Open-label, Single-Arm, Multicenter Study to Evaluate the Safety, Tolerability and Efficacy of Evolocumab for LDL-C Reduction, as Add-on to Diet and Lipid-lowering Therapy, in Pediatric Subjects From 10 to 17 Years of Age With Heterozygous Familial Hypercholesterolemia (HeFH) or Homozygous Familial Hypercholesterolemia (HoFH)
Phase: PHASE3
Conditions: Familial Hypercholesterolemia
Sponsor: Amgen

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
Page 1 of 79 
Amgen Proprietary - Confidential
CONFIDENTIAL 
Title:  Open-label, Single-arm, Multicenter Study to Evaluate the Safety, 
Tolerability and Efficacy of Evolocumab for LDL-C Reduction, as Add-on to Diet 
and Lipid-lowering Therapy, in Pediatric Subjects From 10 to 17 Years of Age With 
Heterozygous Familial Hypercholesterolemia (HeFH) or Homozygous Familial 
Hypercholesterolemia (HoFH) 
HAUSER-OLE 
Evolocumab (AMG 145) 
Amgen Protocol Number (Evolocumab) 20120124 
EudraCT number 2015-002276-25 
Clinical Study Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Phone: +1-805-447-1000 
Key Sponsor Contact: 
 
One Amgen Center Drive 
Thousand Oaks 
California 91320-1799, USA 
Phone:  
Email:  
 
Original, Date: 
27 May 2015 
Amendment 1, Date: 
10 September 2015 
Amendment 2, Date: 
22 June 2016 
Amendment 3, Date: 
26 April 2017 
Amendment 4, Date: 
27 May 2020 
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).
This protocol was developed, reviewed, and approved in accordance with 
Amgen’s standard operating procedures. 
Approved
NCT Number: NCT02624869
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
Page 2 of 79 
Amgen Proprietary - Confidential
CONFIDENTIAL 
Investigator’s Agreement 
I have read the attached protocol entitled “Open-label, Single-Arm, Multicenter Study to 
Evaluate the Safety, Tolerability and Efficacy of Evolocumab for LDL-C Reduction, as 
Add-On to Diet and Lipid Lowering Therapy, in Pediatric Subjects From 10 to 17 Years 
of Age With Heterozygous Familial Hypercholesterolemia (HeFH) or Homozygous 
Familial Hypercholesterolemia (HoFH) HAUSER-OLE”, dated 27 May 2020, and agree 
to abide by all provisions set forth therein.  
I agree to comply with the International Council for 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) 
Approved

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
Page 3 of 79 
Amgen Proprietary - Confidential
CONFIDENTIAL 
Protocol Synopsis 
Title:  Open-label, Single-Arm, Multicenter Study to Evaluate the Safety, Tolerability and Efficacy 
of Evolocumab for LDL-C Reduction, as Add-On to Diet and Lipid Lowering Therapy, in Pediatric 
Subjects From 10 to 17 Years of Age With Heterozygous Familial Hypercholesterolemia (HeFH) 
or Homozygous Familial Hypercholesterolemia (HoFH) HAUSER-OLE 
Study Phase:  3b 
Indication:  Heterozygous familial hypercholesterolemia or homozygous familial 
hypercholesterolemia in pediatric subjects 10 to 17 years of age 
Primary Objective:  To describe the safety and tolerability of 80 weeks of SC evolocumab when 
added to standard of care in pediatric subjects 10 to 17 years of age with HeFH or HoFH  
Secondary Efficacy Objectives: 
•
To describe percent change and change from baseline in LDL-C, and on percent change
from baseline 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 or HoFH after 80 weeks of SC evolocumab, added
to standard of care in pediatric subjects 10 to 17 years of age with HeFH or HoFH
Secondary Safety Objectives: 
•
To describe change from baseline in steroid hormones and the subject incidence of abnormal
muscle and liver enzyme levels after 80 weeks of SC evolocumab, added to standard of care
in pediatric subjects 10 to 17 years of age with HeFH or HoFH
•
To describe changes from baseline in carotid intima-media thickness (cIMT) after 80 weeks
of SC evolocumab, added to standard of care in pediatric subjects 10 to 17 years of age with
HeFH or HoFH
•
To describe change from baseline in growth and pubertal development parameters at
measured timepoints with 80 weeks of SC evolocumab, added to standard of care in pediatric
subjects 10 to 17 years of age with HeFH or HoFH
Other Safety Objectives: 
•
To evaluate the incidence of abnormal neurological examination findings after 80 weeks of
SC evolocumab added to standard of care in pediatric subjects 10 to 17 years of age with
HeFH or HoFH
•
To assess cognitive function, assessed using the change from baseline in the components of
the Cogstate battery at each scheduled administration, after 80 weeks of SC evolocumab
added to standard of care in pediatric subjects 10 to 17 years of age with HeFH or HoFH
Exploratory Objectives: 
•
To describe change and percent change at measured timepoints in LDL-C, total cholesterol,
non-HDL-C, ApoB, total cholesterol/HDL-C ratio, ApoB/ApoA1 ratio, triglycerides, VLDL-C,
HDL-C, ApoA1, lipoprotein(a) [Lp(a)], with 80 weeks of SC evolocumab, added to standard of
care in pediatric subjects 10 to 17 years of age with HeFH or HoFH
•
To describe change at measured timepoints in proprotein convertase subtilisin/kexin type 9
(PCSK9) and high sensitivity C-reactive protein (hsCRP) with 80 weeks of SC evolocumab,
added to standard of care in pediatric subjects 10 to 17 years of age with HeFH or HoFH
•
To describe the incidence of abnormal neurological examination findings with 80 weeks of SC
evolocumab, added to standard of care in pediatric subjects 10 to 17 years of age with HeFH
or HoFH
•
To investigate the relationship between novel and established biochemical cardiovascular
and lipid biomarkers and effects of evolocumab in pediatric subjects 10 to 17 years of age
with HeFH
Approved

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
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• 
In subjects consenting to the optional pharmacogenetics analysis, to investigate potential 
correlations of study data including the subject response to evolocumab with genetic variation 
in markers of  (PCSK9) signaling, low-density lipoprotein receptor (LDLR) turnover, 
cholesterol metabolism, inflammation, and plaque stability 
Hypothesis:  The primary clinical hypothesis is that SC evolocumab will be well tolerated when 
added to standard of care in pediatric subjects 10 to 17 years of age with HeFH or HoFH 
Primary Endpoint:  Treatment emergent adverse events at week 80 
Secondary Efficacy Endpoints:   
• 
Percent change from baseline at week 80 in: 
− 
LDL-C 
− 
non-HDL-C 
− 
ApoB 
− 
total cholesterol/HDL-C ratio 
− 
ApoB/ApoA1 ratio 
• 
Change from baseline in LDL-C at week 80 
Secondary Safety Endpoints:   
• 
Change from baseline in steroid hormones (estradiol in females, testosterone in males; 
follicle-stimulating hormone [FSH], luteinizing hormone [LH], adenocorticotropic hormone 
[ACTH], dehydroepiandrosterone sulfate [DHEA-S], cortisol in all subjects) at week 80 
• 
Abnormal muscle and liver enzyme levels (creatine kinase [CK], aspartate aminotransferase 
[AST], or alanine aminotransferase [ALT]) at week 80 
• 
Change in cIMT from baseline at week 80 
• 
Change from baseline in growth (height and weight) and pubertal development (Tanner 
staging) at weeks 24, 48, and 80 
Study Design:  This is an open-label, single-arm, multicenter study.  Subjects are eligible for 
screening if they have completed Study 20120123 (and did not experience a treatment-related 
serious adverse event) or if they are 10 to 17 years of age at time of enrollment and have HoFH.  
The minimum expected enrollment of HeFH rollover subjects is approximately 70% of subjects 
enrolled in Study 20120123 or approximately 111 subjects.  In addition, approximately 
10 subjects with HoFH (and without prior participation in an evolocumab study) will be enrolled for 
an expected total enrollment of approximately 124 subjects.  Depending on willingness of 
subjects completing Study 20120123 to receive open-label evolocumab, final enrollment may be 
smaller or greater. 
Where permitted by local regulations, the study includes collection of biomarker development 
samples and subjects will be invited to consent/assent to pharmacogenetic analyses. 
Sample Size:  Approximately 124 subjects are anticipated to enroll in this trial.  This corresponds 
to an estimated 70% rollover for subjects with HeFH from the parent study 20120123 and 
approximately 10 subjects with HoFH enrolling in this study.  Depending on rollover rate from 
Study 20120123, final enrollment may be smaller or greater. 
Summary of Subject Eligibility Criteria:  Males and females who have completed 
Study 20120123 (and did not experience a treatment-related serious adverse event) and males 
and females of 10 to 17 years of age with diagnosis of HoFH and receiving optimized standard of 
care lipid-lowering therapy per locally applicable guidelines are eligible for this study.  Diagnosis 
of HoFH must be by genetic confirmation or a clinical diagnosis based on a history of an 
untreated LDL cholesterol concentration greater than 500 mg/dL (13 mmol/L) together with either 
xanthoma before 10 years of age in the subject, or evidence of heterozygous familial 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
Page 5 of 79 
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CONFIDENTIAL 
 
