intramuscular, or oral; Note: hormone replacement therapy is permitted], vitamin A 
derivatives and retinol derivatives for the treatment of dermatologic conditions [eg, 
Accutane; Note: Vitamin A as part of a multivitamin preparation is permitted]). 
• 
prescribed amphetamines, or amphetamine derivatives, and weight loss 
medications.  
• 
all lipid therapies not taken at the time of screening and enrollment 
Please contact the Amgen medical monitor or designee if any of these therapies should 
be initiated during the study.  Note that a change in lipid lowering therapy does not 
necessarily require ending IP (except in case of non-study provided PCSK9 inhibition 
therapy). 
The following treatments are not recommended because of their potential impact on 
metabolism of certain statins: 
• 
medications or foods that are known potent inhibitors of CYP3A (eg, Itraconazole, 
ketoconazole, and other antifungal azoles, macrolide antibiotics erythromycin, 
clarithromycin, and the ketolide antibiotic telithromycin, HIV or hepatitis C virus 
(HCV) protease inhibitors, antidepressant nefazodone and grapefruit juice in large 
quantities (> 1 quart daily [approximately 1 Liter]) should not be used during the 
study.  
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments  
 


Product:  Evolocumab 
Protocol Number:  20120123 
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Page 36 of 84 
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Table 1.  Schedule of Assessments  
Study Day / Week / Other Timepointa 
Screen 
Rand 
D1 
W4 
(±3d) 
W8 
(±3d) 
W12 
(±3d) 
W16 
(±3d) 
W20 
(±3d) 
W22 
(±3d) 
W24 (EOS) 
(±3d) 
Study Daya 
 
D1 
D29±3 
D57±3 
D85±3 
D113±3 
D141±3 
D155±3 
D169±3 
General Procedures 
 
 
 
 
 
 
 
 
 
Parental/guardian informed consent/permission & subject 
assent/consent 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Vital Signs (sitting BP, HR) 
X 
X 
X 
 
X 
 
X 
X 
X 
Review for AEs/SAEs/ADEs/DREs/CV events 
Xb 
X 
X 
(X)b 
X 
(X)b 
X 
X 
X 
Concomitant therapy 
X 
X 
X 
 
X 
 
X 
X 
X 
Dietary instruction 
X 
X 
 
 
 
 
 
 
 
Physical exam (including neurologic examination; see Section 7.7.8) 
X 
 
 
 
 
 
 
 
X 
Body weight, waist circumference, cIMT, Tanner staging 
 
X 
 
 
 
 
 
 
X 
Body height 
 
X 
 
 
 
 
 
 
X 
Cogstate neurocognitive assessmentc 
X 
X 
 
 
 
 
 
 
X 
12 lead ECG 
 
X 
 
 
X 
 
 
 
X 
Randomization 
 
Xd 
 
 
 
 
 
 
 
Central Laboratorye 
 
 
 
 
 
 
 
 
 
Fasting lipidse 
X 
X 
 
 
X 
 
 
X 
X 
ApoA1, ApoB100, Lp(a)f 
 
X 
 
 
X 
 
 
X 
X 
PK (evolocumab), 
 
 
X 
 
 
X 
 
 
X 
X 
Chemistry, including fasting glucosef 
X 
 
 
 
X 
 
 
 
X 
Hematology 
X 
 
 
 
X 
 
 
 
X 
HbA1c 
X 
 
 
 
 
 
 
 
X 
Estradiol (females) / testosterone (males) 
 
X 
 
 
 
 
 
 
X 
hsCRP, CK, FSH, LH, ACTH, DHEA-S, cortisol, Fasting vitamins 
A/D/E/K 
 
X 
 
 
 
 
 
 
X 
TSH 
X 
 
 
 
 
 
 
 
 
Biomarkers (blood)g 
 
X 
 
 
 
 
 
 
X 
Anti-evolocumab antibodies 
 
X 
 
 
X 
 
 
 
X 
HCV testingh 
X 
 
 
 
 
 
 
 
 
HCV viral loadh 
 
X 
 
 
 
 
 
 
X 
Serum pregnancyi 
X 
 
 
 
 
 
 
 
X 
Urine pregnancyi 
 
X 
 
 
X 
 
 
 
 
Urinalysis, urine microalbumin 
 
X 
 
 
X 
 
 
 
X 
Investigational Product 
 
 
 
 
 
 
 
 
 
Screening placebo injection 
X 
 
 
 
 
 
 
 
 
AI/Pen Instruction 
 
X 
X 
 
X 
 
 
 
 
AI/Pen dispensation 
 
 
X 
 
X 
 
 
 
 
AI/Pen reconciliation 
 
 
 
 
X 
 
X 
 
 
IP (AI/Pen) administration on-site 
 
X 
X 
 
X 
 
X 
 
 
IP (AI/Pen) administration on-site or in non-investigator site setting 
 
 
 
X 
 
X 
 
 
 
Footnote defined on the next page. 


Product:  Evolocumab 
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Page 37 of 84 
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a D1 = day of first administration of IP; a visit window of ± 3 days applies to all other visits. Note: Day 1 and week 24 visits must be scheduled at approximately the 
same time of day, and should be performed as close as possible to 8 am as the hormones measured have diurnal variation. 
b only AEs possibly related to study procedures and SAEs are collected during screening (from signing of ICF or subject assent, whichever is later); week 8 and week 
16 AEs/SAEs/ADEs/DREs/CV events collection only if visit to study site. ADEs/Product Complaints are reported that occur after signing of the informed 
consent through 30 days after the last dose of IP or EOS, whichever is later. 
c Cogstate cognitive battery tests (see Section 7.7.7) 
d randomization should be on day 1 or as close as possible to day 1 and must not be earlier than 5 days prior 
e blood samples must be taken prior to IP administration, if applicable 
f if subject is not fasting on day 1, reschedule; if subject is not fasting after day 1, do all procedures except fasting labs and IP administration, if applicable; schedule 
another visit, if possible within the visit window for fasting labs and IP administration 
g if parental/guardian consent or permission and subject consent or assent to pharmacogenetics analyses has been provided, deoxyribonucleic acid (DNA) will be 
extracted from some of the blood samples, eg, biomarker samples 
h HCV antibodies only in subjects at high risk for, or with history of, HCV infection (see Section 7.2.1.2) or if ALT or AST > 2x ULN at any time during screening; viral 
load only in subjects positive for HCV 
i pregnancy testing in females of childbearing potential (additional pregnancy tests may be conducted if there is concern that a female subject has become pregnant).  
Refer to Sections 7.2 through Section 7.7 and the applicable supplemental laboratory manual, ECG manual, IPIM, and IFU for detailed 
study procedures. 


Product:  Evolocumab 
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7.2 
General Study Procedures  
This is a multi-center, randomized, double-blind, placebo-controlled trial.  The study 
consists of 2 periods: 
• 
screening period 
• 
double-blind treatment period 
All on-study visits and dosing should be scheduled from study day 1.  Day 1 and 
week 24 visits must be scheduled at approximately the same time of day, and should be 
performed as close as possible to 8 am as the hormones measured have diurnal 
variation.  The week 4 visit is 4 weeks after the study day 1 visit, corresponding to study 
day 29.  When it is not possible to perform the study visit at the specified time point, the 
visit should be performed within ± 3 days (visit window ± 3 days).  If a study visit is 
missed or late, including visits outside the visit window, subsequent visits should resume 
on the original visit schedule.  Missed assessments at prior visits should not be 
duplicated at subsequent visits.  With the exception of screening and rescreen visits, all 
study procedures for a visit must be completed on the same day. 
It is the responsibility of the investigator to ensure that all procedures are performed 
according to the protocol.  Written informed consent must be obtained and will be 
implemented before protocol specific procedures are carried out.  The risks and benefits 
of participating in the study will be verbally explained to each potential subject prior to 
entering into the study.  The procedures to be performed at each study site visit are 
described below and the timing of the procedures is provided in Table 1.  If IP is 
administered during a study visit, administration must be after completion of vital signs, 
ECG, and blood draw procedures, as applicable. 
Subjects must be fasting for ≥ 9 hours before each study visit.  For procedures if the 
subject is not fasting when presenting at the study site for a visit, please 
see Section 7.2.1.2 and Section 7.2.2 below. 
All screening and on-study laboratory samples will be processed and sent to the central 
laboratory.  Amgen or designee will be responsible for the evaluation of PK 
(evolocumab) and 
 serum levels, anti-evolocumab antibody, and biomarker 
development assessments and the central laboratory will ship the samples to Amgen or 
a specialty laboratory for assay (depending on the assessment). 
The central laboratory will provide a study manual that outlines handling, labeling, and 
shipping procedures for all blood samples.  The date and time of sample collection will 
be recorded in the source documents at the site. 


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Table 2 below outlines the specific analytes for serum chemistry, hematology, urinalysis, 
and other testing to be conducted. 
Table 2.  Analyte Listing1 
Chemistry  
Coagulation 
Urinalysis 
Hematology 
Other Labs 
Sodium 
Potassium 
Chloride 
Bicarbonate  
Total protein 
Albumin 
Calcium 
Magnesium 
Phosphorus 
Fasting glucose 
BUN or Urea 
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin 
CK 
ALP 
LDH 
AST (SGOT) 
ALT (SGPT) 
PT/INR (per 
Appendix A) 
Specific 
gravity 
pH 
Blood 
Protein 
Glucose 
Bilirubin 
WBC 
RBC 
Epithelial 
cells 
Bacteria 
Casts 
Crystals 
Hemoglobin 
Hematocrit 
RBC 
RDW 
MCV  
MCH 
MCHC 
WBC 
Platelets 
 
Fasting lipids 
Total cholesterol 
HDL-C 
LDL-C 
Triglycerides 
VLDL-C 
non-HDL-C 
ApoA1 
ApoB 
Estradiol (females) 
Testosterone (males) 
Cortisol 
Luteinizing hormone (LH) 
Adrenocorticotropic 
hormone (ACTH) 
Dehydroepiandrosterone 
sulfate (DHEA-S) 
Fasting vitamins A, D, 
E, and K 
hsCRP 
Lp(a) 
Anti-evolocumab 
antibodies 
 
Evolocumab (PK) 
HbA1c 
Pregnancy test (females 
of childbearing potential) 
FSH 
TSH 
HCV antibody2 
HCV viral load3 
1 Day 1 and week 24 visits must be scheduled at approximately the same time of day, and should be 
performed as close as possible to 8 am as the hormones measured have diurnal variation. 
2 HCV antibodies are measured before initiating treatment with IP in subjects at high risk for 
(see Section 7.2.1.1), or with history of HCV infection and in subjects with ALT or AST > 2x ULN at any 
time during screening.  Please note that subjects with ALT or AST > 2x ULN must be screen failed unless 
the elevation is transient as confirmed by retesting per Section 7.2.1.4.   
3 Viral load will be tested at the time points indicated in Table 1 in subjects who are positive for HCV. 


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Since some laboratory results may inadvertently unblind investigators to treatment 
assignment to evolocumab, central laboratory results of the lipid panel, ApoA1, ApoB, 
Lp(a), fasting vitamins A, D, E, and K, and 
 will not be reported to the 
investigator (or study personnel) post-screening.  Investigators should not perform 
non-protocol testing of these analytes during a subject’s study participation from first 
administration of IP until at least 12 weeks after last IP administration, or the subject’s 
end of study, whichever is later. 
7.2.1 
Screening Enrollment and Randomization 
Subjects who are considered for entry into the study and have the risks and benefits of 
participating in the study explained, will sign and date the informed consent or subject 
assent form for this study.  Screening starts when the subject’s legally acceptable 
representative has provided informed consent and/or the subject has provided informed 
consent or assent as applicable, whichever is later. Screening should be completed and 
the subject randomized or screen failed within 8 weeks of the screening start date. 
7.2.1.1 
Screening Placebo Administration 
In order to reduce the burden of unnecessary procedures on subjects who subsequently 
elect not to participate in the study or continue with study procedures, all subjects will 
undergo a placebo administration to confirm tolerance of SC administration by SC 
injection prior to enrollment.  This placebo administration can be done before or after 
screening venipuncture procedures but must be done before randomization.  The 
screening placebo administration consists of 1 injection of 1.0 mL placebo, using 
1 prefilled AI/Pen device.  This administration is following the same procedures as 
injections of IP during the treatment period.  Further details are provided in the IPIM. 
7.2.1.2 
Screening 
The following procedures are to be completed during the screening period: 
• 
confirmation that the informed consent and subject assent, if applicable, has been 
signed  
• 
demographic data including sex, age, race, and ethnicity will be collected in order to 
study their possible association with treatment effectiveness, subject safety, or, for 
example, to further study biomarker variability 
• 
medical history  
• 
vital signs (sitting blood pressure [BP], heart rate [HR]; see Section 7.7.1) 
• 
review for adverse events/serious adverse events/ADE (adverse events possibly 
related to study procedures and serious adverse events are collected during 
screening) 


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• 
concomitant therapy  
• 
physical examination (including neurologic examination; see Section 7.7.8) 
• 
Cogstate neurocognitive assessment (see Section 7.7.7) 
• 
blood draw for fasting lipids (≥ 9 hour fasting sample), chemistry (including fasting 
glucose), hematology, HbA1c, TSH, and serum pregnancy (females of childbearing 
potential only). Note: eGFR will be calculated by the central laboratory and will be 
provided to the site for eligibility determination. 
• 
blood draws for HCV antibodies in subjects at high risk for, or with history of, HCV 
infection, or with AST or ALT > 2x ULN at any time during screening* 
− 
High risk subjects for this protocol are those who meet any of the following 
conditions: 
o ever injected illegal drugs 
o were exposed to blood known to be infected with HCV 
o were ever on chronic hemodialysis  
o are known to be infected with HIV 
o have a known HCV-infected sexual partner  
• 
the subject will be instructed to maintain his/her current diet throughout the course of 
the study and avoid going on any strict diet or aiming to lose weight during the study 
• 
screening placebo injection as per Section 7.2.1.1; includes instruction/training on 
AI/Pen device use 
• 
randomization, if eligible (on or as close as possible to Day 1; see Section 7.2.1.3) 
* Please note that subjects with ALT or AST > 2x ULN must be screen failed unless the 
elevation is transient as confirmed by retesting per Section 7.2.1.4. 
If a fasting sample could not be obtained at the initial screening visit and the other 
screening laboratory assessments confirm eligibility for the study, fasting lipid and 
glucose samples to determine eligibility must be obtained before randomization. 
All prohibited lipid lowering therapy (see Section 4.1.2 and Section 6.9) must be 
discontinued ≥ 4 weeks before screening laboratories are taken or as indicated in 
Section 4.1.2 and/or Section 6.9, whichever is longer. 
7.2.1.3 
Randomization 
Subjects who continue to meet all eligibility criteria at the end of screening will be 
randomized and will return to the study site for day 1 procedures while continuing their 
background lipid-lowering treatment.  Randomization should be on day 1 or as close as 
possible and not earlier than maximally 5 days prior. Subjects can only be randomized 
1 time for this study. 


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7.2.1.4 
Retesting 
If, in the investigator’s judgment, lab abnormalities are likely to be transient, (eg, subject 
participated in vigorous exercise and CK is elevated immediately afterwards), laboratory 
tests can be repeated.  Triglycerides, CK, and liver function and other laboratory values, 
except LDL-C, can be retested at any time during screening as long as the subject can 
be evaluated for eligibility and randomized within the allowed screening period. 
7.2.1.5 
Rescreening 
Subjects with any LDL-C < 130 mg/dL (3.4 mmol/L) during screening are considered 
screen failures and cannot be rescreened for this study.  Suitable subjects who are 
ineligible at the initial screening for other reasons and have not been randomized can be 
re-consented and rescreened at a later time unless they withdraw from screening.  For 
subjects who are rescreened, data from the first screening period will not be used for the 
analysis. 
With the exception of the screening placebo injection, rescreened subjects who are 
re-consented will repeat all screening procedures.  Rescreened subjects will maintain 
the originally assigned subject identification number. 
7.2.1.6 
Screen Fail 
Subjects who fail any of the eligibility criteria during screening or rescreening and have 
not been randomized need to be screen failed in IVRS/IWRS before they can be 
re-consented and re-registered in IVRS/IWRS for rescreening. 
7.2.2 
Treatment and End of Study 
Subjects who are randomized will visit the study site for treatment start.  The first 
administration of IP should be on or as close as possible to the day of randomization but 
not later than 5 calendar days after randomization.  Day 1 is defined as the day of first 
administration of IP.  The date of first administration of IP will be recorded in IVRS/IWRS 
and will determine the schedule of subsequent study visits. 
Subjects must be fasting for ≥ 9 hours before each study visit where fasting lipid 
samples are obtained.  If the subject is not fasting for the scheduled study day 1 visit, no 
visit procedures are performed.  The subject must return as soon as possible in a fasting 
state for study day 1 visit procedures.  If the subject is not fasting as required for a visit 
after study day 1, visit procedures should be completed except for fasting laboratory 
sample collection and IP administration, if applicable.  An extra visit must be completed 


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for the omitted procedures as soon as possible and, if possible, within the window for the 
respective visit. 
The following procedures will be completed during the 24 week treatment period at the 
times designated in the Schedule of Assessments (Table 1): 
• 
vital signs (sitting BP, HR; see Section 7.7.1) 
• 
review for adverse events/serious adverse events/ADE/DRE/CV events 
• 
review of concomitant therapy 
• 
encourage subject to maintain a stable diet 
• 
physical examination (including neurologic examination; see Section 7.7.8) 
• 
body weight and waist circumference (see Section 7.7.2) 
• 
body height 
• 
Cogstate neurocognitive assessment (see Section 7.7.7) 
• 
12-lead ECG in triplicate using centralized ECG services equipment 
• 
blood draw for fasting lipids (≥ 9 hour fasting sample), ApoA1, ApoB, chemistry, 
hematology, PK, 
 high sensitivity C-reactive protein (hsCRP), CK, FSH, LH, 
ACTH, DHEA-S, cortisol, fasting vitamins A, D, E, and K, Lp(a), biomarkers, 
anti-evolocumab antibodies, and viral load in subjects positive for HCV 
• 
cIMT 
• 
Tanner staging 
• 
urine sample for urinalysis 
• 
pregnancy testing for females of childbearing potential (serum at screening and 
EOS; urine at other time points) 
• 
IP administration at the study site (must be after completion of vital signs, ECG, and 
blood draw procedures, if applicable) 
• 
dispense AI/Pen device with instructions for use 
No additional blood will be collected for the pharmacogenetics analyses.  For subjects 
who have consented to the pharmacogenetic portion of this study, DNA will be extracted 
from blood samples already collected on day 1 or another visit (see Section 7.5 
“Pharmacogenetic Studies” and Section 7.6 “Sample Storage and Destruction”). 
If a subject withdraws from the study early, all efforts should be made to complete and 
report the observations as thoroughly as possible up to the date of withdrawal.  If 
possible, the procedures of week 24 should be completed at the time of withdrawal. 
Subjects will end the study with the week 24 visit.  Note that the week 24 visit must be 
scheduled at approximately the same time of day as the day 1 visit, as the hormones 
measured have diurnal variation. 


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7.3 
Antibody Testing Procedures 
Blood samples for antibody testing are to be collected per Table 1 for the measurement 
of anti-evolocumab binding antibodies.  All subjects who have received at least 1 
administration of evolocumab will have samples assayed for binding and, if positive, 
neutralizing antibodies. Samples testing positive for binding antibodies will also be tested 
for neutralizing antibodies and may be further characterized for quantity/titer, isotype, 
affinity and presence of immune complexes. Sites will be notified of any positive  
neutralizing antibody results to evolocumab. If results are not provided, no neutralizing 
antibodies to evolocumab have been detected.  Additional blood samples may be 
obtained to rule out anti-evolocumab antibodies during the study. Subjects who test 
positive for neutralizing antibodies to evolocumab at the final scheduled study visit will 
be asked to return for additional follow-up testing. This testing should occur 
approximately every 3 months starting from when the site has been notified of the 
positive result, until: (1) neutralizing antibodies are no longer detectable or (2) the 
subject has been followed for a period of at least 1 year (± 4 weeks). More frequent 
testing (eg, every month) or testing for a longer period of time may be requested in the 
event of safety-related concerns. Follow-up testing will not be required where it is 
established that the subject did not receive evolocumab. All follow-up results, both 
positive and negative will be communicated to the sites. Subjects who test positive for 
binding, non-neutralizing antibodies and have clinical sequelae that are considered 
potentially related to an anti-evolocumab antibody response may also be asked to return 
for additional follow-up testing. 
7.4 
Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention. 
It is expected that further advances will occur in the future in investigational techniques 
that look at markers of 
 
  It is not possible at this stage to anticipate what these 
advances will be; however, considerable benefit could accrue to future sufferers of 
coronary artery disease if these markers can be correlated with the data from the study.  
It is also important to clarify any potential drug interactions in this population of subjects 
who will be on a number of other drugs.  For biomarker analysis 14.5 mL of blood will be 
collected at each of the time points indicated in Table 1 so that biomarkers related to, but 


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not limited to 
 
 
 
 may be studied. 
Refer to the laboratory manual for detailed collection and handling procedures for all 
biomarker development samples. 
7.5 
Pharmacogenetic Studies 
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed.  These optional pharmacogenetics analyses focus on 
inherited genetic variations such as those of the 
 gene or the LDLR gene to 
evaluate their possible correlation to the disease and/or responsiveness to the therapies 
used in this study.  The goals of the optional studies include the use of genetic markers 
to help in the investigation of cardiovascular disease, hyperlipidemia and other metabolic 
disorders and/or to identify subjects who may have positive or negative response to 
evolocumab.  No additional blood will be collected for this analysis.  For subjects who 
have consented to the pharmacogenetic portion of this study, DNA will be extracted from 
blood samples already collected.  Subjects can participate in the main trial irrespective of 
whether they do or do not consent to the pharmacogenetic portion of the study. 
7.6 
Sample Storage and Destruction 
Any blood sample collected according to the Schedule of Assessments (Table 1) can be 
analyzed for any of the tests outlined in the protocol and for any tests necessary to 
minimize risks to study subjects.  This includes testing to ensure analytical methods 
produce reliable and valid data throughout the course of the study.  This can also 
include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability. 
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 permitted by local law and informed consent is provided by the subject, Amgen can do 
additional testing on remaining samples (ie, residual and back-up) to investigate and 
better understand processes related to 
 
 


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 eg, by evolocumab, characterize 
antibody response, and characterize aspects of the molecule (eg, mechanism of 
action/target, metabolites).  Results from this analysis are to be documented and 
maintained, but are not necessarily reported as part of this study.  Samples can be 
retained for up to 20 years. 
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of pharmacogenetic, biomarker development, or other 
exploratory studies are not placed in the subject’s medical record and are not be made 
available to the subject, members of the family, the personal physician, or other third 
parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood samples and any other components from the samples can be located and 
destroyed.  Samples will be destroyed once all protocol-defined procedures are 
completed.  However, information collected from samples prior to the request for 
destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the Investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  
See Section 11.3 for subject confidentiality. 
7.7 
Standardization of Study Procedures 
7.7.1 
Measurement of Vital Signs 
BP and HR will be measured at each visit.  Use of an automated oscillometric device for 
BP measurement is preferred and recommended.  BP will initially be recorded in both of 
the subject’s arms unless a concomitant condition favors the use of a particular arm.  
The arm with the higher systolic reading at screening will then be used for BP 


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determinations throughout the study.  The appropriate size cuff should be used.  BP and 
HR measurements will be determined after the subject has been seated for at least 
5 minutes.  The subject’s pulse should be measured for 30 seconds and the number 
multiplied by 2 to obtain heart rate.  Before randomization, BP measurement can be 
repeated if the previous reading is outside of the eligibility range.  The repeat BP 
measure should be taken at least 2 minutes following the previous measure. 
7.7.2 
Height, Weight, and Waist Circumference 
Height and weight measurement will be obtained at the time points specified in 
the Schedule of Assessments (Table 1).  If possible, visits with height and weight 
measurements should be scheduled at a similar time of day (eg, in the morning).  
Height is measured to the nearest centimeter with the subject’s back against a 
wall.  Use of a stadiometer is preferred and recommended.  Height is defined as 
the maximum distance from the floor to the highest point on the head, when the 
subject is facing directly ahead.  Shoes must be off, feet together, and arms by the 
sides.  Head, upper back, buttocks, and heels should be in contact with the wall 
when the measurement is made.  Two (2) measurements of height should be taken 
at each timepoint and entered into the CRF.  Weight is to be measured to the 
nearest tenth of a kilogram with the subject wearing light clothing and with shoes 
removed.  A properly calibrated digital scale should be used.  The scale should 
weigh in 0.1 kg increments, have a stable weighing platform that can be easily set 
to zero, be calibrated through professional service or by standard known weight. 
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, 
and also marked.  It is recommended to apply an elastic tape horizontally midway 
between the lowest rib margin and the iliac crest, and tie firmly so that it stays in position 
around the abdomen about the level of the umbilicus.  The elastic tape thus defines the 
level of the waist circumference, which can then be measured by positioning the 
measuring tape over the elastic tape.  Subjects are asked to breathe normally, and to 
breathe out gently at the time of the measurement to prevent them from contracting their 
muscles or from holding their breath.  Measurements should be performed using the 


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same procedure throughout the study.  The reading is taken to the nearest centimeter or 
½ inch and entered in the source document. 
7.7.3 
Tanner Staging (Sexual Maturity Ratings) 
Tanner staging is widely used to assess adolescents’ physical development during 
puberty in 5 stages (from preadolescent to adult). Also known as Sexual Maturity 
Ratings (SMRs), Tanner stages are a way of assessing the degree of maturation of 
secondary sexual characteristics (see Appendix D for guidance). The developmental 
stages of the adolescent’s sexual characteristics will be rated and recorded separately 
(ie, one stage for pubic hair and one for breasts in females, one stage for pubic hair and 
one for genitals in males), because these characteristics may differ in their degree of 
maturity. 
7.7.4 
Carotid Intima-Media Thickness (cIMT) 
Carotid intima-media thickness will be measured by ultrasonography at the timepoints 
shown in the Schedule of Assessments in Section 7.1.  Sonograms will be sent to a core 
laboratory for analysis.  Please refer to the cIMT instruction manual for detailed 
information on acquiring, storing, and transmitting the sonograms. 
7.7.5 
Electrocardiograms 
At each scheduled visit where ECGs are being obtained ECGs will be performed in a 
standardized method, in triplicate, and run consecutively (ie, < 30 seconds apart), prior 
to blood draws or other invasive procedures.  Using equipment supplied to each site, all 
protocol-specified ECGs will be acquired and transmitted to the centralized ECG 
services provider.  The Principal investigator (PI) or designated physician will review 
acquired ECGs.  One (1) signed, original ECG tracing should be retained with the 
subject’s source documents.  At the request of the sponsor, the original ECG should be 
made available to Amgen to be manually read by a central reader. 
The centralized ECG services cardiologists will perform standard interpretations of all 
tracings.  A cardiologist reviewed ECG report will be provided to the study site.  
Investigators must initial and date the ECG reports upon receipt.  If the investigator’s 
interpretation of any protocol-specified or unscheduled ECG differs from that supplied by 
centralized ECG services provider, it is the responsibility of the investigator to make the 
final clinical decisions.  The investigator’s interpretation does not need to be reconciled 
with that supplied by centralized ECG services cardiologists.  Any clinical interventions 
based on these results need to be documented in the appropriate source documents 
and eCRF as applicable.  It is the responsibility of the investigator to obtain additional 


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ECGs required for the clinical management of the subject, using centralized ECG 
services equipment or equipment on-site. 
Further detail about the equipment provided and its use for this study will be provided in 
an Investigator ECG Manual distributed to the sites before start of enrollment. 
7.7.6 
Lipid Measurements 
Only the screening LDL-C concentration will be reported to the site for the eligibility 
decision.  Central laboratory results of the lipid panel, as well as ApoA1, ApoB, 
lipoprotein(a), fasting vitamins A, D, E, and K, and 
 will be blinded 
post-treatment until unblinding of the clinical database and will not be reported to the 
investigator post-screening.  In addition, investigators and staff involved with this trial 
and all medical staff involved in the subject’s medical care should refrain from obtaining 
lipid panels from randomization until at least 12 weeks after the subject’s last 
administration of IP or until the subject ends the study, whichever is later (to avoid 
potential unblinding).  If a lipid panel is drawn, all reasonable steps must be undertaken 
to avoid informing the subject and study personnel of the results. 
7.7.7 
Neurocognitive Assessments 
The Cogstate cognitive battery is a set of neuropsychological tests administered to 
subjects via computer.  In Study 20120123, the battery will consist of the following 
4 tests: 
• 
Groton Maze Learning Task (GMLT; Executive Function): The Groton Maze Learning 
task is a measure of problem solving and reasoning and uses a well-validated maze 
learning paradigm.  In this task, the subject is shown a 10 x 10 grid of boxes on a 
computer screen.  A 28-step pathway is hidden among these 100 possible locations.  
Each box represents move locations, and the grid refers to the box array (ie, 10 × 
10).  Subjects are required to find the hidden pathway guided by 4 search rules.  
These rules are: do not move diagonally, do not move more than 1 box (ie, do not 
jump), do not move back on the pathway, and return to the last correct location after 
an error.  At each step, only the most recently selected box is shown.  Feedback is 
given with visual and auditory cues (green check marks and red crosses) to indicate 
whether the selected box is correct or incorrect.  The head of path, or the last correct 
location, flashes with a green check when two errors are made in succession (failing 
to return errors).  There are 20 well-matched alternate pathways available.  The 
software records each move as an error or as a correct move. 
• 
One Card Learning Test (OCL; Visual Memory): The One Card Learning test is a 
measure of visual recognition memory and uses a well-validated pattern separation 
paradigm using card stimuli.  In this test, the cards are similar to those found in a 
deck of playing cards.  The subject is asked whether the card currently being 
presented in the center of the screen was seen previously in this test.  The subject 
responds by pressing the Yes or No key.  Because no card has been presented yet, 
the first response is always No.  


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• 
Identification Test (IDN; Attention/Vigilance): The Identification test is a measure of 
visual attention and uses a well-validated choice reaction time paradigm using card 
stimuli.  In this test, the playing cards are all either red or black.  The subject is asked 
whether the card currently being presented in the center of the screen is red.  The 
subject responds by pressing the Yes key when the card is red and No when it is 
black.  
• 
Detection Test (DET; Psychomotor Speed): The Detection test is a measure of 
information processing speed and uses a well-validated simple reaction time 
paradigm using card stimuli.  In this test, the playing cards are all red and black.  The 
subject is asked to press the Yes key as soon as the card in the center of the screen 
flips over.  
This battery will be administered 3 times during the study: during screening, on study 
Day 1 (baseline), and at Week 24 (EOS).  Completion of this test battery will take 
approximately 15 to 20 minutes at each administration.  The Cogstate tests do not 
require complex language skills for administration, and the forms themselves do not use 
linguistic stimuli or responses.  
Cogstate tests have been used to examine the potential adverse effects of mobile 
telephone use in young adolescents (Abramson et al, 2009), adolescents with eating 
disorders (Allen et al, 2013), skipping breakfast in elementary schoolchildren 
(Kral et al, 2012), dietary patterns in adolescents (Nyaradi et al, 2014), and in utero 
exposure to cocaine (Mayes et al, 2007).  The Cogstate tests have also been used to 
examine the cognitive effects of treatment with stimulant medication in children with 
attention deficit hyperactivity disorder (ADHD) ([Mollica et al, 2004]: 8 to 12 year olds; 
[Snyder et al, 2008]: 6 to 16 year olds), as well as the effects of computerized cognitive 
rehabilitation in pediatric cerebral malaria survivors as young as 5 years old 
[Bangirana et al, 2009]. 
Additionally, regulatory authorities have approved the use of Cogstate tests for 
monitoring and evaluating the safety of central nervous system penetrant drugs in a 
range of pediatric indications, including epilepsy, neurogenic detrusor over-activity, 
bipolar depression, schizophrenia, and hyponatremia, and in children as young as 
4 years old.  In sports, Cogstate tests are being used to make return-to-play decisions in 
suspected concussion.  
7.7.8 
Neurologic Examination 
Physical examination (at screening and EOS) should include a neurologic examination.  
The neurologic physical examination should include assessments of motor, sensory, 
reflexes, coordination, and gait. 


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


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8.3 
Reasons for Removal From Screening, Treatment, or Study  
8.3.1 
Reasons for Removal From Screening 
Reasons for removal from screening include any of the following: 
• 
subject request  
• 
intolerance of placebo injection during screening 
• 
safety concern (eg, due to an adverse event, failure to follow contraception, 
pregnancy, or breast feeding) 
• 
decision by sponsor (other than subject request or safety concern) 
• 
death 
• 
lost to follow-up 
8.3.2 
Reasons for Removal From Treatment 
Reasons for removal from protocol-required investigational product or procedural 
assessments include any of the following: 
• 
subject request 
• 
safety concern (eg, due to an adverse event, failure to follow contraception, 
pregnancy, breast feeding, and/or protocol requirements) 
• 
death 
• 
lost to follow-up 
• 
decision by Sponsor (other than subject request, safety concern, lost to follow-up) 
8.3.3 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
• 
decision by sponsor  
• 
withdrawal of consent from study 
• 
death 
• 
lost to follow-up 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Adverse Events 
9.1.1 
Definition of Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record. 
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease  


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(eg, diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected, and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study or 
involves an intervention such as elective cosmetic surgery or a medical procedure while 
on study, is not considered an adverse event. 
An adverse device effect is any adverse event related to the use of a medical device.  
Adverse device effects include adverse events resulting from insufficient or inadequate 
instructions for use, adverse events resulting from any malfunction of the device, or 
adverse events resulting from use error or from intentional misuse of the device. 
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study. 
9.1.2 
Definition of Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria (unless it meets the definition of a Disease Related Event 
as defined in Section 9.1.3– below) : 
• 
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 subject with the same underlying condition, or 
• 
if the investigator believes a causal relationship exists between the 
investigational medicinal product(s)/protocol-required therapies and the event, 
• 
and the event meets at least 1 of the serious criteria above.   