 
hypercholesterolemia in both parents.  At screening, HoFH subjects must be on a low-fat diet and 
receive background lipid-lowering therapy (such as statins, cholesterol absorption inhibitors, bile 
acid sequestrants, nicotinic acid, or combinations thereof).  Lipid-lowering therapy must be stable 
for ≥ 4 weeks prior to screening.  Fasting LDL-C for HoFH subjects 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 exclusion criteria for subjects with HoFH (those not rolling over from a prior 
evolocumab study):  estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2; 
CK > 3x ULN; AST or ALT > 2x ULN; (all screening by central laboratory); known active infection 
or major hematologic, renal, metabolic, gastrointestinal or endocrine dysfunction; subject has 
taken a cholesterylester transfer protein (CETP) inhibitor in the last 12 months, or mipomersen or 
lomitapide in the last 5 months prior to LDL-C screening, or has received any therapy to inhibit 
proprotein convertase subtilisin/kexin type 9 (PCSK9) within 12 weeks prior to screening; subject 
has a 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, would 
pose a risk to subject safety or interfere with the study evaluation, procedures or completion.  The 
following are major exclusion criteria for all subjects:  subjects cannot be receiving treatment in 
another investigational device or drug study, or less than 30 days since ending treatment on 
another investigational device or drug study (except Study 20120123); female subjects of 
childbearing potential cannot be pregnant or breast feeding or planning to become pregnant or 
planning to breast feed and must be willing to use acceptable method(s) of effective birth control 
(may include true sexual abstinence) during treatment with evolocumab and for an additional 
15 weeks after the end of treatment with evolocumab. 
For a full list of eligibility criteria, please refer to Section 4.1.1 through Section 4.1.2.  
Amgen Investigational Product Dosage and Administration:  Investigational product 
(evolocumab) will be administered subcutaneously using a spring-based prefilled 1.0 mL 
autoinjector/pen (AI/Pen) or automated mini-doser (AMD) (upon availability).  Each prefilled 
AI/Pen will contain 140 mg / 1.0 mL deliverable volume of evolocumab.  The AMD will contain 
420 mg / 3.5 mL deliverable volume of evolocumab.  Subjects will have the opportunity to switch 
between the AI/Pen and AMD at any scheduled time point where evolocumab is supplied to the 
subject, provided the appropriate supply is available.  Dosing will be as follows: 
• 
Evolocumab 420 mg SC QM (3 AI/Pen injections or 1 AMD administration) 
Non Amgen Non-investigational Products:  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 who have completed Study 20120123 (and did not experience a 
treatment-related serious adverse event) and have signed parental/guardian consent/permission 
and subject consent/assent for Study 20120124, will be enrolled.  Subjects with HoFH being 
considered for participation in this study, and who have signed parental/guardian 
consent/permission and subject consent/assent, will be assessed for inclusion and exclusion 
criteria.  Medical and medication history will be obtained.  Subjects will undergo screening 
laboratory assessments, including a SC administration of placebo to evaluate tolerability of the 
SC injection in subjects with HoFH only.  Lipid eligibility screening must be conducted after 
subject has been on a low-fat diet and receiving stable lipid-lowering therapy for ≥ 4 weeks.  
Subjects should maintain their diet, lipid-lowering therapy, and exercise regimen throughout 
screening and all phases of study participation.  Eligible subjects will start receiving open-label 
evolocumab, in addition to their background lipid-lowering therapy.   
Day 1 is defined as the day of first administration of evolocumab.  Subsequent study visits are at 
weeks 4, 12, 24, 36, 48, 60, 72, and 80 (EOS, end-of-study).  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. 
Adverse Events/Serious Adverse Events/Adverse Device Effects (ADE) and concomitant therapy 
will be collected at every study visit.  Other assessments and procedures are done as per 
Schedule of Assessments (Table 2) and include vital signs, dietary instruction, physical exam, 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
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body height and weight, 12-lead electrocardiograms (ECGs), chemistry, hematology, 
anti-evolocumab antibodies, biomarker sample collection, serum pregnancy testing (females of 
childbearing potential), urinalysis, specific laboratory assessments, assessment of growth and 
pubertal development (Tanner staging), carotid intima-media thickness (cIMT), and IP 
administration.  Specific laboratory assessments will include estradiol for girls, testosterone for 
boys, creatinine phosphokinase, FSH, LH, ACTH, DHEA-S, and cortisol.  If the subject consented 
to pharmacogenetics analyses and DNA has not already been obtained after consenting in Study 
20120123, 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 list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments (Table 2).   
Statistical Considerations:   
General Considerations 
Statistical analyses in this open label study are descriptive in nature.  No statistical hypothesis 
testing or missing value imputation is planned.  
Subject disposition, demographics, and baseline characteristics will be summarized.  Summary 
statistics for continuous variables will include the number of subjects, mean, median, standard 
deviation or standard error, minimum, and maximum.  For categorical variables, the frequency 
and percentage will be given. 
For efficacy analyses, the baseline value is defined as: 
• 
Subjects that participated in parent Study 20120123 and with baseline data from the parent 
study:  the baseline is defined as the baseline of the qualifying parent study. 
• 
Subjects not enrolling from a parent study or without baseline data from the parent study:  the 
baseline is defined as the baseline in this study. 
The full analysis set (FAS) includes all subjects with HeFH from parent study 20120123 who are 
enrolled and dosed, and all subjects with HoFH who are enrolled and dosed in this study.  
Analysis of all the endpoints with FAS will be provided.  Subjects will be summarized according to 
whether subject rolled over from a parent study and their treatment allocation from a parent study 
when applicable. 
Interim Analysis and Early Stopping Guidelines 
The interim analysis will be conducted when all the enrolled subjects in the study have 
opportunity to experience 28 weeks of investigation product exposure or have early 
terminated from the study.  At that time, the database related to the interim analyses of the 
study will be cleaned, processed and a snapshot will be taken.  Unless specified 
otherwise, the FAS will be the default analysis set in this study.  Similar to the primary 
analysis, the interim data will be summarized by cohort (HeFH and HoFH).  Statistical 
analysis in this interim analysis is descriptive in nature for all safety and efficacy 
endpoints if applicable.  No statistical hypotheses testing, or missing value imputation is 
planned.  There is no study stopping rule for either futility or efficacy and the current 
design or execution of the study will continue without any changes regardless of the 
result of the interim analysis. 
Analysis of Primary Endpoint 
Subject incidence of all treatment emergent adverse events will be tabulated by system organ 
class and preferred term at week 80.  Tables of fatal adverse events, serious adverse events, 
device related adverse events, adverse events leading to withdrawal from investigational product, 
and significant treatment emergent adverse events will also be provided.  Adverse events will be 
coded using the latest version of Medical Dictionary for Regulatory Activities (MedDRA). 
Analyses of Secondary Endpoints 
Growth and pubertal development parameters will be summarized at weeks 24, 48, and 80.  
Other secondary endpoints will be summarized at week 80.  Descriptive statistics will be 
presented.  
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
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An independent DMC which is external to Amgen will formally review the accumulating data to 
ensure there is no avoidable increased risk for harm to subjects. 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen 
Data Element Standards 
Version(s)/Date(s):  
Version 5 / 20 March 2015 
 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
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CONFIDENTIAL 
 
 
Study Design and Treatment Schema 
Completion of Study 
20120123
(Subjects with HeFH)
Screening, SC Injection 
Tolerance, Lipid 
Stabilization
De-Novo Subjects with 
HoFH
Evolocumab 420 mg SC QM
~111 HeFH Subjects
~10 HoFH Subjects
End Of Study
Max. 8 weeks
Timepoint:
Study Site IP Admin:
Day 1
Week 4 Week 12 Week 24 Week 36 Week 48 Week 60 Week 72
Week 80
EOS
Study Visit
SC IP Administration at study site
EOS = End of Study; HeFH = Heterozygous Familial Hypercholesterolemia; HoFH = Homozygous Familial Hypercholesterolemia; IP = Investigational Product; QM = every 4 weeks; SC = subcutaneous   
 
 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
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Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ADE 
Adverse device effect 
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 
CETP 
Cholesterylester transfer protein 
cIMT 
carotid intima-media thickness 
CK 
Creatine kinase 
CHD 
Coronary heart disease 
CRF 
Case report form 
CRP 
C-reactive protein 
CTCAE 
NCI Common Terminology Criteria for Adverse Events 
DILI 
Drug-induced liver injury 
DMC 
Data monitoring committee (Efficacy and Safety Evaluation 
Committee) 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
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 
End of Study for 
Individual Subject 
Defined as the last day that protocol-specified procedures are 
conducted for an individual subject 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
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Abbreviation or Term 
Definition/Explanation 
End of Study (primary 
completion) 
The end of the study (primary completion) is defined as the last day 
on which an enrolled subject in this study completes the 
end-of-study visit (week 80) or terminates the study early 
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 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; when 
applicable, this paper based form can be used under restricted 
conditions (eg, when EDC system is down) and faxed to Amgen 
FAS 
Full analysis set 
FH 
Familial hypercholesterolemia 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
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 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent ethics committee 
IFU 
Instructions for Use 
Ig 
Immunoglobulin 
IM 
Intramuscular 
IMP 
Investigational medicinal product 
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.  
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.  
IRB 
Institutional Review Board 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
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Abbreviation or Term 
Definition/Explanation 
IP 
Investigational product (evolocumab, administered with the medical 
devices used in this study – the prefilled autoinjector/pen [AI/pen] or 
automated mini-doser [AMD] [upon availability]) 
IPIM 
Investigational Product Instruction Manual 
IVRS/IWRS 
Interactive Voice Response System / Interactive Web Response 
System 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
LDL-C 
Low-density lipoprotein cholesterol 
LDLR 
LDL receptor 
LLN 
Lower limit of normal 
LOF 
Loss of function 
Lp(a) 
Lipoprotein(a) 
MedDRA 
Medical dictionary for regulatory activities 
NASH 
Nonalcoholic steatohepatitis 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PD 
Pharmacodynamic 
PFS 
Pre-filled syringe 
PI 
Principal investigator 
PK 
Pharmacokinetic 
QM 
QM is defined as every 4 weeks with a window of ± 3 days for each 
dose until week 4, then ± 7 days after week 4.  Note:  day 1 and 
week 80 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 
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 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
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Abbreviation or Term 
Definition/Explanation 
TC 
Total cholesterol 
TIA 
Transient ischemic attack 
TNF 
Tumor necrosis factor 
ULN 
Upper limit of normal 
VLDL-C 
Very low-density lipoprotein cholesterol 
WBC 
White blood cell 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
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TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................. 3 
Study Design and Treatment Schema .............................................................................. 8 
Study Glossary .................................................................................................................. 9 
1. 
OBJECTIVES ......................................................................................................... 17 
1.1 
Primary ....................................................................................................... 17 
1.2 
Secondary Efficacy ..................................................................................... 17 
1.3 
Secondary Safety ....................................................................................... 17 
1.4 
Other Safety ............................................................................................... 17 
1.5 
Exploratory ................................................................................................. 17 
2. 
BACKGROUND AND RATIONALE ........................................................................ 18 
2.1 
Hypercholesterolemia and the Pediatric Population ................................... 18 
2.2 
Amgen Investigational Product Background ............................................... 19 
2.3 
Pediatric Risk Assessment ......................................................................... 20 
2.4 
Rationale .................................................................................................... 21 
2.5 
Clinical Hypotheses .................................................................................... 22 
3. 
EXPERIMENTAL PLAN ......................................................................................... 22 
3.1 
Study Design .............................................................................................. 22 
3.2 
Number of Sites .......................................................................................... 22 
3.3 
Number of Subjects .................................................................................... 22 
3.4 
Replacement of Subjects ............................................................................ 23 
3.5 
Estimated Study Duration ........................................................................... 23 
3.5.1 
Study Duration for Subjects ........................................................ 23 
3.5.2 
End of Study ............................................................................... 23 
4. 
SUBJECT ELIGIBILITY .......................................................................................... 23 
4.1 
Inclusion and Exclusion Criteria ................................................................. 24 
4.1.1 
Inclusion Criteria ......................................................................... 24 
4.1.2 
Exclusion Criteria ........................................................................ 24 
5. 
SUBJECT ENROLLMENT ..................................................................................... 26 
6. 
TREATMENT PROCEDURES ............................................................................... 27 
6.1 
Classification of Products and/or Medical Devices ..................................... 27 
6.2 
Amgen Investigational Product Evolocumab .............................................. 27 
6.2.1 
Dosage, Administration, and Schedule ...................................... 27 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ...................................... 28 
6.3 
Non Amgen Non-investigational Products .................................................. 29 
6.4 
Withholding of Amgen Investigational Product or Statin 
Background Therapy due to Elevation of Creatine Kinase (CK) ................ 29 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
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6.5 
Hepatotoxicity Stopping and Rechallenge Rules ........................................ 30 
6.5.1 
Criteria for Withholding and/or Permanent 
Discontinuation of Amgen Investigational Product and 
Other Protocol-required Therapies due to Potential 
Hepatotoxicity ............................................................................. 30 
6.5.2 
Criteria for Rechallenge of Amgen Investigational 
Product and Other Protocol-required Therapies After 
Potential Hepatotoxicity .............................................................. 31 
6.6 
Concomitant Therapy ................................................................................. 32 
6.7 
Medical Devices ......................................................................................... 32 
6.8 
Product Complaints .................................................................................... 32 
6.9 
Excluded Treatments, Medical Devices, and/or Procedures 
During Study Period ................................................................................... 33 
7. 
STUDY PROCEDURES ......................................................................................... 34 
7.1 
Schedule of Assessments .......................................................................... 34 
7.2 
General Study Procedures ......................................................................... 38 
7.2.1 
Screening and Enrollment .......................................................... 40 
7.2.1.1 
Screening Placebo Administration ........................... 40 
7.2.1.2 
Laboratory Testing (Subjects With HoFH 
Only) ........................................................................ 40 
7.2.1.3 
Retesting .................................................................. 41 
7.2.1.4 
Rescreening ............................................................. 41 
7.2.1.5 
Screen Fail ............................................................... 42 
7.2.1.6 
Enrollment ................................................................ 42 
7.2.2 
Treatment and End of Study ....................................................... 42 
7.3 
Antibody Testing Procedures ..................................................................... 43 
7.4 
Biomarker Development ............................................................................. 43 
7.5 
Pharmacogenetic Studies ........................................................................... 44 
7.6 
Sample Storage and Destruction ................................................................ 44 
7.7 
Standardization of Study Procedures ......................................................... 46 
7.7.1 
Lipid Measurements ................................................................... 46 
7.7.2 
Measurement of Vital Signs ........................................................ 46 
7.7.3 
Height and Weight Measurements ............................................. 46 
7.7.4 
Carotid Intima-Media Thickness (cIMT) ...................................... 47 
7.7.5 
Electrocardiograms ..................................................................... 47 
7.7.6 
Physical and Neurologic Examination ........................................ 47 
7.7.7 
Cognitive Assessments (Cogstate Battery) ................................ 48 
7.7.8 
Tanner Staging (Sexual Maturity Ratings) .................................. 49 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 50 
8.1 
Subjects’ Decision to Withdraw .................................................................. 50 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 50 
8.3 
Reasons for Removal From Treatment or Study ........................................ 51 
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8.3.1 
Reasons for Removal From Treatment ...................................... 51 
8.3.2 
Reasons for Removal From Study ............................................. 51 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 51 
9.1 
Definition of Safety Events ......................................................................... 51 
9.1.1 
Adverse Events .......................................................................... 51 
9.1.2 
Serious Adverse Events ............................................................. 52 
9.2 
Safety Event Reporting Procedures ........................................................... 52 
9.2.1 
Adverse Events .......................................................................... 52 
9.2.1.1 
Reporting Procedures for All Adverse 
Events (Serious or Non-serious Adverse 
Events) ..................................................................... 52 
9.2.1.2 
Reporting Procedures for Serious Adverse 
Events ...................................................................... 54 
9.2.1.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 56 
9.3 
Pregnancy and Lactation Reporting ........................................................... 56 
10. 
STATISTICAL CONSIDERATIONS ....................................................................... 57 
10.1 
Study Endpoints, Analysis Sets .................................................................. 57 
10.1.1 
Study Endpoints ......................................................................... 57 
10.1.1.1 
Primary Endpoint ..................................................... 57 
10.1.1.2 
Secondary Endpoints ............................................... 57 
10.1.1.3 
Exploratory Endpoints .............................................. 58 
10.1.1.4 
Other Safety Endpoints ............................................ 58 
10.1.1.5 
Pharmacokinetics Endpoints .................................... 58 
10.1.2 
Analysis Sets .............................................................................. 58 
10.2 
Sample Size Considerations ...................................................................... 59 
10.3 
Planned Analyses ....................................................................................... 59 
10.3.1 
Data Monitoring Committee (DMC) ............................................ 59 
10.3.2 
Interim Analysis and Early Stopping Guidelines ......................... 59 
10.3.3 
Primary Analysis ......................................................................... 59 
10.4 
Planned Methods of Analysis ..................................................................... 60 
10.4.1 
General Considerations .............................................................. 60 
10.4.2 
Primary Endpoint ........................................................................ 60 
10.4.3 
Secondary Endpoints ................................................................. 60 
10.4.3.1 
Secondary Efficacy Endpoints ................................. 60 
10.4.3.2 
Secondary Safety Endpoints .................................... 60 
10.4.4 
Other Safety Endpoints .............................................................. 61 
11. 
REGULATORY OBLIGATIONS ............................................................................. 62 
11.1 
Informed Consent ....................................................................................... 62 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 63 
11.3 
Subject Confidentiality ................................................................................ 63 
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11.4 
Investigator Signatory Obligations .............................................................. 64 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................... 64 
12.1 
Protocol Amendments and Study Termination ........................................... 64 
12.2 
Study Documentation and Archive ............................................................. 64 
12.3 
Study Monitoring and Data Collection ........................................................ 65 
12.4 
Investigator Responsibilities for Data Collection ........................................ 66 
12.5 
Language.................................................................................................... 66 
12.6 
Publication Policy ....................................................................................... 66 
12.7 
Compensation ............................................................................................ 67 
13. 
REFERENCES ....................................................................................................... 68 
14. 
APPENDICES ........................................................................................................ 71 
 