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An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay). 
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, DILI (see Appendix A for 
drug-induced liver injury reporting criteria), or events that necessitate an emergency 
room visit, outpatient surgery, or urgent intervention. 
9.1.3 
Definition of 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, such events include 
atherosclerosis (especially of the coronary arteries) and its complications.  Examples 
include manifestations of myocardial ischemia such as chest pain and myocardial 
infarction, and percutaneous and surgical revascularization procedures.  Such events do 
not meet the definition of an adverse event unless assessed to be more severe than 
expected for the subject’s condition or if the investigator believes there is a causal 
relationship between the investigational product(s)/study treatment protocol 
required therapies and disease worsening. 
Disease Related Events and/or Disease Related Outcomes that do not qualify as 
Serious Adverse Events:  
• 
An event which is part of the normal course of disease under study 
(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. 
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 investigational product(s)/study treatment protocol 
required therapies and disease worsening, this must be reported as an Adverse 
Event or Serious Adverse Event. 
9.2 
Reporting of Adverse Events 
9.2.1 
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur from randomization and all adverse 


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events possibly related to study procedures from signing of the informed consent or 
subject assent through the end of study are reported using the applicable eCRF 
(eg, Adverse Event eCRF). 
The investigator must assign the following adverse event attributes: 
• 
adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
• 
dates of onset and resolution (if resolved), 
• 
severity 
• 
assessment of relatedness to investigational product (evolocumab or placebo or the 
prefilled autoinjector/pen (AI/Pen device), or other protocol-required 
therapies/protocol-required procedure or activity, and 
• 
action taken. 
The adverse event grading scale used will be the most current version of the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
grading scale.  The grading scale used in this study is referenced in Appendix A. 
The investigator must assess whether the adverse event is possibly related to IP 
(evolocumab or placebo).  This relationship is indicated by a “yes” or “no” response to 
the question: Is there a reasonable possibility that the event may have been caused by 
Investigational Medicinal Product? 
The investigator must assess whether the adverse event is possibly related to the 
prefilled autoinjector/pen (AI/Pen) device used to administer IP (evolocumab or 
placebo).  The relationship is indicated by a “yes” or “no” response to the question: Is 
there a reasonable possibility that the event may have been caused by the device? 
The investigator must assess whether the adverse event is possibly related to any other 
study-mandated activity (eg, screening or background therapy/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 study 
procedure/activity?” 
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, 


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clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. 
The Investigator is expected to follow reported adverse events until stabilization or 
reversibility.  If the severity of an adverse event worsens from the date of onset to the 
date of resolution, record a single event for each increased level of severity on the 
Adverse Event eCRF. 
9.2.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through 30 days after the last dose of IP or EOS, whichever is later, are 
recorded in the subject’s medical record and are submitted to Amgen.  All serious 
adverse events must be submitted to Amgen within 24 hours following the investigator’s 
knowledge of the event via the applicable eCRF. 
After the protocol-required reporting period defined above, the investigator does not 
need to actively monitor subjects for serious adverse events.  However, if the 
investigator becomes aware of a serious adverse event after this protocol-required 
reporting period, the investigator will report the event to Amgen within 24 hours following 
the investigator’s knowledge of the event.  Serious adverse events reported outside of 
the protocol-required reporting period will be captured within the safety database as 
clinical trial cases for the purposes of expedited reporting. 
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
Serious Adverse Event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event (eSAE) Contingency Report Form within 24 hours of the 
investigator’s knowledge of the event.  See Appendix B for a sample of the Serious 
Adverse Event Worksheet/electronic Serious Adverse Event Contingency Report Form.  
If the first notification of a Serious Adverse Event is reported to Amgen via the eSAE 
Contingency Report Form, the data must be entered into the EDC system when the 
system is again available. 
The investigator must assess whether the serious adverse event is possibly related to IP 
(evolocumab or placebo).  This relationship is indicated by a “yes” or “no” response to 
the question: Is there a reasonable possibility that the event may have been caused by 
Investigational Medicinal Product? 


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The investigator must assess whether the serious adverse event is possibly related to 
the prefilled autoinjector/pen (AI/Pen) device used to administer IP (evolocumab or 
placebo).  The relationship is indicated by a “yes” or “no” response to the question: Is 
there a reasonable possibility that the event may have been caused by the device? 
The investigator must assess whether the serious adverse event is possibly related to 
any other study-mandated activity (eg, screening procedure or background 
therapy/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 study procedure/activity?” 
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility.  If the severity of a serious adverse event worsens from the date of onset 
to the date of resolution, record a single event for each increased level of severity on the 
Adverse Event eCRF. 
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  The investigator 
may be asked to provide additional follow-up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the applicable CRF (eg, Adverse 
Event eCRF). 
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 good 
clinical practice. 


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The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local procedures and statutes. 
9.2.3 
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 the first dose of investigational 
medicinal product(s) through EOS (including any follow-up visits) are reported using 
the appropriate Event CRF. Additionally, the investigator is required to report a fatal 
disease-related event on the CRF. 
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 investigational product(s)/study treatment protocol 
required therapies and disease worsening, this must be reported as an Adverse 
Event or Serious Adverse Event. 
9.3 
Pregnancy and Lactation Reporting 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking IP (evolocumab or placebo) report the pregnancy to Amgen as specified 
below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies the last dose of IP (evolocumab or placebo) through 15 weeks 
after the end of treatment with IP (evolocumab or 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).  If a lactation case occurs while the 
female subject is taking IP (evolocumab or placebo) report the lactation case to Amgen 
as specified below.  
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur after the last dose of IP (evolocumab or placebo) through 
15 weeks after the end of treatment with IP (evolocumab or placebo).  
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). 


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10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Efficacy Endpoint 
• 
Percent change from baseline to week 24 in LDL-C 
10.1.1.2 
Secondary Efficacy Endpoints 
• 
Mean percent change from baseline to weeks 22 and 24 in LDL-C1 
• 
change from baseline to week 24 in LDL-C2 
• 
percent change from baseline to week 24 in the following3: 
− non-HDL-C 
− ApoB 
− total cholesterol/HDL-C ratio 
− ApoB/ApoA1 ratio 
1,2,3See Section 10.5.1 for details on multiplicity adjustment. 
10.1.1.3 
Tertiary Efficacy Endpoints 
• 
Percent change from baseline to week 24 in the following: 
− total cholesterol 
− VLDL-C 
− HDL-C  
− ApoA1 
− triglycerides 
− Lp(a) 
• 
mean percent change from baseline to weeks 22 and 24 in the following: 
− non-HDL-C 
− ApoB 
− total cholesterol/HDL-C ratio 
− ApoB/ApoA1 ratio 
− total cholesterol 
− VLDL-C 
− HDL-C  
− ApoA1 
− triglycerides 
− Lp(a) 


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10.1.1.4 
Exploratory Endpoints 
10.1.1.5 
Secondary 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 
10.1.1.6 
Secondary Pharmacokinetics Endpoints 
• 
Serum concentration of evolocumab at each scheduled assessment 
10.1.1.7 
Other Safety Endpoints 
• 
Change from baseline score in the components of the Cogstate battery at each 
scheduled administration 


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10.1.2 
Analysis Sets 
The full analysis set (FAS) includes all randomized subjects who received at least 
1 dose of IP.  This analysis set will be used in both efficacy and safety analyses.  In 
efficacy analyses, subjects will be grouped according to their randomized treatment 
group assignment.  For safety analyses, subjects will be grouped according to their 
randomized treatment group assignment with the following exception: if a subject 
receives treatment throughout the study that is different than the randomized treatment 
group assignment, then the subject will be grouped by the actual treatment group.  The 
completer analysis set (CAS) includes subjects in the FAS who adhered to the 
scheduled IP regimen and have an observed value for the primary endpoint. 
10.1.3 
Baseline Covariates and Subgroups 
The following baseline covariates may be used for subgroup or covariate analyses with 
the subgroups as specified or in their original format: 
• age (< 14 years vs ≥ 14 years) 
• sex 
• LDL-C by central laboratory (< 160 mg/dL [4.1 mmol/L] vs ≥ 160 mg/dL) 
Subgroup levels may be combined as appropriate for subgroup analyses. 
10.2 
Sample Size Considerations 
This study is to provide clinical experience with evolocumab in approximately 
150 pediatric subjects, compared to the current experience described in Sections 2.3 
and Section 2.4.  Based on the treatment effect from the global phase 3 study in adult 
subjects with HeFH, evolocumab reduced LDL-C by approximately 55%.  A planned total 
sample size of 150 subjects (100 randomized to evolocumab 420 mg QM and 
50 randomized to placebo QM) will provide approximately 99% power in testing the 
superiority of evolocumab 420 mg QM over placebo.  The sample size calculation is 
performed using a two-sided t-test with a 0.05 significance level, assuming a treatment 
effect of 40% reduction in LDL-C, a common SD of 20%, and 20% of subjects 
discontinuing investigational product prior to completion of the study. 
The power calculation is derived using nQuery version 7.01. 


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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). 
Individual subject treatment assignments will be maintained by the IVRS/IWRS. Any 
unplanned unblinding occurring during the study period will be documented and reported 
in the final clinical study report. 
The independent DMC members and Independent Biostatistical Group (IBG) will have 
access to treatment assignments and subject level data from the clinical trial database.  
Amgen staff members who are involved in randomization, biological sample 
management, performing PK, and anti-evolocumab antibody assay analysis will have 
treatment assignment information but will not have access to subject level data from the 
clinical trial database. 
10.4 
Planned Analyses 
10.4.1 
Data Monitoring Committee (DMC) 
An external independent DMC has been established to formally review the accumulating 
data from this and other completed and ongoing studies with evolocumab to ensure 
there is no avoidable increased risk for harm to subjects.  The independent DMC is 
chaired by an external academic cardiologist who is an expert in lipids and clinical trials. 
Analyses for the DMC are provided by the Independent Biostatistical Group (IBG), which 
is external to Amgen.  Details are provided in the DMC charter. 
10.4.2 
Primary Analysis 
The primary analysis of this study will be conducted when the study is completed.  At 
that time, the database will be cleaned, processed and locked; the study will also be 
unblinded. Unless specified otherwise, the FAS will be the default analysis set in this 
study and data will be summarized by randomized treatment group. 
10.5 
Planned Methods of Analysis  
10.5.1 
General Considerations 
Efficacy and safety analyses will be performed on the FAS. Unless specified otherwise, 
the FAS will be the default analysis set in this study and data will be summarized by 


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randomized treatment group.  The superiority of evolocumab to placebo will be assessed 
for all efficacy endpoints. 
Subject disposition, demographics, baseline characteristics, and exposure to IP will be 
summarized. 
Summary statistics for continuous variables will include the number of subjects, mean, 
median, standard deviation, or standard error, minimum, and maximum.  For categorical 
variables, the frequency and percentage will be given. 
Methods of handling missing data for efficacy endpoints will be described throughout this 
section.  Missing data will not be imputed for safety endpoints. 
Multiplicity Adjustment Method 
To preserve the familywise error rate at 0.05, multiplicity adjustment for the multiple 
endpoints (primary and secondary efficacy endpoints as enumerated in section 10.1.1.2) 
will be performed using sequential gatekeeping and Hochberg procedures 
(Hochberg, 1988) as follows:  
• 
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 secondary 
efficacy endpoint1 and endpoint2 will proceed using the sequential procedure with 
a significance level of 0.05 (ie, secondary endpoint2 will be tested only if 
secondary endpoint1 is statistically significant at 0.05 significance level). 
• 
If the treatment effect from secondary endpoint2 is significant at a significance 
level of 0.05, statistical testing of the secondary endpoints3 will follow the 
Hochberg procedure at a significance level of 0.05. 
Unless specified otherwise, all other hypothesis testing will be 2-sided with a significance 
level of 0.05. 
10.5.2 
Primary Efficacy Endpoint Analyses 
Primary Analyses 
The estimand of primary interest is the difference in mean percent change from 
baseline in LDL-C at week 24 regardless of treatment adherence for subjects in 
FAS.  A repeated measures linear effects model will be used to compare the efficacy of 
evolocumab with placebo.  The repeated measures model will include terms for 
treatment group, stratification factor (as appropriate), scheduled visit and the interaction 
of treatment with scheduled visit.  Missing values will not be imputed when the repeated 
measures linear effects model is used.  The analysis will use LDL-C values measured 
regardless of treatment adherence. 


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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 (Quade test) 
• 
To evaluate the impact of missing values, a sensitivity analysis under the 
assumption that subjects who, discontinued IP and have missing endpoint 
data have a mean zero percent change from baseline will be conducted using 
multiple imputation 
The difference between the number of randomized subjects and the number of 
subjects in the FAS will also be assessed and reported in the Clinical Study 
Report.  
Covariate and Subgroup Analysis 
If applicable, covariate and subgroup analyses on the primary endpoint will be 
conducted using baseline covariates. 
10.5.3 
Secondary Efficacy Endpoints Analyses 
The statistical model and testing of the secondary efficacy endpoints will be similar to the 
primary analysis of the primary endpoint. 
Multiplicity adjustment procedures are defined in Section 10.5.1. 
10.5.4 
Tertiary Efficacy Endpoint Analyses 
Analysis of the tertiary efficacy endpoints will be similar to the primary analysis of the 
primary endpoint.  No multiplicity adjustment will be applied.  
10.5.5 
Secondary Safety and Pharmacokinetic Endpoint Analyses 
Adverse Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  Tables of fatal adverse events, serious adverse events, 
adverse events leading to withdrawal from investigational product will also be provided.  
Subject-level data may be provided instead of tables if the subject incidence is low. 


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Safety Laboratory Parameters 
Laboratory parameters will be summarized for each treatment group using descriptive 
statistics at each scheduled visit. Laboratory shift tables for certain analytes will be 
provided using the CTCAE v.4 toxicity criteria. The results will be based on the 
maximum (ie, worst) shift from baseline to the EOS. 
Vital Signs 
Vital signs will be summarized for each treatment group using descriptive 
statistics at each scheduled visit. 
Anti-evolocumab antibodies 
The incidence and percentages of subjects who develop anti-evolocumab 
antibodies (binding and neutralizing) at any time will be tabulated. 
Pharmacokinetic 
Unbound evolocumab serum concentrations by time will be summarized using 
descriptive statistics. 
10.5.6 
Other Safety Endpoint Analyses 
Neurologic examination 
The incidence of abnormal neurologic findings overall and in each exam area will be 
summarized by treatment group. 
Cogstate neurocognitive assessment 
For each test, the change from baseline to EOS in the standardized score will be 
summarized by treatment group. 
10.5.7 
Exploratory Endpoint Analyses 
 
 
 
 
 
 
 


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11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the template are to 
be communicated formally in writing from the Amgen Clinical Study Manager or 
designee to the investigator.  The written informed consent document is to be prepared 
in the language(s) of the potential patient population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject or legally acceptable representative 
after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study and before any protocol-specific screening procedures or any 
investigational product(s) is/are administered.  A legally acceptable representative is an 
individual or other body authorized under applicable law to consent, on behalf of a 
prospective subject, to the subject’s participation in the clinical study.  
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record.  
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 informed consent form is to be signed and personally dated by the 
subject or a legally acceptable representative and by the person who conducted the 
informed consent discussion.  The original signed informed consent form is to be 
retained in accordance with institutional policy, and a copy of the signed consent form is 
to be provided to the subject or legally acceptable representative. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood. 


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In this study, obtaining subject assent from the child and consent from the parents or 
legally authorized representative, except if the child is very young, as defined by local 
law will apply.  A child is defined as a person who has not attained the legal age for 
consent for treatments or procedures involved in clinical investigations, under the 
applicable law of the jurisdiction in which the clinical investigation will take place.  The 
local IRB/IEC will determine the process for obtaining and documenting the subject 
assent process for pediatric subject, but should follow the guidelines established by the 
Department of Health and Human Services (DHHS) Office of Human Research 
Protections guidelines, which state an explanation of the procedures involved in the 
study should be made in a language appropriate to the child’s age, experience, maturity, 
and condition. 
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IRB/IEC for 
written approval.  A copy of the written approval of the protocol and informed consent 
form must be received by Amgen before recruitment of subjects into the study and 
shipment of Amgen investigational product. 
The investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator is to notify the IRB/IEC of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures. 
The investigator is responsible for obtaining annual IRB/IEC approval or renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IRB/IEC continuance of approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
• 
Subjects are to be identified by a unique subject identification number. 
• 
Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations. 
• 
On the CRF demographics page, in addition to the unique subject identification 
number, include the age at time of enrollment. 


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


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


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


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Amgen (or designee) will perform self-evident corrections to obvious data errors in the 
clinical trial database, as documented in the Study Specific Self Evident Corrections 
Plan.  Examples of obvious data errors that may be corrected by Amgen (or designee) 
include deletion of obvious duplicate data (eg, same results sent twice with the same 
date with different visit-week 4 and early termination) and clarifying “other, specify” if 
data are provided (eg, race, physical examination).  Each investigative site will be 
provided a list of the types of corrections applied to study data at the initiation of the trial 
and at study closeout. 
12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 1), the investigator can search publically available 
records [where permitted]) to ascertain survival status.  This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible. 
12.5 
Language 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
12.6 
Publication Policy 
To coordinate dissemination of data from this study, Amgen encourages the formation of 
a publication committee consisting of several investigators and appropriate Amgen staff, 
the governance and responsibilities of which are set forth in a Publication Charter.  The 
committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff as appropriate as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 


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


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13. 
REFERENCES 
Abramson MJ, Benke GP, Dimitriadis C, et al. Mobile telephone use is associated with 
changes in cognitive function in young adolescents. Bioelectromagnetics. 
2009;30(8):678-686. doi:10.1002/bem.20534 
Abifadel M, Rabes 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(4):520-529. 
Allen KL, Byrne SM, Hii H, van Eekelen A, Mattes E, Foster JK. Neurocognitive 
functioning in adolescents with eating disorders: A population-based study. Cogn 
Neuropsychiatry. 2013;18(5):355-375. doi:10.1080/13546805.2012.698592 
Amgen. AMG 145 Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc. 
Austin MA, Hokanson JE, Edwards KL.  Hypertriglyceridemia as a cardiovascular risk 
factor.  Am J Cardiol.  1998;81:7B-12B. 
Bangirana P, Giordani B, John CC, Page C, Opoka RO, Boivin MJ. Immediate 
neuropsychological and behavioral benefits of computerized cognitive rehabilitation in 
Ugandan pediatric cerebral malaria survivors. J Dev Behav Pediatr. 2009;30(4):310-318. 
Cohen J, Pertsemlidis A, Kotowski IK, et al.  Low LDL cholesterol in individuals of 
African descent resulting from frequent nonsense mutations in PCSK9.  Nature Genetics 
2005;37:161-165. 
Cohen JC, Boerwinkle E, Mosley TH, Jr, Hobbs HH.  Sequence variations in PCSK9, 
low LDL, and protection against coronary heart disease.  N Engl J Med.  
2006;354:1264-1272. 
Daniels SR, Greer FR.  Committee on Nutrition.  Lipid screening and cardiovascular 
health in childhood.  Pediatrics.  2008;122:198-208. 
Goldstein J, Hobbs H, Brown, M.  Familial hypercholesterolemia.  In: The Metabolic and 
Molecular Bases of Inherited Disease.  Scriver C, Beaudet A, Sly W, Valle D, eds.  New 
York, NY: McGraw-Hill; 2001;2863–2913. 
Grundy SM, Cleeman JI, Merz CN, et al.  Implications of recent clinical trials for the 
National Cholesterol Education Program Adult Treatment Panel III Guidelines.  
Circulation.  2004;110:227-239. 
Hochberg Y.  A sharper Bonferroni procedure for multiple tests of significance.  
Biometrika 1988;75:800-802. 
Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR.  The C679X mutation in PCSK9 is 
present and lowers blood cholesterol in a Southern African population.  Atherosclerosis   
2007;193:445-448.  
Kavey RE, Allada V, Daniels SR, et al.  Cardiovascular risk reduction in high-risk 
pediatric patients: a scientific statement from the American Heart Association Expert 
Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in 
the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, 
High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart 
Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes 
Research: endorsed by the American Academy of Pediatrics.  Circulation.  
2006;114:2710-2738. 