List of Tables 
Table 1.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies due to Potential Hepatotoxicity ............................................... 31 
Table 2.  Schedule of Assessments ................................................................................ 35 
Table 3.  Analyte Listing1 ................................................................................................. 39 
 
List of Appendices 
Appendix A.  Additional Safety Assessment Information ................................................ 72 
Appendix B.  Sample Electronic Serious Adverse Event Contingency Report 
Form ......................................................................................................... 74 
Appendix C.  Sample Pregnancy and Lactation Notification Worksheets ....................... 77 
Appendix D.  Tanner Stages (Sexual Maturity Ratings) .................................................. 79 
 
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1. 
OBJECTIVES 
1.1 
Primary 
To describe the safety and tolerability of 80 weeks of SC evolocumab when added to 
standard of care in pediatric subjects 10 to 17 years of age with HeFH or HoFH. 
1.2 
Secondary Efficacy 
• 
To describe percent change and change from baseline in LDL-C, and on percent 
change from baseline 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 or HoFH after 
80 weeks of SC evolocumab, added to standard of care in pediatric subjects 10 to 
17 years of age with HeFH or HoFH 
1.3 
Secondary Safety 
• 
To describe change from baseline in steroid hormones and the subject incidence of 
abnormal muscle and liver enzyme levels after 80 weeks of SC evolocumab, added 
to standard of care in pediatric subjects 10 to 17 years of age with HeFH or HoFH 
• 
To describe changes from baseline in carotid intima-media thickness (cIMT) after 
80 weeks of SC evolocumab, added to standard of care in pediatric subjects 10 to 
17 years of age with HeFH or HoFH 
• 
To describe change from baseline in growth and pubertal development parameters 
at measured timepoints with 80 weeks of SC evolocumab, added to standard of care 
in pediatric subjects 10 to 17 years of age with HeFH or HoFH  
1.4 
Other Safety 
• 
To evaluate the incidence of abnormal neurological examination findings after 
80 weeks of SC evolocumab added to standard of care in pediatric subjects 10 to 
17 years of age with HeFH or HoFH 
• 
To assess cognitive function, assessed using the change from baseline in the 
components of the Cogstate battery at each scheduled administration, after 
80 weeks of SC evolocumab added to standard of care in pediatric subjects 10 to 
17 years of age with HeFH or HoFH 
1.5 
Exploratory 
• 
To describe change and percent change at measured timepoints in LDL-C, total 
cholesterol, non-HDL-C, ApoB, total cholesterol/HDL-C ratio, ApoB/ApoA1 ratio, 
triglycerides, VLDL-C, HDL-C, ApoA1, lipoprotein(a) [Lp(a)], with 80 weeks of SC 
evolocumab, added to standard of care in pediatric subjects 10 to 17 years of age 
with HeFH or HoFH 
• 
To describe change at measured timepoints in proprotein convertase subtilisin/kexin 
type 9 (PCSK9) and high sensitivity C-reactive protein (hsCRP) with 80 weeks of SC 
evolocumab, added to standard of care in pediatric subjects 10 to 17 years of age 
with HeFH or HoFH 
• 
To describe the incidence of abnormal neurological examination findings with 
80 weeks of SC evolocumab, added to standard of care in pediatric subjects 10 to 
17 years of age with HeFH or HoFH 
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• 
To investigate the relationship between novel and established biochemical 
cardiovascular and lipid biomarkers and effects of evolocumab in pediatric subjects 
10 to 17 years of age with HeFH 
• 
In subjects consenting to the optional pharmacogenetics analysis, to investigate 
potential correlations of study data including the subject response to evolocumab 
with genetic variation in markers of  (PCSK9) signaling, low-density lipoprotein 
receptor (LDLR) turnover, cholesterol metabolism, inflammation, and plaque stability 
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, 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).  Because premature 
atherosclerosis and especially coronary artery disease are part of the natural history of 
FH, events related to coronary artery disease and its complications (eg, manifestations 
of myocardial ischemia such as chest pain and myocardial infarction; percutaneous and 
surgical revascularization procedures, etc.) are expected to occur in this population at 
some frequency regardless of drug exposure.   
In the adult population, hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase 
inhibitors (statins) are currently the treatment of choice for patients with HeFH and HoFH 
patients (Grundy et al, 2004).  Although statins reduce mortality in this patient population 
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(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 
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 Background 
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. 
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Refer to the evolocumab Investigator’s Brochure for more information on 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). 
The subjects in this study are a pediatric and adolescent population.  In Amgen’s 
development program for evolocumab, 2 studies to date have included adolescent 
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.  Per 
protocol, of the 14 subjects participating in Study 20110271, 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, as of 01 July 2014, 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 were reported.  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 investigational product (IP), and 
are both known consequences of the subjects’ underlying FH. 
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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 adult studies, 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. 
2.4 
Rationale 
FH is a genetic disorder which typically requires lifelong treatment, sometimes beginning 
in childhood.  Therefore, it is important to study the long-term 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; cognition) are appropriate. 
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 (Studies 20110233 and 20110271), evolocumab lowered 
LDL-C and other lipid parameters in subjects aged 12-17 years.  At the time of 
enrollment in Study 20120124, subjects with HeFH will have completed the double-blind, 
placebo-controlled study 20120123 in which they will have been randomized to 
evolocumab or placebo for 24 weeks.  Study 20120124 is designed to provide 
longer-term clinical experience with evolocumab in subjects 10 to 17 years of age.  The 
primary endpoint of Study 20120124 is the incidence of treatment emergent adverse 
events at week 80.  Assessments of several lipid parameters, including LDL-C, Lp(a), 
non-HDL-C, ApoB, total cholesterol/HDL-C ratio, and ApoB/ApoA1 ratio were chosen as 
additional endpoints to evaluate stability of the treatment effect over the duration of the 
study. 
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 the range already 
observed in the evolocumab development program. 
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2.5 
Clinical Hypotheses 
The primary hypothesis is that SC evolocumab will be well tolerated when added to 
standard of care in pediatric subjects 10 to 17 years of age with HeFH or HoFH. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is an open-label, single-arm, multicenter study.  Subjects are eligible for screening if 
they have completed Study 20120123 (and did not experience a treatment-related 
serious adverse event) or if they are 10 to 17 years of age at time of enrollment and 
have HoFH.  The minimum expected enrollment of HeFH (rollover) subjects is 
approximately 70% of subjects enrolled in Study 20120123 or approximately 
111 subjects.  In addition, approximately 10 subjects with HoFH (and without prior 
participation in an evolocumab study) will be enrolled for an expected total enrollment of 
approximately 124 subjects.  Depending on willingness of 20120123 subjects to continue 
evolocumab administration, final enrollment may be smaller or greater. 
Where permitted by local regulations, the study includes collection of biomarker 
development samples and subjects will be invited to consent/assent to pharmacogenetic 
analyses. 
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 56 sites in North America, Latin America, Europe, 
Australia, South Africa, 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 enroll 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”. 
Approximately 124 subjects are anticipated to enroll in this trial.  This corresponds to an 
estimated 70% rollover for subjects with HeFH from the parent study 20120123 and 
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approximately 10 subjects with HoFH enrolling in this study.  Depending on rollover rate 
from Study 20120123, final enrollment may be smaller or greater. 
3.4 
Replacement of Subjects 
There will be no replacement of subjects. 
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
HeFH (rollover) subjects should enroll in Study 20120124 at the time of the week 24 
(end of study [EOS]) visit in Study 20120123.  For all subjects, after enrollment, the 
duration of study participation for a subject will be 80 weeks or approximately 
18 ½ months. 
3.5.2 
End of Study 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s), whether the study concluded as planned in the protocol or was 
terminated early. 
The primary completion date is the same as the end of study date and is the date when 
the last enrolled subject has completed the end-of-study visit (week 80) (ie, last subject 
last visit). 
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study:  The end of the study date is defined as the last day on which an enrolled 
subject in this study completes the end-of-study visit (week 80) or terminates the study 
early. 
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 
(IVR)/Interactive Web Response (IWR) system. 
Before any study-specific activities/procedure, the appropriate written informed consent 
(and assent, when applicable) must be obtained (see Section 11.1).  For subjects who 
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are not of legal age, informed consent from a legally acceptable representative must be 
obtained, in addition to assent of the child, where locally required. 
4.1 
Inclusion and Exclusion Criteria 
4.1.1 
Inclusion Criteria 
All Subjects: 
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. 
Subjects with HeFH: 
103 
Completed Study 20120123 while still on assigned investigational product and 
did not experience a treatment-related serious adverse event. 
Subjects with HoFH: 
104 
Male or female, ≥ 10 to ≤ 17 years of age at time of enrollment (includes the year 
after the subject completes the 17th year after birth but not the day of completing 
the 18th year after birth). 
105 
Diagnosis of HoFH by genetic confirmation or a clinical diagnosis based on a 
history of an untreated LDL cholesterol concentration > 500 mg/dL (13 mmol/L) 
together with either xanthoma before 10 years of age or evidence of 
heterozygous familial hypercholesterolemia in both parents. 
106 
Subject must be on a low-fat diet and receiving background lipid-lowering therapy 
(such as statins, cholesterol absorption inhibitors, bile acid sequestrants, nicotinic 
acid, or combinations thereof). 
107 
Lipid-lowering therapy, including statin dose, must be unchanged for ≥ 4 weeks 
prior to LDL-C screening; fibrates must be stable for at least 6 weeks prior to 
screening. 
108 
Fasting LDL-C at screening ≥ 130 mg/dL (3.4 mmol/L) as determined by central 
laboratory. 
109 
Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) by central laboratory at screening. 
4.1.2 
Exclusion Criteria 
All Subjects: 
201 
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); except Study 20120123.  Other investigational procedures or 
treatments while participating in this study are excluded. 
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202 
Female subject who has experienced menarche and unwilling to use acceptable 
method(s) of effective birth control during treatment with evolocumab and for an 
additional 15 weeks after the end of treatment with evolocumab.  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.   
203 
Female subject is pregnant or breast feeding, or planning to become pregnant or 
planning to breastfeed during screening, during treatment with evolocumab, and 
within 15 weeks after the end of treatment with evolocumab. 
204 
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). 
205 
Subject will not be available for or likely not to comply with protocol-required 
study visits or procedures, to the best of the subject and investigator’s knowledge 
(Note:  Day 1 and week 80 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). 
206 
Known sensitivity to any of the active substances or their excipients to be 
administered during dosing, eg, carboxymethylcellulose. 
Subjects with HoFH: 
207 
Moderate to severe renal dysfunction, defined as an estimated glomerular 
filtration rate (eGFR) < 30 ml/min/1.73m2 at screening. 
208 
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. 
209 
CK > 3 times the ULN at screening. 
210 
Known active infection or major hematologic, renal, metabolic, gastrointestinal or 
endocrine dysfunction in the judgment of the investigator. 
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211 
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. 
212 
Subject has received evolocumab or any other therapy to inhibit PCSK9 within 
12 weeks of screening. 
213 
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, 
Evolocumab 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 and/or subject assent form before commencement of 
study-specific activities/procedures. 
Subjects with HeFH will keep the same subject identification number from 
Study 20120123.  Subjects with HoFH who enter into the screening period for the study 
will receive a unique subject identification number before any study-related 
activities/procedures are performed.  The subject identification number will be assigned 
by the IVR/IWR system.  The investigator or designee must contact the IVR/IWR system 
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.  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. 
Sites participating in Study 20120123 and in this study will be assigned the same site 
number as the one used in Study 20120123.   
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 case report form (CRF). 
All subjects participating in Study 20120124 will receive open-label evolocumab. 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
Page 27 of 79 
Amgen Proprietary - Confidential 
CONFIDENTIAL 
 
 
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Products and/or Medical Devices 
The Amgen investigational product used in this study is evolocumab (Amgen 
investigational medicinal product [IMP]).  The medical devices used in this study to 
deliver or administer the IMP are the prefilled autoinjector/pen (AI/Pen) or the automated 
mini-doser (AMD) (upon availability). 
The Non-Amgen Non-investigational product(s) used in this study include the subjects’ 
pharmacological background lipid-lowering therapies, including statin therapy. 
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 Amgen investigational product.  
6.2 
Amgen Investigational Product Evolocumab 
Evolocumab will be manufactured and packaged by Amgen Inc. and distributed using 
Amgen clinical IP distribution procedures.  Evolocumab will be presented for fixed dose, 
subcutaneous injection as a sterile, preservative-free solution in a prefilled AI/Pen or 
AMD.  The prefilled, single use, disposable, handheld mechanical (spring-based) AI/Pen 
contains a 140 mg / 1.0 mL deliverable volume of evolocumab.  The AMD is a single 
use, disposable, on body electro-mechanical injection device containing 420 mg / 3.5 mL 
deliverable volume of evolocumab. 
IP (evolocumab) 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 or AMD. 
The prefilled AI/Pen or AMD 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 or AMD should be reported to Amgen.  Further details 
are provided in the IPIM and IFU. 
6.2.1 
Dosage, Administration, and Schedule 
IP (evolocumab) 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 
all other procedures, including vital signs, electrocardiogram (ECG), Cogstate testing, 
cIMT imaging, blood draw procedures, and apheresis.  Apheresis is permitted only for 
subjects with HoFH; blood draw procedures are to occur before apheresis.  All subjects 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
Page 28 of 79 
Amgen Proprietary - Confidential 
CONFIDENTIAL 
 
 
will be held for observation for at least 30 minutes after IP administration before being 
discharged at the first dosing visit. 
Each QM administration of IP with the AI/Pen will consist of 3 injections of 140 mg 
evolocumab in 1.0 mL for a total of 420 mg / 3.0 mL of evolocumab administered.  The 
SC injections should be administered in a consecutive fashion with all injections 
completed within 30 minutes. 
Each QM administration of IP with the AMD will consist of 1 injection of 420 mg / 3.5 mL 
of evolocumab. 
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 the 
subject (or designee, if not a healthcare professional) must be administered at the site 
under the supervision of a healthcare provider. 
Subjects will have the opportunity to switch between the AI/Pen and AMD at any 
scheduled time point where evolocumab is supplied to the subject, provided the 
appropriate supply is available.  The first self-administration after switching the device 
should be done at a regularly scheduled visit under the supervision of the investigator or 
qualified study center staff. 
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 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
Page 29 of 79 
Amgen Proprietary - Confidential 
CONFIDENTIAL 
 