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Kotseva K, Wood D, De Backer G, De Bacquer D, Pyörälä K, Keil U, for the 
EUROSPIRE Study Group.  Cardiovascular prevention guidelines in daily practice: a 
comparison of EUROASPIRE I, II, and III surveys in eight European countries.  Lancet.  
2009;373:929-940. 
Kral TV, Heo M, Whiteford LM, Faith MS. Effects on cognitive performance of eating 
compared with omitting breakfast in elementary schoolchildren. J Dev Behav Pediatr. 
2012;33(1):9-16. doi:10.1097/DBP.0b013e31823f2f35 
Kuklina EV, Shaw KM, Hong Y.  Vital signs:  prevalence, treatment, and control of high 
levels of low-density lipoprotein cholesterol—United States, 1999-2002 and 2005-2008.  
JAMA.  2011;305:1086-1088. 
Lifshitz F, editor. Pediatric Endocrinology, Volume 2: Growth, Adrenal, Sexual, Thyroid, 
Calcium, and Fluid Balance Disorders. 5th ed. New York, NY : Informa Healthcare; 2007. 
Mayes L, Snyder PJ, Langlois E, Hunter N. Visuospatial working memory in school-aged 
children exposed in utero to cocaine. Child Neuropsychol. 2007;13(3):205-218. 
doi:10.1080/09297040600888753 
Mollica CM, Maruff P, Vance A. Development of a statistical approach to classifying 
treatment response in individual children with ADHD. Hum Psychopharmacol. 
2004;19(7):445-456. 
McCrindle BW, Urbina EM, Dennison BA, et al.  Drug therapy of high-risk lipid 
abnormalities in children and pediatrics: a scientific statement from the American Heart 
Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council of 
Cardiovascular Disease in the Young, with the Council on Cardiovascular Nursing.  
Circulation.  2007;115:1948-1967. 
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, 
and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third 
Report of the National Cholesterol Education Program (NCEP) Expert Panel on 
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult 
Treatment Panel III) final report. Circulation. 2002;106:3143-3421. 
National Collaborating Centre for Primary Care.  Identification and Management of 
Familial Hypercholesterolaemia (FH).  London, UK: National Institute for Health and 
Clinical Excellence (NICE); 2008. 
Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is 
underdiagnosed and undertreated in the general population: guidance for clinicians to 
prevent coronary heart disease: consensus statement of the European Atherosclerosis 
Society. Eur Heart J. 2013;34:3478-3490a. 
Nyaradi A, Foster JK, Hickling S, et al. Prospective associations between dietary 
patterns and cognitive performance during adolescence. J Child Psychol Psychiatry. 
2014;55(9):1017–1024. doi:10.1111/jcpp.12209 
Raal FJ, Pilcher GJ, Panz VR, et al.  Reduction in mortality in subjects with homozygous 
familial hypercholesterolemia associated with advances in lipid-lowering therapy.  
Circulation.  2011;124:2202-2207. 
Raal FJ, Honorpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in 
homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-
blind, placebo-controlled trial. The Lancet. 2014: doi:10.1016/S0140-6736(08)61345-8 
[Epub ahead of print]. 


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Rader DJ, Cohen J, Hobbs HH.  Monogenic hypercholesterolemia: new insights in 
pathogenesis and treatment.  J Clin Invest.  2003;111:1795-1803. 
Reiner Z, Catapano AL, De Backer G, et al. ESC/EAS Guidelines for the management of 
dyslipidaemias: the Task Force for the management of dyslipidaemias of the European 
Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart 
J. 2011;32:1769-1818. 
Sarwar N, Danesh J, Eiriksdottir G, et al.  Triglycerides and the risk of coronary heart 
disease: 10,158 incident cases among 262,525 participants in 29 Western prospective 
studies.  Circulation.  2007;115:450-458. 
Scientific Steering Committee. Risk of fatal coronary heart disease in familial 
hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome 
Register Group.  BMJ. 1991;303:893-896. 
Snyder AM, Maruff P, Pietrzak RH, Cromer JR, Snyder P. Effect of treatment with 
stimulant medication on nonverbal executive function and visuomotor speed in children 
with attention deficit/hyperactivity disorder (ADHD). Child Neuropsychol. 2008;14(3):211-
226. 
Tolonen H, Keil U, Ferrario M, Evans A; WHO MONICA Project.  Prevalence, awareness 
and treatment of hypercholesterolaemia in 32 populations: results from the WHO 
MONICA Project.  Int J Epidemiol.  2005;34:181-192. 
Williams RR, Hunt SC, Schumacher MC, et al. Diagnosing heterozygous familial 
hypercholesterolemia using new practical criteria validated by molecular genetics. Am J 
Cardiol 1993;72(2):171-176. 
World Health Organization. Familial hypercholesterolemia – Report of a Second WHO 
Consultation, WHO publication no: WHO/HGN/FH/CONS/00.2, Geneva, 1999; 
http://apps.who.int/iris/handle/10665/66346. 
Zhao Z, Tuakli-Wosornu Y, Lagace TA, et al.  Molecular characterization of 
loss-of-function mutations in PCSK9 and identification of a compound heterozygote.  
Am J Hum Genet.  2006;79:514-523. 


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14. 
APPENDICES 


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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
Refer to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 
for adverse event grading and information.  The CTCAE is available at the following link: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications\ctc.htm. 
Pediatric Drug-induced Liver Injury Reporting & Additional Assessments  
Reporting 
Cases with  
AST or ALT ≥ 3 x ULN and TBL > 2 x ULN or INR > 1.5  
or 
AST or ALT ≥ 3 x ULN with signs and symptoms consistent with hepatitis must 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).   
Cases with  
AST or ALT > 3 x ULN (if baseline ALT or AST is ≤ 3 x ULN) 
AST or ALT > 5 x ULN (if baseline ALT or AST is ≤ 5 x ULN) 
are to be reported as adverse events. 
The appropriate CRF (eg, Adverse Event CRF) that captures information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities is to be completed and 
sent to the Amgen. 
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.1.2. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational medicinal product(s) or protocol-required therapies 
is/are withheld (either permanently or conditionally) due to potential DILI as specified in 
Sections 6.5.1 and Section 6.5.2 or who experience AST or ALT elevations > 3x ULN (if 
baseline ALT or AST is ≤ 3 x ULN) or who experience AST or ALT > 5 x ULN (if baseline 


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ALT or AST is ≤ 5 x ULN)  are to undergo a period of “close observation” until 
abnormalities return to normal or to the subject’s baseline levels.   
The following evaluations are to be performed during this period:   
1. Repeat liver tests AST, ALT, ALP, bilirubin (total and direct), and INR as clinically 
necessary until laboratory abnormalities improve .   
2. Obtain pediatric gastroenterologist or pediatric hepatologist consult. 
The diagnostic approach (including blood tests) to investigate alternative causes for 
abnormal liver tests is to be determined in consultation with a pediatric 
gastroenterologist or hepatologist. 
The “close observation” is to continue until all laboratory abnormalities return to baseline 
or normalize and subject’s clinical condition improves. 


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Appendix B.  Sample Electronic Serious Adverse Event (eSAE) Contingency 
Report Form 


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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 


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Appendix D.  Tanner Stages (Sexual Maturity Ratings) 
The table below or equivalent locally used guidance should be used for the assessment of sexual maturity (Tanner Staging) in this study.  
The table is adapted from Lifshitz (2007). 
FEMALES: 
Stage 
BREAST 
PUBIC HAIR STAGING 
CONCOMITANT CHANGES 
1 
Prepubertal, papilla elevation 
No pigmented hair 
 
2 
Budding; larger areole; palpable and 
visible elevated contour 
Pigmented hair, mainly labial 
Accelerating growth rate 
3 
Enlargement of the breast and areola 
Coarser, spread of pigmented hair 
over mons 
Peak growth rate, thicker vaginal 
mucosa, axillary hair 
4 
Secondary mound of areola and papilla 
Adult type but smaller area 
Menarche (stage 3 or 4) decelerating 
growth rate 
5 
Mature 
Adult distribution 
 
MALES: 
Stage 
GENITAL SIZE 
PUBIC HAIR STAGING 
CONCOMITANT CHANGES 
PRADER 
ORCHIDOMETER 
1 
Prepubertal 
No pigmented hair 
Long testis axis < 1.5 cm 
1 – 3 mL 
2 
Early testicular, penile and 
scrotal growth 
Minimal pigmented hair at base 
of penis 
Early voice changes; testes length 
2.5 – 3.3 cm 
3 – 6 mL 
3 
Increased penile length and 
width; scrotal and testes 
growth 
Dark, coarse, curly hair extends 
midline above penis 
Light hair on upper lip, acne, 
maximal growth, testes length 3.3 – 
4.0 cm 
8 – 12 mL 
4 
Increased penis size including 
breadth; pigmented scrotum 
Considerable, but less than 
adult distribution 
Early sideburns; testes 4.0 – 4.5 
cm 
> 12 mL 
5 
Adult size and shape 
Adult distribution, spread to 
medial thighs or beyond 
Beard growth; testes > 4.5 cm 
> 15 mL 
 


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Amendment 2 
Protocol Title:  Double-blind, Randomized, Multicenter, Placebo-controlled, 
Parallel Group Study to Characterize the Efficacy, Safety, and Tolerability of 24 
Weeks of Evolocumab for Low Density Lipoprotein-cholesterol (LDL-C) Reduction, 
as Add-on to Diet and Lipid-lowering Therapy, in Pediatric Subjects 10 to 17 Years 
of Age With Heterozygous Familial Hypercholesterolemia (HeFH) 
 
Amgen Protocol Number Evolocumab (AMG 145) 20120123 
EudraCT number 2014-002277-11 
 
Original, Date: 
09 December 2014 
Amendment 1, Date: 
20 May 2015 
Amendment 2, Date: 
01 September 2015 
 
Rationale: 
• 
To address regulatory feedback. 
• 
To clarify specific details of the statistical analysis 
• 
To add safety assessments 


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Description of Changes: 
Section:  Global 
Change: Updated the amendment 2 date throughout to 01 September 2015. 
Grammatical changes throughout (correction of prior errors or omissions). 
Abbreviation ADE and DRE added globally.  
Section: Title Page 
Replace: 
Key Sponsor Contact(s): 
1 Sanderson Road (Uxbridge Business Park) 
Uxbridge UB8 1DH 
United Kingdom 
Phone:
Fax:
Email:
 
 
Date: 
09 December 2014 
Amendment 1: 
20 May 2015 
 
 
With: 
Key Sponsor Contact(s): 
One Amgen Center Drive 
Mail Stop 27-1-F 
Thousand Oaks, CA 91320, USA 
Phone:
Fax:
Email:
 
Original, Date: 
09 December 2014 
Amendment 1, Date: 
20 May 2015 
Amendment 2, Date  
01 September 2015 
Section: Protocol Synopsis, Secondary Efficacy Objectives 
Replace: 
Secondary Objectives: 
to evaluate the safety of SC evolocumab compared with placebo, when added to 
standard of care, in pediatric subjects 10 to 17 years of age with HeFH 
to assess the effects of SC evolocumab compared with placebo, when added to 
standard of care, on mean percent change from baseline to weeks 22 and 24 and 
change from baseline to week 24 in LDL-C, and on percent change from baseline to 
week 24 in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B 


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(ApoB), total cholesterol/HDL-C ratio, and ApoB/Apolipoprotein A-1 (ApoA1) ratio, in 
pediatric subjects 10 to 17 years of age with HeFH 
• 
to characterize pharmacokinetic (PK) exposure 
With: 
Secondary Efficacy Objectives 
• 
to evaluate the safety of SC evolocumab compared with placebo, when added to 
standard of care, in pediatric subjects 10 to 17 years of age with HeFH 
Secondary Efficacy Objectives:  to assess the effects of SC evolocumab compared 
with placebo, when added to standard of care, on mean percent change from baseline to 
weeks 22 and 24 and change from baseline to week 24 in LDL-C, and on percent 
change from baseline to week 24 in non-high-density lipoprotein cholesterol 
(non-HDL-C), apolipoprotein B (ApoB), total cholesterol/HDL-C ratio, and 
ApoB/Apolipoprotein A-1 (ApoA1) ratio, in pediatric subjects 10 to 17 years of age with 
HeFH 
Secondary Safety Objectives:  to evaluate the safety of SC evolocumab compared 
with placebo, when added to standard of care, in pediatric subjects 10 to 17 years of age 
with HeFH 
Secondary Pharmacokinetic Objective:  to characterize pharmacokinetic (PK) 
exposure 
Section:  Protocol Synopsis, Summary of Subject Eligibility Criteria: 
Replace:   
The following are the major exclusion criteria: type 1 diabetes or recently diagnosed 
(within 3 months of randomization) or poorly controlled (HbA1c > 8.5%) type 2 diabetes 
or newly diagnosed impaired glucose tolerance; thyroid stimulating hormone (TSH) < 
lower limit of normal (LLN) or TSH > 1.5x upper limit of normal (ULN) and free thyroxine 
(T4) levels that are outside normal range, estimated glomerular filtration rate (eGFR) 
< 30 ml/min/1.73m2, aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) > 2x ULN, creatine kinase (CK) > 3x ULN (all screening by central laboratory); 
known active infection, or major hematologic, renal, metabolic, gastrointestinal or 
endocrine dysfunction.  Subjects are excluded if they have taken any cholesterylester 
transfer protein (CETP) inhibitor in the last 12 months, mipomersen or lomitapide in the 
last 5 months, lipid apheresis within the last 12 weeks, or if they have previously 
received evolocumab or any other investigational therapy to inhibit proprotein convertase 
subtilisin/kexin type 9 (PCSK9).  Subjects cannot be enrolled in another investigational 
device or drug study, receive other investigational agent(s) or procedures, or be within 
less than 30 days since ending another investigational device or drug study.  Female 
subjects of childbearing potential cannot be pregnant, planning to become pregnant, 
breast feeding or planning to breastfeed and must be willing to use acceptable 
method(s) of effective contraception  during treatment with IP (evolocumab or placebo) 
and for an additional 15 weeks after the end of treatment with IP (evolocumab or 
placebo). 
With: 
The following are the major exclusion criteria: homozygous familial 
hypercholesterolemia, type 1 diabetes or recently diagnosed (within 3 months of 
randomization) or poorly controlled (HbA1c > 8.5%) type 2 diabetes or newly diagnosed 
impaired glucose tolerance; thyroid stimulating hormone (TSH) < lower limit of normal 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 4 of 23 
CONFIDENTIAL 
 
 
(LLN) or TSH > 1.5x upper limit of normal (ULN) and free thyroxine (T4) levels that are 
outside normal range, estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2, 
aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2x ULN, creatine 
kinase (CK) > 3x ULN (all screening by central laboratory); known active infection, or 
major hematologic, renal, metabolic, gastrointestinal or endocrine dysfunction.  Subjects 
are excluded if they have taken any cholesterylester transfer protein (CETP) inhibitor in 
the last 12 months, mipomersen or lomitapide in the last 5 months, lipid apheresis within 
the last 12 weeks, or if they have previously received evolocumab or any other 
investigational therapy to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9).  
Subjects cannot be enrolled in another investigational device or drug study, receive 
other investigational agent(s) or procedures, or be within less than 30 days since ending 
another investigational device or drug study.  Female subjects of childbearing potential 
cannot be pregnant, planning to become pregnant, breast feeding or planning to 
breastfeed and must be willing to use acceptable method(s) of effective contraception  
during treatment with IP (evolocumab or placebo) and for an additional 15 weeks after 
the end of treatment with IP (evolocumab or placebo). 
Section: Protocol Synopsis, Investigational Product 
Replace: 
Assessments and procedures include vital signs, adverse events/serious adverse 
events/cardiovascular (CV) events, and concomitant therapy, dietary instruction, 
physical exam including neurologic examination and assessment of waist circumference, 
body height and weight, 12-lead electrocardiograms (ECGs), fasting lipids, chemistry, 
hematology, anti-evolocumab antibodies, biomarker sample collection, serum pregnancy 
testing (females of childbearing potential), urinalysis, assessment of growth and pubertal 
development (Tanner staging), Cogstate neurocognitive assessment, carotid intima-
media thickness (cIMT), and IP administration.  In addition, specific laboratory 
assessments will be performed, including estradiol for girls, testosterone for boys, 
creatinine phosphokinase, follicle-stimulating hormone, luteinizing hormone, 
adenocorticotropic hormone, dehydroepiandrosterone, and cortisol.  If the subject 
consented to pharmacogenetics analyses, DNA will be extracted from some of the blood 
samples.  IP administration by SC injection, if applicable, will be done after all other 
procedures have been completed. 
With: 
Assessments and procedures include vital signs, adverse events/serious adverse 
events/adverse device effects (ADE)/disease related events (DRE)/cardiovascular 
(CV) events, and concomitant therapy, dietary instruction, physical exam including 
neurologic examination and assessment of waist circumference, body height and weight, 
12-lead electrocardiograms (ECGs), fasting lipids, chemistry, hematology, 
anti-evolocumab antibodies, biomarker sample collection, serum pregnancy testing 
(females of childbearing potential), urinalysis, assessment of growth and pubertal 
development (Tanner staging), Cogstate neurocognitive assessment, carotid intima-
media thickness (cIMT), and IP administration.  In addition, specific laboratory 
assessments will be performed, including estradiol for girls, testosterone for boys, 
creatinine phosphokinase, follicle-stimulating hormone, luteinizing hormone, 
adenocorticotropic hormone, dehydroepiandrosterone, and cortisol.  If the subject 
consented to pharmacogenetics analyses, DNA will be extracted from some of the blood 
samples.  IP administration by SC injection, if applicable, will be done after all other 
procedures have been completed. 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 5 of 23 
CONFIDENTIAL 
 