 
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 
Non Amgen Non-investigational Products 
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.  
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. 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
Page 30 of 79 
Amgen Proprietary - Confidential 
CONFIDENTIAL 
 
 
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) discovered during study participation (as part of usual practice or 
standard of care) 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 Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies due 
to Potential Hepatotoxicity 
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver biomarkers (TBL, INR, and transaminases) has not been 
identified (Table 1). 
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 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
Page 31 of 79 
Amgen Proprietary - Confidential 
CONFIDENTIAL 
 
 
• 
nonalcoholic fatty liver disease including steatohepatitis (NASH)  
• 
Non-hepatic causes (eg, rhabdomyolysis, hemolysis) 
If investigational product(s) is/are withheld, the subject is to be followed according to 
recommendations in Appendix A for possible drug-induced liver injury (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 6.5.2). 
Table 1.  Conditions for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies due to Potential 
Hepatotoxicity 
Analyte 
Temporary Withholding 
Permanent Discontinuation 
TBL 
> 3x ULN at any time 
> 2x ULN 
 
 
OR 
INR 
-- 
> 1.5 (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 8x ULN at any time 
 
> 5x ULN but < 8x ULN for 
≥ 2 weeks 
 
> 5x ULN but < 8x ULN and unable 
to adhere to enhanced monitoring 
schedule 
 
> 3x ULN with clinical signs or 
symptoms that are consistent with 
hepatitis (such as right upper 
quadrant pain/tenderness, fever, 
nausea, vomiting, jaundice). 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values 
 
> 3x ULN (when baseline was 
< ULN) 
 
OR 
ALP 
> 8x ULN at any time 
-- 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal. 
6.5.2 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
Page 32 of 79 
Amgen Proprietary - Confidential 
CONFIDENTIAL 
 
 
If signs or symptoms recur with rechallenge, then Amgen investigational product and 
other protocol-required therapies, as appropriate, should be permanently discontinued.  
Subjects who clearly meet the criteria for permanent discontinuation (as described in 
Table 1) should not 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. 
6.7 
Medical Devices 
Evolocumab will be provided by prefilled AI/Pen or AMD (upon availability) (Section 6.2). 
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard of care.  These 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(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material.  This includes any drug(s) or device(s) or combination product(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 AMD 
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. 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
Page 33 of 79 
Amgen Proprietary - Confidential 
CONFIDENTIAL 
 
 
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 or AMD) 
• 
missing labels, illegible labels, incorrect labels, and/or suspect labels  
• 
change in IP appearance, for example color change or visible presence of foreign 
material 
• 
unexpected quantity or volume, for example number of tablets or amount of fluid in 
the prefilled AI/Pen or AMD 
• 
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 
through 30 days after the last dose of IP or EOS, whichever is later, are reported to 
Amgen within 24 hours of discovery or notification of the product and/or device 
complaint. 
For more details regarding the identification and reporting of product and device 
complaints, refer to the IPIM and the IFU. 
6.9 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
The following treatments are not permitted during the study, including screening: 
• 
treatments for inhibition of PCSK9 or any investigational therapies other than study 
provided investigational product 
• 
mipomersen or lomitapide 
• 
prescribed amphetamines, or amphetamine derivatives, and weight loss 
medications.  
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). 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
Page 34 of 79 
Amgen Proprietary - Confidential 
CONFIDENTIAL 
 
 
The following treatments are not recommended because of their potential impact on 
metabolism of certain statins: 
• 
medications or foods that are known potent inhibitors of CYP3A (eg, Itraconazole, 
ketoconazole, and other antifungal azoles, macrolide antibiotics erythromycin, 
clarithromycin, and the ketolide antibiotic telithromycin, HIV or HCV protease 
inhibitors, antidepressant nefazodone and grapefruit juice in large quantities 
(> 1 quart daily [approximately 1 Liter]) should not be used during the study.  
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments 
 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
Page 35 of 79 
Amgen Proprietary - Confidential 
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Table 2.  Schedule of Assessments 
Study Day / Week / Other Timepointa 
Screening 
D1/Parent 
Study EOS 
W4c 
(±3d) 
W12 
(±7d) 
W24 
(±7d) 
W36 
(±7d) 
W48 
(±7d) 
W60 
(±7d) 
W72 
(±7d) 
W80 (EOS) 
(±7d) 
HoFH 
HeFHb 
General Procedures 
Informed parental/guardian consent/permission and 
subject consent/assent – HoFH subjects 
X 
 
 
 
 
 
 
 
 
 
 
Informed parental/guardian consent/permission and 
subject consent/assent – HeFH subjects 
 
X 
X 
 
 
 
 
 
 
 
 
Enrollment 
 
 
Xd 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs (sitting BP, HR) 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
Review for AEs/SAEs/ADEs 
Xe 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dietary instruction 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Physical exam (including neurologic examination) 
X 
 
 
 
 
 
 
 
 
 
X 
Height, weight, cIMT, Tanner staging 
 
 
Xf 
 
 
X 
 
X 
 
 
X 
Neurocognitive assessment (Cogstate battery) 
X 
 
Xg 
 
 
X 
 
Xg 
 
 
X 
12 lead ECG 
 
 
X 
 
 
 
 
 
 
 
X 
Central Laboratoryh 
Fasting lipidsh 
X 
Xi 
X 
 
X 
 
 
X 
 
 
X 
ApoA1, ApoB100, Lp(a)h 
 
 
X 
 
X 
 
 
 
 
 
X 
PK (evolocumab), PCSK9 
 
 
X 
 
X 
 
 
 
 
 
X 
Chemistry, including fasting glucoseh 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Hematology 
X 
X 
 
 
 
 
 
X 
 
 
X 
Estradiol (females) / testosterone (males) 
 
Xi 
X 
 
 
 
 
 
 
 
X 
HbA1c, FSH, LH, ACTH, DHEA-S, cortisol, hsCRP, 
fasting vitamins A/D/E/Kj 
 
Xi 
X 
 
 
 
 
 
 
 
X 
CK 
X 
Xi 
X 
 
X 
 
 
X 
 
 
X 
Biomarkers (blood)k 
 
 
X 
 
 
 
 
 
 
 
X 
Anti-evolocumab antibodies 
 
 
X 
 
 
 
 
 
 
 
X 
HCV testingl 
X 
 
 
 
 
 
 
 
 
 
 
HCV viral loadl 
 
 
X 
 
 
 
 
X 
 
 
X 
Serum pregnancym 
X 
X 
 
 
 
 
 
 
 
 
X 
Urine pregnancym 
 
 
Xn, o 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis, urine microalbumin, urine creatinine, urine 
albumin/creatinine ratio 
 
 
X 
 
 
 
 
 
 
 
X 
Page 1 of 2 
Footnotes displayed on the next page of the Table 
 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
Page 36 of 79 
Amgen Proprietary - Confidential 
CONFIDENTIAL 
 
 
Table 2.  Schedule of Assessments 
Study Day / Week / Other Timepointa 
Screening 
D1/Parent 
Study EOS 
W4c 
(±3d) 
W12 
(±7d) 
W24 
(±7d) 
W36 
(±7d) 
W48 
(±7d) 
W60 
(±7d) 
W72 
(±7d) 
W80 (EOS) 
(±7d) 
HoFH 
HeFHb 
Investigational Product 
Screening placebo AI/Pen (HoFH subjects only) 
X 
 