 
Section:  1.2 Secondary Efficacy 
Replace: 
• 
to evaluate the safety of SC evolocumab compared with placebo, when added to 
standard of care, in pediatric subjects 10 to 17 years of age with HeFH 
• 
to assess the effects of SC evolocumab compared with placebo, when added to 
standard of care, on mean percent change from baseline to weeks 22 and 24 and 
change from baseline to week 24 in LDL-C, and on percent change from baseline to 
week 24 in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B 
(ApoB), total cholesterol/HDL-C ratio, and ApoB/Apolipoprotein A-1 (ApoA1) ratio, in 
pediatric subjects 10 to 17 years of age with HeFH 
• 
To characterize pharmacokinetic (PK) exposure 
With: 
• 
to evaluate the safety of SC evolocumab compared with placebo, when added to 
standard of care, in pediatric subjects 10 to 17 years of age with HeFH 
• 
to assess the effects of SC evolocumab compared with placebo, when added to 
standard of care, on mean percent change from baseline to weeks 22 and 24 and 
change from baseline to week 24 in LDL-C, and on percent change from baseline to 
week 24 in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B 
(ApoB), total cholesterol/HDL-C ratio, and ApoB/Apolipoprotein A-1 (ApoA1) ratio, in 
pediatric subjects 10 to 17 years of age with HeFH 
1.3 
Secondary Safety 
• 
to evaluate the safety of SC evolocumab compared with placebo, when added to 
standard of care, in pediatric subjects 10 to 17 years of age with HeFH 
1.4 
Secondary Pharmacokinetic 
• 
to characterize pharmacokinetic (PK) exposure 
Section:  1.6 Exploratory 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 6 of 23 
CONFIDENTIAL 
 
 
Section:  3.1 Study Design 
Replace: 
Events of death, myocardial infarction (MI), hospitalization for unstable angina, coronary 
revascularization, stroke, transient ischemic attack (TIA), and hospitalization for heart 
failure will be adjudicated by an independent Clinical Events Committee (CEC). Subject 
incidence of exploratory endpoint events will be summarized for each treatment group.  
Processes of event identification and submission to the CEC are described in a CEC 
Manual of Operations. 
With: 
Events of death, myocardial infarction (MI), hospitalization for unstable angina, coronary 
revascularization, stroke, transient ischemic attack (TIA), and hospitalization for heart 
failure will be adjudicated by an independent Clinical Events Committee (CEC). Subject 
incidence of exploratory endpoint events will be summarized for each treatment group.  
Processes of event identification and submission to the CEC are described in a CEC 
Endpoint Reporting Manual. 
Section:  4 Subject Eligibility 
Replace: 
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1).  In addition to written informed consent from a 
legally acceptable representative, the assent of the child also must be obtained, as 
appropriate if requested by the institutional review board/independent ethics committee 
(IRB/IEC). 
With: 
Before any study-specific activities/procedure, the appropriate written informed consent 
(and assent, when applicable) must be obtained (see Section 11.1).  In addition to 
written informed consent from a legally acceptable representative, the assent of the child 
also must be obtained, as appropriate if requested by the institutional review 
board/independent ethics committee (IRB/IEC). 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 7 of 23 
CONFIDENTIAL 
 
 
Section:  4.1.1 Inclusion Criteria 
Replace: 
101 
Subject has provided informed consent or subject assent prior to initiation of any 
study-specific activities/procedures. 
106 
If taking any other lipid-lowering therapy (eg, ezetimibe, bile-acid sequestering 
resin, omega 3 fatty acids or niacin), this therapy must be unchanged for ≥ 4 weeks prior 
to LDL-C screening; fibrates must be stable for at least 6 weeks prior to screening. 
With: 
101 
Subject has provided written informed consent or subject assent prior to 
initiation of any study-specific activities/procedures. 
106 
Subject must be on a low-fat diet, and if taking any other lipid-lowering therapy 
(eg, ezetimibe, bile-acid sequestering resin, omega 3 fatty acids or niacin), this therapy 
must be unchanged for ≥ 4 weeks prior to LDL-C screening; fibrates must be stable for 
at least 6 weeks prior to screening. 
Section:  4.1.2 Exclusion Criteria 
Replace: 
201 
Type 1 diabetes or newly diagnosed (within 3 months of randomization) type 2 
diabetes, or poorly controlled type 2 diabetes (HbA1c > 8.5%) or newly diagnosed 
impaired glucose tolerance (within 3 months of randomization). 
213 
Female subject who has experienced menarche and unwilling to use 
acceptable method(s) of effective birth control during treatment with IP 
(evolocumab or placebo) and for an additional 15 weeks after the end of 
treatment with IP (evolocumab or placebo). A female who has experienced 
menarche is considered of childbearing potential. 
• 
Acceptable methods of preventing pregnancy include: true sexual 
abstinence when this is in line with the preferred and usual lifestyle of the 
subject (periodic abstinence [eg, calendar, ovulation, symptothermal, 
post-ovulation methods], declaration of abstinence for the duration of the 
study, and withdrawal are not acceptable methods of contraception), or 
use of hormonal birth control methods (oral, implantable, injectable, 
transdermal, intravaginal), intrauterine devices (IUDs), intrauterine 
hormonal-releasing system (IUS), or two (2) barrier methods (one by 
each partner and at least one of the barrier methods must include 
spermicide, unless spermicide is not approved in the country or 
region - the male must use a condom and the female must choose either 
a diaphragm OR cervical cap, OR contraceptive sponge.  Note: a male 
and female condom cannot be used together due to the risk of tearing.)  


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 8 of 23 
CONFIDENTIAL 
 
 
Note:  If additional medications are given during treatment which may 
alter the contraceptive requirements (these additional medications may 
require an increase in the number of contraceptive methods and/or length 
of time that contraception is to be utilized after the last dose of 
protocol-required therapies) the investigator is to discuss these changes 
with the study subject.   
With: 
201 
Homozygous familial hypercholesterolemia 
202 
Lipid apheresis within the last 12 weeks prior to screening 
203 
Type 1 diabetes or newly diagnosed (within 3 months of randomization) type 2 
diabetes, or poorly controlled type 2 diabetes (HbA1c > 8.5%) or newly 
diagnosed impaired glucose tolerance (within 3 months of randomization). 
213 
Female subject who has experienced menarche and unwilling to use acceptable 
method(s) of effective birth control during treatment with IP (evolocumab or 
placebo) and for an additional 15 weeks after the end of treatment with IP 
(evolocumab or placebo). A female who has experienced menarche is 
considered of childbearing potential. 
• 
Acceptable methods of preventing pregnancy include: true sexual 
abstinence when this is in line with the preferred and usual lifestyle of the 
subject (periodic abstinence [eg, calendar, ovulation, symptothermal, 
post-ovulation methods], declaration of abstinence for the duration of the 
study, and withdrawal are not acceptable methods of contraception), or 
use of hormonal birth control methods (oral, implantable, injectable, 
transdermal, intravaginal), intrauterine devices (IUDs), intrauterine 
hormonal-releasing system (IUS), or two (2) barrier methods (one by 
each partner and at least one of the barrier methods must include 
spermicide, unless spermicide is not approved in the country or 
region - the male must use a condom and the female must choose either 
a diaphragm OR cervical cap, OR contraceptive sponge.  Note: a male 
and female condom cannot be used together due to the risk of tearing.)  
Note:  If additional medications are given during treatment which may 
alter the contraceptive requirements (these additional medications may 
require an increase in the number of contraceptive methods and/or length 
of time that contraception is to be utilized or length of time 
breastfeeding is to be avoided after the last dose of protocol-required 
therapies) the investigator is to discuss these changes with the study 
subject.   
216 
Lipid apheresis within the last 12 weeks prior to screening.  
Section:  6.1 Classification of Products and Medical Devices 
Replace: 
An Investigational Product Instruction Manual (IPIM) and the Instructions For Use (IFU), 
documents external to this protocol, contain detailed information regarding the storage, 
preparation, and administration of investigational product. 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 9 of 23 
CONFIDENTIAL 
 
 
With: 
An Investigational Product Instruction Manual (IPIM) and the Instructions For Use (IFU), 
documents external to this protocol, contain detailed information regarding the storage, 
preparation, destruction, and administration of investigational product. 
Section:  6.7 Medical Devices 
Replace: 
Medical devices (eg, syringes, sterile needles, alcohol prep pads), that are commercially 
available are not usually provided or reimbursed by Amgen (except, for example, if 
required by local regulation).  The investigator will be responsible for obtaining supplies 
of these devices. 
With: 
Ancillary medical devices (eg, syringes, sterile needles, alcohol prep pads), that are 
commercially available are not usually provided or reimbursed by Amgen (except, for 
example, if required by local regulation).  The investigator will be responsible for 
obtaining supplies of these devices. 
Section:  6.8 Product Complaints 
Replace: 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug or device after it is released for distribution to market or clinic by 
either Amgen or by distributors and partners for whom Amgen manufactures the 
material. 
With: 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug or device after it is released for distribution to market or clinic by 
either Amgen or by distributors and partners for whom Amgen manufactures the 
material.  This includes any drug(s) or device(s) provisioned and/or 
repackaged/modified by Amgen. Drug(s) or device(s) includes investigational 
product. 
 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 10 of 23 
CONFIDENTIAL 
 
 
Section: 7.1 Schedule of Assessments 
Replace: 
Review for AEs/SAEs//CV events 
Xb 
X 
X 
(X)b 
X 
(X)b 
X 
X 
X 
hsCRP, CK, FSH, LH, ACTH, DHEA-S, cortisol 
 
X 
 
 
 
 
 
 
X 
b. 
only AEs possibly related to study procedures and SAEs are collected during screening (from signing of ICF or subject assent, 
whichever is later); week 8 and week 16 AEs/SAEs/CV events collection only if visit to study site 
With: 
Review for AEs/SAEs/ADEs/DREs/CV events 
Xb 
X 
X 
(X)b 
X 
(X)b 
X 
X 
X 
hsCRP, CK, FSH, LH, ACTH, DHEA-S, cortisol, Fasting vitamins 
A/D/E/K 
 
X 
 
 
 
 
 
 
X 
 
b. only AEs possibly related to study procedures and SAEs are collected during screening (from signing of ICF or subject assent, 
whichever is later); week 8 and week 16 AEs/SAEs/ADEs/DREs/CV events collection only if visit to study site.  ADEs/Product 
Complaints are reported that occur after signing of the informed consent through 30 days after the last dose of IP or EOS, 
whichever is later. 
 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 11 of 23 
CONFIDENTIAL 
 
 
Section:  7.2 General Study Procedures 
Replace:  Table 2: Analyte Listing1 
Chemistry  
Coagulation 
Urinalysis 
Hematology 
Other Labs 
Sodium 
Potassium 
Chloride 
Bicarbonate  
Total protein 
Albumin 
Calcium 
Magnesium 
Phosphorus 
Fasting glucose 
BUN or Urea 
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin 
CK 
ALP 
LDH 
AST (SGOT) 
ALT (SGPT) 
PT/INR (per 
Appendix A) 
Specific 
gravity 
pH 
Blood 
Protein 
Glucose 
Bilirubin 
WBC 
RBC 
Epithelial 
cells 
Bacteria 
Casts 
Crystals 
Hemoglobin 
Hematocrit 
RBC 
RDW 
MCV  
MCH 
MCHC 
WBC 
Platelets 
 
Fasting lipids 
Total cholesterol 
HDL-C 
LDL-C 
Triglycerides 
VLDL-C 
non-HDL-C 
ApoA1 
ApoB 
Estradiol (females) 
Testosterone (males) 
Cortisol 
Luteinizing hormone (LH) 
Adrenocorticotropic 
hormone (ACTH) 
Dehydroepiandrosterone 
sulfate (DHEA-S) 
hsCRP 
Lp(a) 
Anti-evolocumab 
antibodies 
Evolocumab (PK) 
HbA1c 
Pregnancy test (females 
of childbearing potential) 
FSH 
TSH 
HCV antibody2 
HCV viral load3 
Since some laboratory results may inadvertently unblind investigators to treatment 
assignment to evolocumab, central laboratory results of the lipid panel, ApoA1, ApoB, 
Lp(a), and 
will not be reported to the investigator (or study personnel) 
post-screening.  Investigators should not perform non-protocol testing of these analytes 
during a subject’s study participation from first administration of IP until at least 12 weeks 
after last IP administration, or the subject’s end of study, whichever is later. 
 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 12 of 23 
CONFIDENTIAL 
 
 
With: 
Table 2: Analyte Listing1 
Chemistry  
Coagulation 
Urinalysis 
Hematology 
Other Labs 
Sodium 
Potassium 
Chloride 
Bicarbonate  
Total protein 
Albumin 
Calcium 
Magnesium 
Phosphorus 
Fasting glucose 
BUN or Urea 
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin 
CK 
ALP 
LDH 
AST (SGOT) 
ALT (SGPT) 
PT/INR (per 
Appendix A) 
Specific 
gravity 
pH 
Blood 
Protein 
Glucose 
Bilirubin 
WBC 
RBC 
Epithelial 
cells 
Bacteria 
Casts 
Crystals 
Hemoglobin 
Hematocrit 
RBC 
RDW 
MCV  
MCH 
MCHC 
WBC 
Platelets 
 
Fasting lipids 
Total cholesterol 
HDL-C 
LDL-C 
Triglycerides 
VLDL-C 
non-HDL-C 
ApoA1 
ApoB 
Estradiol (females) 
Testosterone (males) 
Cortisol 
Luteinizing hormone (LH) 
Adrenocorticotropic 
hormone (ACTH) 
Dehydroepiandrosterone 
sulfate (DHEA-S) 
Fasting vitamins A, D, 
E, and K 
hsCRP 
Lp(a) 
Anti-evolocumab 
antibodies 
 
Evolocumab (PK) 
HbA1c 
Pregnancy test (females 
of childbearing potential) 
FSH 
TSH 
HCV antibody2 
HCV viral load3 
Since some laboratory results may inadvertently unblind investigators to treatment 
assignment to evolocumab, central laboratory results of the lipid panel, ApoA1, ApoB, 
Lp(a), fasting vitamins A, D, E, and K, and 
 will not be reported to the 
investigator (or study personnel) post-screening.  Investigators should not perform 
non-protocol testing of these analytes during a subject’s study participation from first 
administration of IP until at least 12 weeks after last IP administration, or the subject’s 
end of study, whichever is later. 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 13 of 23 
CONFIDENTIAL 
 
 
Section:  7.2.1.2 Screening 
Replace: 
• 
review for adverse events/serious adverse events/(adverse events possibly 
related to study procedures and serious adverse events are collected during 
screening) 
With: 
• 
review for adverse events/serious adverse events/ADE (adverse events possibly 
related to study procedures and serious adverse events are collected during 
screening) 
Section:  7.2.2 Treatment and End of Study 
Replace: 
• 
review for adverse events/serious adverse events/CV events 
• 
blood draw for fasting lipids (≥ 9 hour fasting sample), ApoA1, ApoB, chemistry, 
hematology, PK, 
 high sensitivity C-reactive protein (hsCRP), Lp(a), 
biomarkers, anti-evolocumab antibodies, and viral load in subjects positive for 
HCV 
With: 
• 
review for adverse events/serious adverse events/ADE/DRE/CV events 
• 
blood draw for fasting lipids (≥ 9 hour fasting sample), ApoA1, ApoB, chemistry, 
hematology, PK, 
 high sensitivity C-reactive protein (hsCRP), CK, FSH, 
LH, ACTH, DHEA-S, cortisol, fasting vitamins A, D, E, and K, Lp(a), 
biomarkers, anti-evolocumab antibodies, and viral load in subjects positive for 
HCV 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 14 of 23 
CONFIDENTIAL 
 
 
Section: 7.7.2 Waist Circumference 
Replace:  
7.7.2 Waist Circumference 
Subjects should wear minimal clothing to ensure that the measuring tape is correctly 
positioned.  Subjects should stand erect with the abdomen relaxed, arms at the sides, 
feet together and with their weight equally divided over both legs.   
With: 
7.7.2 Height, Weight, and Waist Circumference 
Height and weight measurement will be obtained at the time points specified in 
the Schedule of Assessments (Table 1).  If possible, visits with height and weight 
measurements should be scheduled at a similar time of day (eg, in the morning).  
Height is measured to the nearest centimeter with the subject’s back against a 
wall.  Use of a stadiometer is preferred and recommended.  Height is defined as 
the maximum distance from the floor to the highest point on the head, when the 
subject is facing directly ahead.  Shoes must be off, feet together, and arms by the 
sides.  Head, upper back, buttocks, and heels should be in contact with the wall 
when the measurement is made.  Two (2) measurements of height should be taken 
at each timepoint and entered into the CRF. Weight is to be measured to the 
nearest tenth of a kilogram with the subject wearing light clothing and with shoes 
removed.  A properly calibrated digital scale should be used.  The scale should 
weigh in 0.1 kg increments, have a stable weighing platform that can be easily set 
to zero, be calibrated through professional service or by standard known weight. 
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.   
Section: 7.7.6 Lipid Measurements 
Replace: 
Only the screening LDL-C concentration will be reported to the site for the eligibility 
decision.  Central laboratory results of the lipid panel, as well as ApoA1, ApoB, 
lipoprotein(a), and 
 will be blinded post-treatment until unblinding of the clinical 
database and will not be reported to the investigator post-screening.  In addition, 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 15 of 23 
CONFIDENTIAL 
 
 
investigators and staff involved with this trial and all medical staff involved in the 
subject’s medical care should refrain from obtaining lipid panels from randomization until 
at least 12 weeks after the subject’s last administration of IP or until the subject ends the 
study, whichever is later (to avoid potential unblinding).  If a lipid panel is drawn, all 
reasonable steps must be undertaken to avoid informing the subject and study 
personnel of the results. 
With: 
Only the screening LDL-C concentration will be reported to the site for the eligibility 
decision.  Central laboratory results of the lipid panel, as well as ApoA1, ApoB, 
lipoprotein(a), fasting vitamins A, D, E, and K, and 
 will be blinded 
post-treatment until unblinding of the clinical database and will not be reported to the 
investigator post-screening.  In addition, investigators and staff involved with this trial 
and all medical staff involved in the subject’s medical care should refrain from obtaining 
lipid panels from randomization until at least 12 weeks after the subject’s last 
administration of IP or until the subject ends the study, whichever is later (to avoid 
potential unblinding).  If a lipid panel is drawn, all reasonable steps must be undertaken 
to avoid informing the subject and study personnel of the results. 
Section: 9.1.1 Definition of Adverse Events 
Replace: 
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition (eg, diabetes, migraine 
headaches, gout) has increased in severity, frequency, and/or duration, and/or has an 
association with a significantly worse outcome.  A pre-existing condition that has not 
worsened during the study or involves an intervention such as elective cosmetic surgery 
or a medical procedure while on study, is not considered an adverse event. 
With: 
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease  (eg, 
diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected, and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study or 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 16 of 23 
CONFIDENTIAL 
 
 
involves an intervention such as elective cosmetic surgery or a medical procedure while 
on study, is not considered an adverse event. 
Section: 9.1.2 Definition of Serious Adverse Events 
Replace: 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria: 
With: 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria (unless it meets the definition of a Disease Related Event 
as defined in Section 9.1.3– below): 
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 
investigational medicinal product(s)/protocol-required therapies and the event, 
• 
and the event meets at least 1 of the serious criteria above.   
Section: 9.1.3 Definition of Disease-related Events 
Replace: 
Disease-related events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease.  In this study, such events include 
atherosclerosis (especially of the coronary arteries) and its complications.  Examples 
include manifestations of myocardial ischemia such as chest pain and myocardial 
infarction, and percutaneous and surgical revascularization procedures.  Such events do 
not meet the definition of an adverse event unless assessed to be more severe than 
expected for the subject’s condition. 
With: 
Disease-related events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease.  In this study, such events include 
atherosclerosis (especially of the coronary arteries) and its complications.  Examples 
include manifestations of myocardial ischemia such as chest pain and myocardial 
infarction, and percutaneous and surgical revascularization procedures.  Such events do 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 17 of 23 
CONFIDENTIAL 
 
 
not meet the definition of an adverse event unless assessed to be more severe than 
expected for the subject’s condition or if the investigator believes there is a causal 
relationship between the investigational product(s)/study treatment protocol 
required therapies and disease worsening. 
Disease Related Events and/or Disease Related Outcomes that do not qualify as 
Serious Adverse Events:  
• 
An event which is part of the normal course of disease under study (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. 
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 investigational product(s)/study treatment protocol 
required therapies and disease worsening, this must be reported as an Adverse 
Event or Serious Adverse Event. 
Section: 9.2.1 Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
Replace: 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after randomization and all adverse 
events possibly related to study procedures from signing of the informed consent or 
subject assent through the end of study are reported using the applicable eCRF (eg, 
Adverse Event eCRF). 
The investigator must assign the following adverse event attributes: 
• 
adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
• 
dates of onset and resolution (if resolved), 
• 
severity 
• 
assessment of relatedness to investigational product (evolocumab or placebo) or the 
prefilled autoinjector/pen (AI/Pen) device, or other protocol-required therapies, and 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 18 of 23 
CONFIDENTIAL 
 
 
With: 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur from randomization and all adverse 
events possibly related to study procedures from signing of the informed consent or 
subject assent through the end of study are reported using the applicable eCRF (eg, 
Adverse Event eCRF). 
The investigator must assign the following adverse event attributes: 
• 
adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
• 
dates of onset and resolution (if resolved), 
• 
severity 
• 
assessment of relatedness to investigational product (evolocumab or placebo or the 
prefilled autoinjector/pen (AI/Pen device), or other protocol-required 
therapies/protocol-required procedure or activity, and 
Section:  9.2.3 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 the first dose of investigational 
medicinal product(s) through the safety follow-up visit are reported using the appropriate 
Event CRF. Additionally, the investigator is required to report a fatal disease-related 
event on the CRF. 
Events assessed by the investigator to be related to the investigational medicinal 
product(s) or study treatment and determined to be serious require reporting of the event 
on an 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 the first dose of investigational 
medicinal product(s) through EOS (including any follow-up visits) are reported using 
the appropriate Event CRF. Additionally, the investigator is required to report a fatal 
disease-related event on the CRF. 
Events assessed by the investigator to be related to the investigational medicinal 
product(s) or study treatment and determined to be serious require reporting of the event 
on an Event CRF. 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 19 of 23 
CONFIDENTIAL 
 
 
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 investigational product(s)/study treatment protocol 
required therapies and disease worsening, this must be reported as an Adverse 
Event or Serious Adverse Event. 
Section:  9.3 Pregnancy and Lactation Reporting 
Replace: 
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur after the last dose of IP (evolocumab or placebo) 
through 15 weeks after the end of treatment with IP (evolocumab or placebo). 
The pregnancy should be reported to Amgen’s global Pregnancy Surveillance Program 
within 24 hours of the investigator’s knowledge of the event of a pregnancy.  Report a 
pregnancy on the Pregnancy Notification Worksheet (Appendix C).  The Pregnancy 
Surveillance Program (PSP) will seek to follow the pregnant woman throughout her 
pregnancy and her baby up to 12 months after birth. 
Any lactation case should be reported to Amgen’s global Lactation Surveillance Program 
(LSP) within 24 hours of the investigator’s knowledge of event.  Report a lactation case 
on the Lactation Notification Worksheet (Appendix C). 
With: 
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur after the last dose of IP (evolocumab or placebo) 
through 15 weeks after the end of treatment with IP (evolocumab or 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).  The Pregnancy Surveillance Program 
(PSP) will seek to follow the pregnant woman throughout her pregnancy and her baby 
up to 12 months after birth. 
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). 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 20 of 23 
CONFIDENTIAL 
 
 
Section 10.1.1.4 Exploratory Endpoints 
Section: 10.1.1.5 Safety Endpoints 
Added: 
10.1.1.5 Secondary Safety Endpoints 
Section:  10.1.1.6 Pharmacokinectics Endpoints 
Added: 
10.1.1.6 Secondary Pharmacokinetics Endpoints 
Section: 10.1.1.7 Other Safety Endpoints 
Added:  
• 
Change from baseline score in the components of the Cogstate battery at 
each scheduled administration 
Section: 10.5.2 Primary Efficacy Endpoint Analyses 
Replace: 
Primary Analyses 
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 to compare the efficacy 
of evolocumab with placebo. The repeated measures model will include terms for 
treatment group, stratification factor (as appropriate), scheduled visit and the interaction 
of treatment with scheduled visit.  Missing values will not be imputed when the repeated 
measures linear effects model is used. 
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 (Quade test) 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 21 of 23 
CONFIDENTIAL 
 
 
With: 
Primary Analyses 
The estimand of primary interest is the difference in mean percent change from 
baseline in LDL-C at week 24 regardless of treatment adherence for subjects in 
FAS.  A repeated measures linear effects model will be used to compare the efficacy of 
evolocumab with placebo. The repeated measures model will include terms for treatment 
group, stratification factor (as appropriate), scheduled visit and the interaction of 
treatment with scheduled visit.  Missing values will not be imputed when the repeated 
measures linear effects model is used.  The analysis will use LDL-C values measured 
regardless of treatment adherence. 
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 (Quade test) 
• 
To evaluate the impact of missing values, a sensitivity analysis under the 
assumption that subjects who, discontinued IP and have missing endpoint 
data have a mean zero percent change from baseline will be conducted using 
multiple imputation. 
The difference between the number of randomized subjects and the number of 
subjects in the FAS will also be assessed and reported in the Clinical Study 
Report. 
Section: 10.5.5 Secondary Safety and Pharmacokinetic Endpoint Analyses 
Added: 
Vital Signs 
Vital signs will be summarized for each treatment group using descriptive 
statistics at each scheduled visit. 
Anti-evolocumab antibodies 
The incidence and percentages of subjects who develop anti-evolocumab 
antibodies (binding and neutralizing) at any time will be tabulated. 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 22 of 23 
CONFIDENTIAL 
 
 
Pharmacokinetic 
Unbound evolocumab serum concentrations by time will be summarized using 
descriptive statistics. 
Added new Section: 10.5.6 Other Safety Endpoint Analyses 


Product:  Evolocumab 
Protocol Number:  20120123 
Date:  01 September 2015 
Page 23 of 23 
CONFIDENTIAL 
 
 
Section: Appendices, Appendix D. Tanner Stages (Sexual Maturity Ratings) 
Replace: 
MALES: 
Stage 
GENITAL SIZE 
PUBIC HAIR STAGING 
CONCOMITANT CHANGES 
PRADER 
ORCHIDOMETER 
1 
Prepubertal, papilla elevation 
No pigmented hair 
Long testis axis < 1.5 cm 
1 – 3 mL 
With: 
MALES: 
Stage 
GENITAL SIZE 
PUBIC HAIR STAGING 
CONCOMITANT CHANGES 
PRADER 
ORCHIDOMETER 
1 
Prepubertal, papilla elevation 
No pigmented hair 
Long testis axis < 1.5 cm 
1 – 3 mL 
 


Product:  Evolocumab  
Protocol Number:  20120123 
Date:  20 May 2015 
Page 1 of 34 
CONFIDENTIAL 
 
 
Amendment #1 
Protocol Title:  Double-blind, Randomized, Multicenter, Placebo-controlled, 
Parallel Group Study to Characterize the Efficacy, Safety, and Tolerability of 
24 Weeks of Evolocumab for Low Density Lipoprotein-cholesterol (LDL-C) 
Reduction, as Add-on to Diet and Lipid-lowering Therapy, in Pediatric Subjects 
10 to 17 Years of Age With Heterozygous Familial Hypercholesterolemia (HeFH) 
 
Amgen Protocol Number (Evolocumab) 20120123 
 
Amendment Date: 
20 May 2015 
 
Rationale: 
The following items were added to the protocol at the request of the FDA:  
• 
Hematology, urinalysis and anti-evolocumab antibody assessments at Week 12  
• 
Explicit exclusion of apheresis subjects  
• 
Documentation of historical lipid therapies  
• 
 (added as an exploratory endpoint) 
• 
Clarification that the calculation of sample size accounts for 20% of randomized 
subjects discontinuing investigational product prior to completion of the study 
The following changes were also made: 
• 
The key Sponsor contact was changed 
• 
The exploratory endpoint of “
 
” was deleted. 
• 
Editorial changes or corrections for clarity and accuracy. 

SAP_001.pdf: 
Product:  Evolocumab
Statistical Analysis Plan:  20120123
Date: 16 Sep 2019
Page 1
STATISTICAL ANALYSIS PLAN
A Double-blind, Randomized, Multicenter, Placebo-controlled, Parallel Group 
Study to Characterize the Efficacy, Safety, and Tolerability of 24 Weeks of
Evolocumab for Low Density Lipoprotein-cholesterol (LDL-C) Reduction, as
Add-on to Diet and Lipid-Lowering Therapy, in Pediatric Subjects 10 to 17 Years of 
Age With Heterozygous Familial Hypercholesterolemia (HeFH)
Protocol Number:
20120123
Version:
2.0
Date:
16 Sep 2019
Authors:
NCT Number: NCT02392559
This NCT number has been applied to the document for
purposes of posting on clinicaltrials.gov


Product:  Evolocumab
Statistical Analysis Plan:  20120123
Date: 16 Sep 2019
Page 2
Table of Contents
Table of Abbreviations.....................................................................................................5
1.
Introduction...........................................................................................................10
2.
Objectives.............................................................................................................10
2.1
Primary .....................................................................................................10
2.2
Secondary Efficacy ...................................................................................10
2.3
Secondary Safety......................................................................................10
2.4
Secondary Pharmacokinetic......................................................................10
2.5
Tertiary......................................................................................................10
2.6
Exploratory................................................................................................11
3.
Study Overview ....................................................................................................11
3.1
Study Design.............................................................................................11
3.2
Sample Size..............................................................................................12
4.
Study Endpoints and Covariates...........................................................................12
4.1
Study Endpoints........................................................................................12
4.1.1
Primary Efficacy Endpoint..........................................................12
4.1.2
Secondary Efficacy Endpoints...................................................12
4.1.3
Tertiary Efficacy Endpoints........................................................13
4.1.4
Exploratory Endpoints ...............................................................13
4.1.5
Secondary Safety Endpoints .....................................................14
4.1.6
Secondary Pharmacokinetics Endpoints....................................14
4.1.7
Other Safety Endpoints .............................................................14
4.2
Planned Covariates...................................................................................14
5.
Hypotheses and/or Estimations ............................................................................14
6.
Definitions.............................................................................................................15
6.1
Study Time Points.....................................................................................15
6.2
Demographics and Baseline Related Definitions.......................................16
6.3
Other Study Related Definitions ................................................................18
7.
Analysis Subsets ..................................................................................................19
7.1
Full Analysis Set........................................................................................19
7.2
Completer Analysis Set.............................................................................20
7.3
Subgroup Analyses...................................................................................20
8.
Interim Analysis and Early Stopping Guidelines....................................................20
9.
Data Screening and Acceptance...........................................................................20
9.1
General Principles.....................................................................................20
9.2
Data Handling and Electronic Transfer of Data..........................................21
9.3
Handling of Missing and Incomplete Data .................................................21


Product:  Evolocumab
Statistical Analysis Plan:  20120123
Date: 16 Sep 2019
Page 3
9.3.1
Patterns of Missing Data............................................................21
9.3.2
Missing Lipid Measurements .....................................................21
9.3.3
Handling of Incomplete Dates....................................................21
9.4
Detection of Bias.......................................................................................22
9.5
Outliers .....................................................................................................22
9.6
Distributional Characteristics.....................................................................23
9.7
Validation of Statistical Analyses...............................................................23
10.
Statistical Methods of Analysis..............................................................................23
10.1
General Principles.....................................................................................23
10.2
Subject Accountability ...............................................................................24
10.3
Important Protocol Deviations ...................................................................24
10.4
Demographic and Baseline Characteristics...............................................25
10.5
Efficacy Analyses......................................................................................26
10.5.1
Analyses of Primary Endpoints..................................................28
10.5.1.1
Primary Analysis of Primary Efficacy 
Endpoints................................................................28
10.5.1.2
Sensitivity Analyses of Primary Efficacy 
Endpoints................................................................28
10.5.1.3
Subgroup Analyses of Primary Efficacy 
Endpoints................................................................28
10.5.2
Analyses of Secondary Efficacy Endpoints................................29
10.5.3
Analyses of Tertiary Efficacy Endpoints.....................................29
10.5.4
Analyses of Exploratory Endpoints ............................................29
10.6
Safety Analyses ........................................................................................29
10.6.1
Adverse Events .........................................................................29
10.6.2
Laboratory Test Results.............................................................30
10.6.3
Vital Signs .................................................................................30
10.6.4
Electrocardiogram (ECG) ..........................................................30
10.6.5
Neurologic Examination.............................................................31
10.6.6
Cogstate Neurocognitive Assessment .......................................31
10.6.7
Antibody Formation ...................................................................31
10.6.8
Exposure to Investigational Product ..........................................31
10.6.9
Exposure to Concomitant Medication ........................................31
10.7
Pharmacokinetic Analyses ........................................................................31
11.
Changes From Protocol-specified Analyses..........................................................32
12.
Literature Citations / References...........................................................................33
13.
Appendices...........................................................................................................34
List of Tables
Table 1.  Key Efficacy Analyses Summary Table...........................................................26


Product:  Evolocumab
Statistical Analysis Plan:  20120123
Date: 16 Sep 2019
Page 4
List of Appendices
Appendix A.  Analytical Study Week Assignments.........................................................35
Appendix B.  Common Terminology Criteria for AEs (CTCAE)......................................36
Appendix C.  Lipid Modifying Background Therapy........................................................37


Product:  Evolocumab
Statistical Analysis Plan:  20120123
Date: 16 Sep 2019
Page 5
Table of Abbreviations
Abbreviation or Term
Definition/Explanation
AE 
Adverse Event
AHA
American Heart Association
AI
Autoinjector
ALT
alanine aminotransferase
ApoA1 
Apolipoprotein A-1 
ApoB 
Apolipoprotein B 
AST
aspartate aminotransferase
BMI 
Body mass index 
CAS 
Completer analysis set 
CEC 
Clinical Events Committee 
CHD 
Coronary Heart Disease 
CI
confidence interval
CK 
Creatine phosphokinase 
CV 
Cardiovascular 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events
DBP 
Diastolic blood pressure 
DHEA-S
Dehydroepiandrosterone sulfate
DMC 
Data Monitoring Committee 
DQR 
Data Quality Review 
ECG 
Electrocardiogram 
eCRF
electronic case report form
EOI 
Events of Interest 
EOS 
End of Study (end of trial), defined as the time when the last subject 
is assessed or receives an intervention for evaluation in the study.
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FRS 
Framingham Risk Score 
HepBsAg
Hepatitis B virus Surface Antigen
HDL-C 
High-density lipoprotein cholesterol 
HeFH 
Heterozygous Familial Hypercholesterolemia 
hsCRP 
High sensitivity C-reactive protein 
IBG 
Independent biostatistical group 
IEC/IRB 
Independent Ethics Committee / Institutional Review Board 
INR 
International normalized ratio 


Product:  Evolocumab
Statistical Analysis Plan:  20120123
Date: 16 Sep 2019
Page 6
Abbreviation or Term
Definition/Explanation
IP
investigational product
IPD 
Important protocol deviation 
IVRS 
Interactive voice response system 
LDL-C 
Low-density lipoprotein cholesterol 
LDLR 
Low-density lipoprotein receptor
LFT 
Liver function test 
LOCF
Last observation carried forward
Lp(a) 
Lipoprotein(a) 
MedDRA 
Medical dictionary for regulatory activities 
MoI 
Medications of interest 
NCEP 
National Cholesterol Education Program 
NCEP ATP III 
National Cholesterol Education Panel Adult Treatment Panel III 
NCI
National Cancer Institute
NHLBI 
National Heart, Lung, and Blood Institute 
 
 
PK 
Pharmacokinetic(s)
PKDM 
Pharmacokinetics and drug metabolism 
QM 
Monthly (Every 4 weeks) 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 
SD 
Standard deviation 
TEAE 
Treatment-Emergent Adverse Event 
TIA 
Transient ischemic attack 
UC 
Ultracentrifugation 
ULN 
Upper limit of normal 
VLDL-C 
Very low-density lipoprotein cholesterol 


Product:  Evolocumab
Statistical Analysis Plan:  20120123
Date: 16 Sep 2019
Page 7
Version Number
Date
(DDMMMYYYY)
Summary of Changes, 
including rationale for changes
Original (v1.0)
22 Oct 2015
Amendment 1 (v2.0)
16 Sep 2019
Section 6.1 Study Time Points Added the 
definition of First Dose Date of 
Investigational  Product. 
Added the definition of Last Dose Date of 
Investigational Product. 
Removed the definition of End of 
Investigational Product (IP) Admin Date. 
Rationale: To align with other studies for 
the product. 
Section 6.3 Other Study Related 
Definition
Updated the definition of IP Exposure 
Period in Months.
Updated the definition of Treatment-
emergent adverse event.
Removed the definition of Treatment-
emergent disease-related event.
Updated the definition of Reflexive 
Approach for LDL-C and VLDL-C.
Rationale: To align with other studies for 
the product. 
Section 9.3.2 Missing Lipid
Measurements
Removed sensitivity analysis using LOCF.
Rationale: Analysis no longer being 
performed and to align with other studies 
for the product. 
Section 9.3.3 Handling of Incomplete 
Dates
Updated the imputed rule in text toTable 
1. Imputation Rules for Incomplete Dates
Section 9.4 Detection of Bias
Removed the listing of unblinding 
Section 10.2 Subject Accountability
Added ‘The number and percent of 
subjects randomized will be tabulated by 
the stratification factors.’
Rationale: To align with other studies for 
the product. 