 
 
 
 
 
 
 
 
 
IP administration on-site / instruction as needed 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
AI/Pen or AMD dispensationp 
 
 
Xq 
X 
X 
X 
X 
X 
X 
X 
 
AI/Pen or AMD reconciliation 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Page 2 of 2 
ACTH = adrenocorticotropic hormone, ADE = adverse device effect, AE = adverse event, AI/Pen = autoinjector/pen, ALT = alanine aminotransferase, 
AMD = automated mini-dose, ApoA1 = apolipoprotein A-1, ApoB100 = apolipoprotein B100, AST = aspartate aminotransferase, BP = blood pressure, cIMT = Carotid 
Intima-Media Thickness, CK = creatine kinase, D = day, DHEA-S = dehydroepiandrosterone sulfate, ECG = electrocardiogram, EOS = end-of-study (for the individual 
subject), FSH = follicle-stimulating hormone, HbA1c = hemoglobin A1C, HCV = hepatitis C virus, HeFH = heterozygous familial hypercholesterolemia, HoFH = 
homozygous familial hypercholesterolemia, HR = heart rate, hsCRP = high sensitivity C-reactive protein, ICF = informed consent form, IP = investigational product, 
LH = luteinizing hormone, Lp(a) = lipoprotein(a), PCSK9 = proprotein convertase subtilisin/kexin type 9, PK = pharmacokinetic, SAE = serious adverse event, ULN = 
upper limit of normal, W = week 
a D1 = day of first administration of IP; this visit should also coincide with EOS visit for parent study in subjects rolling over from Study 20120123; procedures NOT 
conducted as part of EOS visit for parent study should be completed at this visit. 
b For rollover subjects only, when time between Study 20120123 EOS visit and Study 20120124 day 1 visit exceeds 4 weeks. 
c Week 4 training visit applies to HoFH subjects only (due to lack of prior experience of in-home use of IP). 
d Enrollment should be on day 1 or as close as possible to day 1 and must not be earlier than 5 days prior. 
e Only AEs possibly related to study procedures, SAEs, and ADEs (placebo injections for HoFH subjects) are collected during the screening period (from signing of 
ICF). 
f Study 20120124 day 1 cIMT is not required for rollover subjects completing the 20120123 EOS cIMT (regardless of time between Study 20120123 EOS and 
Study 20120124 day 1). 
g HoFH subjects only. 
h Blood samples must be taken prior to IP administration and apheresis, if applicable.  Note:  apheresis is permitted only for subjects with HoFH. 
i For rollover subjects that have performed the screening visit will not have to repeat the labs that were performed at screening at day 1:  fasting lipids, hormones, 
HbA1, FSH, LH, ACTH, DHEA-S, CK, Cortisol, hsCRP, fasting vitamins A,D,E,K. 
j If a subject with HoFH is not fasting on day 1, reschedule.  All other subjects or timepoints:  if the subject is not fasting, 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. 
k If the subject consented to pharmacogenetics analyses, deoxyribonucleic acid (DNA) will be extracted from some of the blood samples, eg, biomarker samples. 
l 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. 
m Pregnancy testing in females of childbearing potential; if urine test is positive, perform confirmatory serum pregnancy test. 
n For rollover subjects:  urine pregnancy test at day 1 is not required in lieu of serum pregnancy at Study 20120123 EOS visit if completed within 7 days of initiation of 
evolocumab in Study 20120124. 
o For rollover subjects that have performed the screening visit:  urine pregnancy test at day 1 is not required in lieu of serum pregnancy at screening visit if completed 
within 7 days of day 1. 
 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
Page 37 of 79 
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p Subjects will have the opportunity to switch between the AI/Pen and AMD at any scheduled time point where evolocumab is supplied to the subject, provided the 
appropriate supply is available.  The first self-administration after switching the device should be done at a regularly scheduled visit under the supervision of the 
investigator or qualified study center staff. 
q HeFH subjects only. 
 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
Page 38 of 79 
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7.2 
General Study Procedures 
It is the responsibility of the investigator to ensure that all procedures are performed 
according to the protocol.  Written informed consent must be obtained 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 are described below and the timing of the procedures is 
provided in Table 2.   
Subjects must be fasting for ≥ 9 hours before each study visit where fasting samples are 
being taken.  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.  If IP is administered 
during a study visit, administration must be after completion of all other visit procedures, 
including vital signs, ECG, Cogstate testing, cIMT imaging, blood draw procedures, and 
apheresis.  Apheresis is permitted only for subjects with HoFH; blood draw procedures 
are to occur before apheresis. 
All on-study visits and dosing should be scheduled from study day 1.  Day 1 and 
week 80 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.  Weeks are counted from day 1, the first day of IP administration, eg, 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 the visit window as specified in the Schedule of Assessments 
(Table 2).  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 (HoFH subjects only), all study procedures for a visit must 
be completed on the same day. 
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. 
All screening, if applicable, and on-study laboratory samples will be processed and sent 
to the central laboratory.  Amgen or designee will be responsible for the evaluation of PK 
(evolocumab) and PCSK9 serum levels, anti-evolocumab antibody, and biomarker 
development assessments and the central laboratory will ship the samples to Amgen or 
a specialty laboratory for assay (depending on the assessment). 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  27 May 2020 
Page 39 of 79 
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The central laboratory will provide a study manual that outlines handling, labeling, and 
shipping procedures for all blood samples.  The date and time of sample collection will 
be recorded in the source documents at the site. 
Table 3 below outlines the specific analytes for serum chemistry, hematology, urinalysis, 
and other testing to be conducted. 
Table 3.  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 
Urine Creatinine 
Urine 
microalbumin 
Urine Albumin/ 
Creatinine ratio 
Hemoglobin 
Hematocrit 
RBC 
RDW 
MCV  
MCH 
MCHC 
WBC 
Platelets 
Differential 
• 
Neutrophils 
• 
Bands 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
Fasting lipids 
Total cholesterol 
HDL-C 
LDL-C 
Triglycerides 
VLDL-C 
non-HDL-C 
ApoA1 
ApoB 
Estradiol (females) 
Testosterone (males) 
Cortisol 
Luteinizing hormone (LH) 
Adrenocorticotropic 
hormone (ACTH) 
Dehydroepiandrosterone 
sulfate (DHEA-S) 
hsCRP 
Fasting vitamins A, D, E, 
and K 
Lp(a) 
Anti-evolocumab 
antibodies 
PCSK9 
Evolocumab (PK) 
HbA1c 
Pregnancy test (females 
of childbearing potential) 
FSH 
HCV antibody2 
HCV viral load3 
1 Day 1 and week 80 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 HoFH subjects only at high risk for (see 
Section 7.2.1.1), or with history of HCV infection and in HoFH subjects with ALT or AST > 2x ULN at any 
time during screening.  Please note that HoFH subjects with ALT or AST > 2x ULN must be screen failed 
unless the elevation is transient as confirmed by retesting per Section 7.2.1.3.   
3 Viral load will be tested at the time points indicated in Table 2 in subjects who are positive for HCV. 
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7.2.1 
Screening and Enrollment 
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.  
Subjects completing Study 20120123 (rollover subjects) should be informed of 
Study 20120124 so that the informed consent process and screening can be completed 
in time for the subject, if interested and eligible, to be enrolled in Study 20120124 at the 
time of the last 20120123 study visit (week 24; end-of-study).  Only subjects from 
Study 20120123 that did not experience a treatment-related serious adverse event will 
be eligible.  For subjects rolling over from Study 20120123, if the period between 
Study 20120123 EOS visit and Study 20120124 day 1 visit exceeds 4 weeks, certain 
screening tests (as outlined in Table 2) will need to be repeated. 
Subjects with HoFH considered for enrollment in Study 20120124 should complete 
screening and the subject enrolled 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, subjects with 
HoFH who are considered for the study will undergo a placebo administration to confirm 
tolerance of SC administration by SC injection prior to enrollment.  This placebo 
administration can be done before or after screening venipuncture procedures but must 
be done before enrollment.  The 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 
Laboratory Testing (Subjects With HoFH Only) 
Screening fasting lipids and glucose must be collected after ≥ 9 hour fasting by the 
subject.  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 enrollment. 
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All prohibited lipid-lowering therapy (see Section 6.9) must be discontinued ≥ 4 weeks 
before lipid screening laboratories are taken or as indicated in Section 4.1.1 and/or 
Section 4.1.2, whichever is longer. 
Note that eGFR will be calculated by the central laboratory and will be provided to the 
site for eligibility determination. 
Screening includes blood laboratory collection for hepatitis C virus (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: 
○ ever injected illegal drugs 
○ were exposed to blood known to be infected with HCV 
○ were ever on chronic hemodialysis  
○ are known to be infected with HIV 
○ have a known HCV-infected sexual partner  