Product:  Evolocumab
Statistical Analysis Plan:  20120123
Date: 16 Sep 2019
Page 8
Section 10.4 Demographic and Baseline 
Characteristics 
Added detailed demographic and baseline 
disease characteristics. 
Rationale: To align with other studies for 
the product. 
Section 10.5 Efficacy Analyses 
Updated Table 1 with Table 2 
Updated months with weeks in Table 2 
Section 10.5.1.2 Sensitivity Analyses of 
Primary Efficacy Endpoints 
Added To evaluate the impact of missing 
data with missing value imputed.
Added details to the multiple imputation 
using non-missing data from subjects who 
discontinued IP within the same treatment 
group. 
Rationale: To address feedback from 
FDA. 
Removed ANOCOVA using LOCF. 
Section 10.6.1 Adverse Events
Updated MedDRA version 17.0 with 19.0. 
Removed all disease-related events 
(DREs) related content. 
Rationale: To align with the company 
policy regarding DRE and to align with 
other studies for the product.
Updated all treatment-emergent with TE.
Removed all adverse events associated 
with lipid-lowering therapies. 
Removed potential hepatitis C infections. 
Removed incidence of new-onset 
diabetes.  
Removed the High Level Group Terms of 
neurocognitive events.
Rationale: To update the analyses to align 
with the product safety profile and also to 
align with other studies for the product.
Section 10.7 Pharmacokinetic Analysis 
Added this section to include the PK 
analysis. 
Appendix 
Added day 175 as maximum value to 
Appendix A. Analytical Study Week 


Product:  Evolocumab
Statistical Analysis Plan:  20120123
Date: 16 Sep 2019
Page 9
Assignments.
Updated day 196 with 175 for cIMT for the 
maximum window. 
Removed Appendix D. Definition of New-
onset Diabetes Mellitus
Removed Appendix E. Treatment
Emergent Adverse Event Algorithm


Product:  Evolocumab
Statistical Analysis Plan:  20120123
Date: 16 Sep 2019
Page 10
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 for evolocumab Study 20120123 
dated 01 September 2015. The scope of this plan includes the final analyses that are 
planned and will be executed by the Biostatistics department unless otherwise specified.
2.
Objectives
2.1
Primary
To evaluate the effect of 24 weeks of subcutaneous (SC) evolocumab compared with 
placebo, when added to standard of care, on percent change from baseline in
low-density lipoprotein cholesterol (LDL-C) in pediatric subjects 10 to 17 years of age 
with heterozygous familial hypercholesterolemia (HeFH).
2.2
Secondary Efficacy

to assess the effects of SC evolocumab compared with placebo, when added to
standard of care, on mean percent change from baseline to weeks 22 and 
24 and change from baseline to week 24 in LDL-C, and on percent change from 
baseline to week 24 in non-high-density lipoprotein cholesterol (non-HDL-C), 
apolipoprotein B (ApoB), total cholesterol/HDL-C ratio, and ApoB/Apolipoprotein 
A-1 (ApoA1) ratio, in pediatric subjects 10 to 17 years of age with HeFH
2.3
Secondary Safety

to evaluate the safety of SC evolocumab compared with placebo, when added to 
standard of care, in pediatric subjects 10 to 17 years of age with HeFH
2.4
Secondary Pharmacokinetic

to characterize pharmacokinetic (PK) exposure
2.5
Tertiary

to assess the effects of SC evolocumab compared with placebo, when added to
standard of care, on percent change from baseline to week 24 in total 
cholesterol, very low-density lipoprotein cholesterol (VLDL-C), HDL-C, ApoA1, 
triglycerides, and lipoprotein(a) [Lp(a)], in pediatric subjects 10 to 17 years of age 
with HeFH

to assess the effects of SC evolocumab compared with placebo, when added to
standard of care, on mean percent change from baseline to weeks 22 and 24 in
non-HDL-C, ApoB, total cholesterol/HDL-C ratio, ApoB/ApoA1 ratio, total
cholesterol, very low-density lipoprotein cholesterol (VLDL-C), HDL-C, ApoA1, 
triglycerides, and Lp(a), in pediatric subjects 10 to 17 years of age with HeFH


Product:  Evolocumab
Statistical Analysis Plan:  20120123
Date: 16 Sep 2019
Page 11
2.6
Exploratory
3.
Study Overview
3.1
Study Design
This is a randomized, placebo-controlled, double-blind, parallel group, multicenter study.
Subjects are eligible for screening if they are 10 to 17 years of age at time of
randomization and have met the local applicable diagnostic criteria for HeFH. Subjects
considered for enrollment will undergo screening assessments, including laboratory
screening by central laboratory. Approximately 150 eligible subjects will be randomized
in a 2:1 ratio to receive 24 weeks of QM evolocumab or placebo. Randomization will be
stratified by screening LDL-C (< 160 mg/dL [4.1 mmol/L] vs ≥ 160 mg/dL) and age
(< 14 years vs ≥14 years) at randomization.
The study includes collection of biomarker development samples. Where permitted by
local regulations, subjects will be invited to consent to pharmacogenetic analyses.
Events of death, myocardial infarction (MI), hospitalization for unstable angina, coronary
revascularization, stroke, transient ischemic attack (TIA), and hospitalization for heart
failure will be adjudicated by an independent Clinical Events Committee (CEC). Subject 
incidence of exploratory endpoint events will be summarized for each treatment group.  
Processes of event identification and submission to the CEC are described in a CEC 
Endpoint Reporting Manual.
An independent data monitoring committee (DMC) will formally review the accumulating 
data from this and other completed and ongoing studies with evolocumab to ensure 


Product:  Evolocumab
Statistical Analysis Plan:  20120123
Date: 16 Sep 2019
Page 12
there is no avoidable increased risk for harm to subjects. Analyses for the DMC will be 
provided by a group which is external to Amgen.
After completion of Study 20120123, subjects will be offered participation in an extension
study where they will receive open-label evolocumab.
The overall study design is described by a study schema at the end of the protocol 
synopsis section. 
The study endpoints are defined in Section 4.1
3.2
Sample Size
This study is to provide clinical experience with evolocumab in approximately 
150 pediatric subjects, compared to the current experience described in the Protocol
Sections 2.3 and Section 2.4. Based on the treatment effect from the global phase 3 
study in adult subjects with HeFH, evolocumab reduced LDL-C by approximately 55%. A 
planned total sample size of 150 pediatric subjects (100 randomized to evolocumab
420 mg QM and 50 randomized to placebo QM) will provide approximately 99% power in 
testing the superiority of evolocumab 420 mg QM over placebo. The sample size 
calculation is performed using a two-sided t-test with a 0.05 significance level, assuming 
a treatment effect of 40% reduction in LDL-C, a common standard deviation (SD) of 
20%, and 20% of subjects discontinuing investigational product prior to completion of the 
study.
The power calculation is derived using nQuery version 7.01.
4.
Study Endpoints and Covariates
4.1
Study Endpoints
4.1.1
Primary Efficacy Endpoint

Percent change from baseline to week 24 in LDL-C
4.1.2
Secondary Efficacy Endpoints

Mean percent change from baseline to weeks 22 and 24 in LDL-C1

Change from baseline to week 24 in LDL-C2

Percent change from baseline to week 24 in the following3:

non-HDL-C

ApoB

total cholesterol/HDL-C ratio

ApoB/ApoA1 ratio
1,2,3 See section 10.1 for detail on multiplicity adjustment


Product:  Evolocumab
Statistical Analysis Plan:  20120123
Date: 16 Sep 2019
Page 13
4.1.3
Tertiary Efficacy Endpoints

Percent change from baseline to week 24 in the following:

total cholesterol

VLDL-C

HDL-C

ApoA1

Triglycerides

Lp(a)

Mean percent change from baseline to weeks 22 and 24 in the following:

non-HDL-C

ApoB

total cholesterol/HDL-C ratio

ApoB/ApoA1 ratio

total cholesterol

VLDL-C

HDL-C

ApoA1

triglycerides

Lp(a)
4.1.4
Exploratory Endpoints


Product:  Evolocumab
Statistical Analysis Plan:  20120123
Date: 16 Sep 2019
Page 14
4.1.5
Secondary 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
4.1.6
Secondary Pharmacokinetics Endpoints

Serum concentration of evolocumab at each scheduled assessment
4.1.7
Other Safety Endpoints

Change from baseline score in the components of the Cogstate battery at each 
scheduled administration
4.2
Planned Covariates
Stratification factors

Screening LDL-C (< 160 mg/dL [4.1 mmol/L], ≥ 160 mg/dL) 

Age (< 14 years, ≥ 14 years) 
Baseline characteristics

Gender  

Race (black, white, and other)

Region (North America, Europe, other)

LDL-C (< baseline median, ≥baseline median) 

Glucose tolerance status (type 2 diabetes mellitus, metabolic syndrome, neither 
type 2 diabetes mellitus nor metabolic syndrome)

Lipid modifying background therapy (statin intensity defined based on modified 
ACC/AHA guidance, see Appendix C)
5.
Hypotheses and/or Estimations
The primary hypothesis of the primary endpoint is: the null hypothesis is that there is no  
difference in the mean percent change from baseline at week 24 in LDL-C between 


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evolocumab and placebo, when added to standard of care, and the alternative 
hypothesis is that a mean difference does exist.
6.
Definitions
6.1
Study Time Points
Enrollment Date 
Enrollment Date is defined as the date collected on the eCRF. 
Randomization date
Randomization date is defined as the date subject was allocated to a treatment group. 
Study Day 1 
For each subject, Study Day 1 is defined as the first day of investigational product (IP) 
administration.
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 Investigational Product 
For each subject, the First Dose Date of Investigational Product is defined as the 
date of the first administration of IP as recorded on the IP administration eCRF, 
equivalent to study day 1.
Last Dose Date of Investigational Product 
For each subject, the Last Dose Date of Investigational Product is defined as the 
date of the last administration of IP.
End of Study (EOS) Date 
End of study for each subject is defined as the date the subject last completed a 
protocol-specified procedure. The date will be recorded on the End of Study CRF page. 
Study End Date
The Study End Date is the last EOS date of all randomized subjects. 


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6.2
Demographics and Baseline Related Definitions
Age 
Age at randomization will be derived in years in the clinical database. 
Baseline Lipid and Lipid-related Parameters 
Baseline values for fasting lipids (total cholesterol, HDL-C, LDL-C, VLDL-C and 
triglycerides), ApoA1, ApoB, hsCRP, 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. 
BMI 
Subject’s BMI will be derived in kg/m2 in the clinical database.
Other Baseline Values 
For ECG, the baseline value is defined as the mean over all non-missing triplicate 
averages of 3 (or all available) readings from each set of triplicate taken prior to or on 
Study Day 1. 
For 
 the baseline value is defined as the average of the last two non-missing 
values collected prior to first IP administration. If for any reason only 1 value is available, 
then that value will be used as baseline. 
For cIMT, the baseline value is defined as the non-missing value collected on or 
prior to study day 28. 
For all other variables, 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] 


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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, 
Fryar et al 2012, Ji et al 2010). Subjects with type II diabetes cannot be categorized as 
having metabolic syndrome. 
Age 10 to <16 years 
Risk Factor 
Defining Level 
Elevated waist circumference: 
Non-Asian (Fryar et al., 2012):
              Male:
                       Age 10
                       Age 11
                       Age 12
                       Age 13
                       Age 14
                       Age 15
              Female:
                       Age 10
                       Age 11
                       Age 12
                       Age 13
                       Age 14
                       Age 15
Asian (Ji et al, 2010):
              Male:
                       Age 10
                       Age 11
                       Age 12
                       Age 13
                       Age 14
                       Age 15
              Female:
                       Age 10
                       Age 11
                       Age 12
                       Age 13
                       Age 14
                       Age 15
Obesity ≥90 percentile or adult cut-off if lower (refer to 
the cut-offs below) 
≥85.6 cm
≥90.4 cm
≥93.7 cm
≥96.7 cm
≥101.3 cm
≥99.9 cm
≥84.1 cm
≥88 cm
≥88 cm
≥88 cm
≥88 cm
≥88 cm
≥73.1 cm
≥75.6 cm
≥77.4 cm
≥78.6 cm
≥79.6 cm
≥80.5 cm
≥67.8 cm
≥70.4 cm
≥72.6 cm
≥74.0 cm
≥74.9 cm
≥75.5 cm
Triglycerides 
≥1.7 mmol/L (150 mg/dL)


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HDL cholesterol  
<1.03 mmol/L (40 mg/dL)
Blood pressure 
SBP ≥130 mmHg or DBP ≥85 mmHg 
OR Hypertension checked ‘yes’ on CV 
Medical History eCRF 
Fasting glucose 
≥5.6 mmol/L (100 mg/dL) 
For Age >=16 years
Risk Factor 
Defining Level 
Elevated waist circumference: 
Non-Asian: 
Male
Female 
Asian: 
Male
Female
≥ 102 cm 
≥ 88 cm 
≥ 90 cm 
≥ 80 cm 
Triglycerides 
≥1.7 mmol/L (150 mg/dL)
HDL cholesterol 
Male
Female
<1.03 mmol/L (40 mg/dL)
< 1.29 mmol/L (50 mg/dL)
Blood pressure 
SBP ≥ 130 mmHg or DBP ≥ 85 mmHg 
OR Hypertension checked ‘yes’ on CV 
Medical History eCRF 
Fasting glucose 
≥5.6 mmol/L (100 mg/dL)
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 eCRF 

low HDL-C defined as baseline HDL-C < 40 mg/dL for both males and females 
with age 10 to < 16 years; < 40 mg/dL in male and < 50 mg/dL in female with 
age >= 16 years. 
6.3
Other Study Related Definitions
Analytical Study Week Assignments


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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 study that is different than the randomized treatment 
group assignment, in which case the actual treatment group is the treatment received.
Investigational Product (IP)
Evolocumab SC 420 mg QM and placebo SC QM.
Study Exposure Period in Months 
For each randomized subject, Study Exposure Period = (EOS date – Enrollment Date 
+ 1) / 365.25 * 12
IP Exposure Period in Months
IP Exposure Period = [min (Last IP Dose Date + 28 days, EOS Date) - Study Day 1 + 1 
]/ 365.25 * 12
Treatment-emergent adverse event
Treatment emergent adverse events are events categorized as Adverse Events 
(AEs) starting on or after first dose of investigational product as determined by 
“Did event start before first dose of investigational product” equal to No or 
missing on the Events eCRF and up to and including 30 days after last dose of 
investigational product or the EOS date, whichever is earlier. Any AE that cannot 
be defined clearly as a TEAE will be considered a TEAE in the database.
Reflexive Approach for LDL-C and VLDL-C
For all analyses related to LDL-C and VLDL-C, unless specified otherwise, an LDL-C 
reflexive approach will be used. When calculated LDL-C is less than 40 mg/dL or
triglycerides > 400 mg/dL, the UC LDL-C value from the same blood sample will be 
used instead of calculated LDL-C and the UC VLDL-C value from the same blood 
sample will be used instead of calculated VLDL-C, if available.
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. It will be used for both efficacy and safety analyses. In efficacy analyses, 


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subjects will be grouped according to their randomized treatment group assignment, 
regardless of the treatment received. For safety analyses, subjects will be grouped 
according to their actual treatment group (as defined in Section 6.3).
7.2
Completer Analysis Set
The completer analysis set (CAS) includes subjects in the FAS who adhered to the 
scheduled IP and have observed values for the primary endpoints. The completer 
analysis set will be used in sensitivity analyses of the primary endpoints.   
7.3
Subgroup Analyses
Subgroup by stratification factor 

Screening LDL-C (< 160 mg/dL, ≥160 mg/dL) 

Age (< 14 years, ≥14 years)
Subgroup by baseline characteristics 

Gender 

Race (black, white, and other)

Region (North America, Europe, other)

LDL-C (< baseline median, ≥baseline median) 

Glucose tolerance status (type 2 diabetes mellitus, metabolic syndrome, neither 
type 2 diabetes mellitus nor metabolic syndrome)

Lipid modifying background therapy (statin intensity defined based on modified 
ACC/AHA guidance, see Appendix C) 
8.
Interim Analysis and Early Stopping Guidelines
No interim analysis is planned for this study. 
An external independent DMC has been established to formally review the accumulating 
data from this and other completed and ongoing studies with evolocumab to ensure 
there is no avoidable increased risk of harm to subjects. The independent DMC is 
chaired by an external academic cardiologist who is an expert in lipids and clinical trials. 
Analyses for the DMC are provided by the Independent Biostatistical Group (IBG), which 
is external to Amgen. 
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. Final PK data for all randomized subjects will be transferred 
from statistical programming to Amgen’s PKDM group. Unblinded subject and box ID 
randomization lists will be provided by Amgen’s randomization group and the IVRS when 
the study stops. Details on data transfer will be provided in the Data Transfer Plan.
9.3
Handling of Missing and Incomplete Data
9.3.1
Patterns of Missing Data
Subjects may be missing specific data points for various reasons. In general, data may 
be missing due to a subject’s early withdrawal from study, a missed visit, or non-
evaluability of a data point or an endpoint at a particular point in time. In the Data Quality 
Review (DQR) process, queries will be made to the sites to distinguish true missing 
values from other unknown values (e.g. due to measurement or sample processing 
error). All attempts will be made to capture missing or partial data for this trial prior to the 
database lock. 
The frequency and pattern of missing data for efficacy endpoints will be assessed 
through descriptive summaries of the measurements over time.
9.3.2
Missing Lipid Measurements
For primary efficacy endpoint, the primary analysis will be performed using repeated 
measures linear effects model without imputation. To assess the impact of missing 
data, sensitivity analyses will be performed based on multiple imputation (details in 
section 10.5.1).
Imputation will not be performed for other efficacy endpoints.
9.3.3
Handling of Incomplete Dates
Adverse event and concomitant medication with completely or partially missing 
start dates will be queried. After the 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


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Missing
Imputation
Exception
Start date (AE and 
concomitant 
medication)
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 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. 
For DMC related analyses, details of access to subject level treatment assignments are 
provided in the protocol, Section 10.3. 
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 
ensure accuracy. The primary analyses will include outliers in the data. Sensitivity 
analyses may be undertaken if extreme outliers for a variable are observed.


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9.6
Distributional Characteristics
Distributional assumptions for the primary and secondary 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 9.3 or 
later.
10.
Statistical Methods of Analysis
10.1
General Principles
The final analysis will be conducted when all subjects have either completed all the 
scheduled study visits or have early terminated from the study. At that time, the 
database will be cleaned, processed and a snapshot will be taken; the study will also be 
unblinded. Based on the snapshot, efficacy and safety analyses will be performed on the 
FAS. Unless specified otherwise, the FAS will be the default analysis set in this study 
and data will be summarized by randomized treatment group. The superiority of 
evolocumab to placebo will be assessed for all efficacy endpoints.
Subject disposition, demographics, baseline characteristics, and exposure to IP will be
summarized.
Summary statistics for continuous variables will include the number of subjects, mean, 
median, standard deviation or standard error, minimum, and maximum. For categorical 
variables, the frequency and percentage will be summarized. 
Methods of handling missing data for efficacy endpoints will be described throughout this
section. Missing data will not be imputed for safety endpoints.
Multiplicity Adjustment Method
In order to preserve the familywise error rate at 0.05, multiplicity adjustment for the
multiple endpoints (primary efficacy endpoint: percent change from baseline to 
week 24 in LDL-C and secondary efficacy endpoints: mean percent change from 


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baseline to weeks 22 and 24 in LDL-C, change from baseline to week 24 in LDL-C 
and percent change from baseline to week 24 in non-HDL-C, ApoB, total 
cholesterol/HDL-C ratio and ApoB/ApoA1 ratio) will be performed using sequential 
gatekeeping and Hochberg procedures (Hochberg, 1988) as follows:
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 mean percent 
change from baseline to weeks 22 and 24 in LDL-C and change from 
baseline to week 24 in LDL-C will proceed using the sequential procedure with 
a significance level of 0.05 (ie, change from baseline to week 24 in LDL-C will 
be tested only if mean percent change from baseline to weeks 22 and 24 in 
LDL-C is statistically significant at 0.05 significance level).
2. If the treatment effect from change from baseline to week 24 in LDL-C is 
significant at a significance level of 0.05, statistical testing of the percent change 
from baseline to week 24 in non-HDL-C, ApoB, total cholesterol/HDL-C ratio 
and ApoB/ApoA1 ratio will follow the Hochberg procedure at a significance 
level of 0.05.
Unless specified otherwise, all other hypothesis testing will be 2-sided with a 
significance level of 0.05.
10.2
Subject Accountability
The number of subjects screened, randomized, receiving IP, and completing the study 
will be summarized. Key study dates for the first subject enrolled, last subject enrolled 
and last subject’s end of study will be presented.
Study discontinuation and IP discontinuation will be tabulated separately by reasons for 
discontinuation. 
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 


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database lock.  These definitions of IPD categories, sub-category codes, and 
descriptions will be used during the course of the study. 
Eligibility deviations are defined in the protocol.
10.4
Demographic and Baseline Characteristics
Demographic (ie, gender, race, region) and baseline disease characteristics 
(cardiovascular medical history, laboratory parameters 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:
Table 2.  Key Efficacy Analyses Summary Table
Endpoint
Statistical Analysis Method
P-values from the Statistical 
Tests
Hierarchical Testing Procedure for 
testing of Treatment Effect vs. 
Placebo. As specified in the Multiplicity 
Adjustment Method diagram
Primary Endpoint
Percent change in LDL-C from 
baseline to week 24 
Repeated measures model
P1= the p-values for the primary 
endpoint
P1 compare to α = 0.05
Secondary Endpoint1
Mean percent change from baseline 
at weeks 22 and 24 in LDL-C
Repeated measures model
P2a=the p-values for the 
secondary endpoint1
If  P1 < 0.05
P2a will be tested and 
compare to α = 0.05
Else(i.e. primary endpoint is not 
significant)
No further testing
Secondary Endpoint2 
Change from baseline to week 24 in 
LDL-C
Repeated measures model
P2b= the p-values for the 
secondary endpoint2
If  P2a < 0.05
P2b tested and compare to
α = 0.05
Else(i.e. secondary endpoint1 is not 
significant)
No further testing
Page 1 of 2


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Table 2.  Key Efficacy Analyses Summary Table
Endpoint
Statistical Analysis Method
P-values from the Statistical 
Tests
Hierarchical Testing Procedure for 
testing of Treatment Effect vs. 
Placebo. As specified in the Multiplicity
Adjustment Method diagram
Secondary Endpoints3
Percent change from baseline to 24
weeks
In each of the following lipid 
parameters:

non-HDL-C

ApoB

total cholesterol/HDL-C ratio

ApoB/ApoA1 ratio
Repeated measures model
For each lipid parameter
P2c= p-values for each lipid 
parameter
If P2b < 0.05,
All P2c’s from each lipid 
parameter will be tested 
through Hochberg method with 
α = 0.05
Else(i.e. secondary endpoint2 is not 
significant)
No further testing
Page 2 of 2


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10.5.1
Analyses of Primary Endpoints
10.5.1.1
Primary Analysis of Primary Efficacy Endpoints
The estimand of primary interest is the difference in mean percent change from baseline 
in LDL-C at week 24 regardless of treatment adherence for subjects in FAS. A repeated 
measures linear effects model (Littell et al, 2000) will be used to compare the efficacy of 
evolocumab with placebo. The repeated measures model will include terms for treatment 
group, stratification factors (as appropriate), scheduled visit and the interaction of 
treatment with scheduled visit. 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. Missing values will not be imputed when the repeated 
measures linear effects model is used. The analysis will use LDL-C values measured 
regardless of treatment adherence.
Multiplicity adjustment procedures are defined in Section 10.1.
10.5.1.2
Sensitivity Analyses of Primary Efficacy Endpoints
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 (Quade test). 

To evaluate the impact of missing data, 

A sensitivity analysis under the assumption that subjects that discontinued IP 
and have missing endpoint data have a mean zero percent change from 
baseline will be conducted using multiple imputation. 

If there are at least 25 subjects who discontinue IP but have non-
missing week 24 endpoint data, the primary analysis model will be 
repeated using FAS with missing values imputed for subjects who 
discontinued IP. Missing values will be imputed using non-missing data 
from subjects who discontinued IP within the same treatment group.
If there is notable number of subjects randomized but did not receive IP, ad hoc analysis 
(e.g. repeating primary analysis using all randomized subjects) may be performed. 
10.5.1.3
Subgroup Analyses of Primary Efficacy Endpoints
Subgroup analyses on the primary efficacy endpoints will be conducted using the 
subgroups specified in Section 7.3. 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.


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For 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 will be similar to the 
primary analysis of the primary endpoint. 
Multiplicity adjustment procedures are defined in Section 10.1
10.5.3
Analyses of Tertiary Efficacy Endpoints
Analysis of the tertiary efficacy endpoints will be similar to the primary analysis of the 
primary endpoints. No multiplicity adjustment will be applied.
10.5.4
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 (AE) to a system organ class and 
a preferred term. Severity of AEs will be graded using the CTCAE (Appendix B) and 
recorded on the eCRF. All adverse event tables will be summarized by actual treatment 
group. Treatment-emergent adverse events are events with an onset after the 
administration of the first dose of IP. 
Subject Incidence of AEs will be summarized for all TEAEs, TE serious AEs, TEAE 
leading to withdrawal of investigational product and fatal TEAEs. Subject incidence of all 
treatment-emergent AEs, serious TEAEs, TEAEs leading to withdrawal of investigational 
product and fatal TEAE will be tabulated by system organ class, high level group term
and preferred term.
Summaries of TE AEs occurring in at least 1% of the subjects by preferred term in any 
treatment arm will be provided in descending order of frequency.  


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Subject incidence of adverse events related to a device will be tabulated by preferred 
term in descending order of frequency by treatment group.
Subject incidence of adverse events associated with injectable protein therapies:

Injection site reactions

Hypersensitivity or allergic reactions

potential neurocognitive events 
will be summarized by category and preferred term.
Tanner stage will be summarized by treatment group and gender. A shift table for 
hsCRP will be provided, for levels at baseline to maximum post-baseline value (<1, 1-3, 
>3 mg/L), by treatment group. HbA1c, carotid intimal-medial thickness (cIMT) and 
steroid hormones will be summarized at each scheduled assessment 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 2. Lab shift tables using the CTCAE v4.03 or 
later grading will be used for analytes of interest, when applicable. The results will be 
based on the maximum (ie, worst) shift from baseline to the EOS. 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 Alkaline Phosphatase 
<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
Electrocardiogram (ECG)
For post-baseline assessments where ECG is performed in triplicate, the average of the 
3 (or all available) readings will be used for analysis. Observations with the following 
diagnosis or findings will be excluded from analysis: artificial pacemaker, atrial 


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fibrillation, atrial flutter, left bundle branch block, and right bundle branch block. PR, 
QRS, QT, QTc and RR intervals and their change from baseline will be summarized for 
each treatment group by scheduled visit. In each treatment group, subjects will be 
categorized and summarized per their maximum post-baseline absolute QTc interval 
using limits of 450 ms, 480 ms, and 500 ms. They will also be categorized per their 
maximum change from baseline QTc interval using limits of 30 ms and 60 ms.
10.6.5
Neurologic Examination
The incidence of abnormal neurologic findings overall and in each exam area will be 
summarized by treatment group.
10.6.6
Cogstate Neurocognitive Assessment
For each test, the change from baseline to EOS in the standardized score will be 
summarized by treatment group.
10.6.7
Antibody Formation
The incidence and percentage of subjects who develop anti-evolocumab antibodies 
(binding and if positive, neutralizing) at anytime will be tabulated.
10.6.8
Exposure to Investigational Product
Descriptive statistics will be produced to describe the patient-month exposure to 
investigational product and the categorical representation of dose received. Exposure 
definitions are provided in Section 6.3.
10.6.9
Exposure to Concomitant Medication 
The number and proportion of subjects receiving the lipid regulating medications of 
interest (MOI) will be summarized by category and preferred term for each treatment 
group as coded by the World Health Organization Drug (WHODRUG) dictionary. 
10.7
Pharmacokinetic Analyses
Individual and mean serum evolocumab and 
 concentration-time profiles 
will be provided nominal times. The data set will be analyzed and stored in the 
Pharsight Knowledgebase Server (PKS) data repository using the current version 
of Phoenix WinNonlin.Evolocumab or 
 serum concentrations with values 
below the lower limit of quantification will be reported as less than their respective 
values but will be set to zero for analysis. PK parameters following the last dose 
will include but not limited to the maximum and minimum evolocumab serum 
concentrations observed at the collected timepoints. Individual and summary 
statistics for PK concentrations will be provided. 


Product:  Evolocumab
Statistical Analysis Plan:  20120123
Date:  16 Sep 2019
Page 32
These analyses will be performed by the PKDM group. 
Compartmental exposure-response analyses will not be specified in this analysis 
plan but may be included in a subsequent population PK analysis using a single 
study or as part of a metadata analysis. 
11.
Changes From Protocol-specified Analyses
As per the memo dated 11th March 2019, Disease-Related Events (DREs) will be 
removed from protocols and no longer need to be collected by Investigators.  
The 20120123 protocol is not being amended to reflect this change since it is an 
ongoing study close to primary analysis.  However, the SAP has been modified to 
remove all DRE language.  DREs will not be reported separately (as specified in 
the protocol) but will be included as AEs.


Product:  Evolocumab
Statistical Analysis Plan:  20120123
Date:  16 Sep 2019
Page 33
12.
Literature Citations / References
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. 
Biometrika 1988;75:800-802. 
Littell, R.M., Pendergast, J and Natarajan, R. Tutorial in Biostatistics. Modelling 
covariance structure in the analysis of repeated measures data. Stat Med. 2000;19: 
1793-1819. 
Wilson PWF et al. Prediction of Coronary Heart Disease Using Risk Factor Categories. 
Circulation. 1998; 97:1837-1847
Ji C et al. Waist Circumference Distribution of Chinese School-age Children and 
Adolescents. Biomedical and Environmental Sciences. 2010; 23 (1): 12-20.
Fryar CD, Gu Q, Ogden CL. Anthropometric Reference Data for Children and Adults: 
United Stages, 2007-2010. Vital Health Stat 11. 2012 Oct; (252): 1-48.
Rubin DB. (2004) Multiple Imputation for Nonresponse in Surveys. 2nd edition. New York: 
Wiley & Sons.


Product:  Evolocumab
Statistical Analysis Plan:  20120123
Date:  16 Sep 2019
Page 34
13.
Appendices 


Product:  Evolocumab
Statistical Analysis Plan:  20120123
Date:  16 Sep 2019
Page 35
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:
Analytical Study week
Week
4
Week
8
Week
12
Week
16
Week
20
Week
22
Week
24
Scheduled Visit day
29
57
85
113
141
155
169
Vital Signs(sitting BP, HR)
(1,56]
(56,112]
(112,147]
(147,161]
(161,175]
Physical exam(including 
neurologic examination)
(1,175]
Body weight, waist 
circumference, Tanner 
staging, Body height
(1,175]
cIMT
(29,196]
Cogstate neurocognitive 
assessment
(1,175]
12 lead ECG
(1,126]
(126,175]
Fasting Lipids
(1,119]
(119,161]
(161,175]
Lp(a), ApoA1, ApoB
(1,119]
(119,161]
(161,175]
PK, 
(1,119]
(119,161]
(161,175]
Chemistry, including fasting 
glucose
(1,126]
(126,175]
Hematology
(1,126]
(126,175]
Estradiol (females) / 
testosterone (males) 
(1,175]
HbA1c, hsCRP, CK, FSH, 
LH, ACTH, DHEA-S, 
cortisol
(1,175]
Anti-evolocumab antibodies
(1,126]
(126,175]
HCV viral load
(1,175]
Urinalysis, urine 
microalbumin
(1,126]
(126,175]
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.


Product:  Evolocumab
Statistical Analysis Plan:  20120123
Date:  16 Sep 2019
Page 36
Appendix B. Common Terminology Criteria for AEs (CTCAE)
Refer to the NCI Common Terminology Criteria for Adverse Events (CTCAE) for adverse 
event grading and information. The CTCAE is available at the following link: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 


Product:  Evolocumab
Statistical Analysis Plan:  20120123
Date:  16 Sep 2019
Page 37
Appendix C.  Lipid Modifying Background Therapy
Criteria modified from ACC/AHA guidelines:
HIGH-
INTENSITY 
STATIN 
THERAPY 
MODERATE-
INTENSITY 
STATIN 
THERAPY
LOW-
INTENSITY 
STATIN 
THERAPY
Notes (modifications from 
ACC/AHA guideline)
Atorvastatin
40 mg or 
greater QD
10 mg QD up 
to less than 
40 mg QD
Less than 
10 mg QD
Atorvastatin 30 mg QD 
is Moderate intensity.
Rosuvastatin
20 mg or 
greater QD
5 – < 20 mg 
QD
less than 
5 mg QD
Rosuvastatin < 5 mg QD is low 
intensity , Rosuvastatin 15 mg 
QD = moderate
Simvastatin
80 mg or 
greater QD
20-80 mg 
QD
< 20 mg QD
And Simvastatin > 40 and 
< 80 mg QD is moderate, 
Simvastatin 80 mg or greater 
QD = high, Simvastatin < 20 mg 
QD is low-intensity
Pravastatin
40 mg or 
greater QD
less than 
40 mg QD
Pravastatin < 10 mg QD is low 
intensity
Lovastatin
40 mg or 
greater QD
less than 
40 mg QD
Lovastatin 80 mg 
QD = moderate, Lovastatin 
10 mg QD = Low-intensity
Fluvastatin
80 mg QD
less than 
80 mg QD
Fluvastatin 10 mg 
QD = Low-intensity
Pitavastatin
≥ 2 mg QD
< 2 mg QD
UNKNOWN-INTENSITY STATIN THERAPY if dose frequency is other or dose unit is 
other and therefore total daily dose in mg cannot be derived; NO STATIN THERAPY if 
subject does not use any statin at baseline.