* Please note that subjects with ALT or AST > 2x ULN must be screen failed unless the 
elevation is transient as confirmed by retesting per Section 7.2.1.3. 
7.2.1.3 
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 enrolled within the allowed screening period.  Retesting of 
laboratory samples must occur at least 1 week after previous sample. 
7.2.1.4 
Rescreening 
HoFH 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 enrolled 
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. 
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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. 
7.2.1.5 
Screen Fail 
Subjects who fail any of the eligibility criteria during screening or rescreening and have 
not been enrolled need to be screen failed in IVRS/IWRS before they can be 
re-consented and re-registered in IVRS/IWRS for rescreening. 
7.2.1.6 
Enrollment 
Subjects who continue to meet all eligibility criteria at the end of screening will be 
enrolled (Section 5).   
7.2.2 
Treatment and End of Study 
Rollover subjects (HeFH subjects) should complete their day 1 procedures for 
Study 20120124 and initiate open-label evolocumab administration at the end of the 
week 24 (EOS) visit in Study 20120123 (see Section 7.2.1 for guidance).  HoFH subjects 
will visit the study site upon enrollment for day 1 procedures and initiation of open-label 
evolocumab administration while continuing their background lipid-lowering treatment.  
Day 1 in Study 20120124 is defined as the day of first administration of open-label 
evolocumab (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 samples are 
obtained.  If the subject is not fasting for the scheduled study day 1 visit, no visit 
procedures are performed.  The subject must return as soon as possible in a fasting 
state for study day 1 visit procedures.  If the subject is not fasting as required for a visit 
after study day 1, visit procedures should be completed except for fasting laboratory 
sample collection and IP administration, if applicable.  An extra visit must be completed 
for the omitted procedures as soon as possible and, if possible, within the window for the 
respective visit. 
No additional blood will be collected for the pharmacogenetics analyses.  For subjects 
who have consented to the pharmacogenetic portion of this study, DNA will be extracted 
from blood samples already collected on day 1 or another visit (see Section 7.5 
“Pharmacogenetic Studies” and Section 7.6 “Sample Storage and Destruction”). 
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If a subject withdraws from the study early, all efforts should be made to complete and 
report the observations as thoroughly as possible up to the date of withdrawal.  If 
possible, the procedures of week 80 should be completed at the time of withdrawal. 
Subjects will end the study with the week 80 visit.  Note that the week 80 visit must be 
scheduled at approximately the same time of day as the day 1 visit, as the hormones 
measured have diurnal variation. 
7.3 
Antibody Testing Procedures 
Blood samples for antibody testing are to be collected per Table 2 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 PCSK9 signaling, LDLR turnover, cholesterol metabolism, 
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inflammation, and plaque stability.  It is not possible at this stage to anticipate what these 
advances will be; however, considerable benefit could accrue to future sufferers of 
coronary artery disease if these markers can be correlated with the data from the study.  
It is also important to clarify any potential drug interactions in this population of subjects 
who will be on a number of other drugs.  For biomarker analysis, where local regulations 
permit, blood will be collected at each of the time points indicated in Table 2 so that 
biomarkers related to, but not limited to PCSK9 signaling, LDLR turnover, cholesterol 
metabolism, inflammation, and plaque stability such as certain glycosylated proteins, 
matrix metalloproteinases, additional markers of inflammation such as myeloperoxidase, 
bromo and nitro-tyrosine, tumor necrosis factor (TNF), and cellular adhesion molecules 
may be studied. 
Refer to the laboratory manual for detailed collection and handling procedures for all 
biomarker development samples. 
7.5 
Pharmacogenetic Studies 
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed.  These optional pharmacogenetics analyses focus on 
inherited genetic variations such as those of the PCSK9 gene or the LDLR gene to 
evaluate their possible correlation to the disease and/or responsiveness to the therapies 
used in this study.  The goals of the optional studies include the use of genetic markers 
to help in the investigation of cardiovascular disease, hyperlipidemia and other metabolic 
disorders and/or to identify subjects who may have positive or negative response to 
evolocumab.  No additional blood will be collected for this analysis.  For subjects who 
have consented to the pharmacogenetic portion of this study, DNA will be extracted from 
blood samples already collected.  Subjects can participate in the main trial irrespective of 
whether they do or do not consent to the pharmacogenetic portion of the study. 
7.6 
Sample Storage and Destruction 
Any blood sample collected according to the Schedule of Assessments (Table 2) 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 
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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 PCSK9 signaling, LDLR turnover, cholesterol 
metabolism, inflammation, and plaque stability such as certain glycosylated proteins, 
matrix metalloproteinases, additional markers of inflammation such as myeloperoxidase, 
bromo and nitro-tyrosine, TNF, and cellular adhesion molecules, the dose response 
and/or prediction of response to PCSK9 inhibition, eg, by evolocumab, characterize 
antibody response, and characterize aspects of the molecule (eg, mechanism of 
action/target, metabolites).  Results from this analysis are to be documented and 
maintained, but are not necessarily reported as part of this study.  Samples can be 
retained for up to 20 years. 
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of pharmacogenetic, biomarker development, or other 
exploratory studies are not placed in the subject’s medical record and are not be made 
available to the subject, members of the family, the personal physician, or other third 
parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood samples and any other components from the samples can be located and 
destroyed.  Samples will be destroyed once all protocol-defined procedures are 
completed.  However, information collected from samples prior to the request for 
destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the Investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  See 
Section 11.3 for subject confidentiality. 
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7.7 
Standardization of Study Procedures 
7.7.1 
Lipid Measurements 
For subjects rolling over from Study 20120123, central laboratory results of the lipid 
panel, as well as ApoA1, ApoB, Lp(a), and PCSK9 will be unblinded when the subject 
has reached week 12 in Study 20120124.  For these subjects, vitamins A, D, E, and K 
will also be blinded until the Study 20120123 database is locked.  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 until week 12 in 
Study 20120124 and, if a lipid panel is drawn, all reasonable steps must be undertaken 
to avoid informing the subject and study personnel of the results. 
7.7.2 
Measurement of Vital Signs 
Blood pressure (BP) and heart rate (HR) will be measured as per Schedule of 
Assessment (Table 2).  Use of an automated oscillometric device for BP measurement is 
preferred and recommended.  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.  For subjects with HoFH, BP will initially be recorded 
in both of the subject’s arms unless a concomitant condition favors the use of a 
particular arm.  The arm with the higher systolic reading at screening will then be used 
for BP determinations throughout the study.  For subjects rolling over from 
Study 20120123, the same arm should be used for measurement as in Study 20120123.   
7.7.3 
Height and Weight Measurements 
Height and weight measurement will be obtained at the time points specified in the 
Schedule of Assessments (Table 2).  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 
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that can be easily set to zero, be calibrated through professional service or by standard 
known weight.  
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 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 CRF as applicable.  It is the responsibility of the investigator to obtain additional 
ECGs required for the clinical management of the subject, using centralized ECG 
services equipment or equipment on-site. 
Further detail about the equipment provided and its use for this study will be provided in 
an Investigator ECG Manual distributed to the sites before start of enrollment. 
7.7.6 
Physical and Neurologic Examination 
Physical examination (at screening and EOS) should include a neurologic examination.  
The neurologic 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.  Any clinically significant changes in the physical examination per the 
investigator’s opinion should be recorded on the Adverse Event CRF. 
7.7.7 
Cognitive Assessments (Cogstate Battery) 
The Cogstate battery is a largely language-independent battery of neurologic tests 
administered via computer which has been validated for use in the age group to be 
studied in Study 20120124.  The Cogstate battery has a significant normative database, 
and has been used in over 190 clinical trials to detect both enhancement and 
deterioration associated with drug effects.  Subject performance on the Cogstate battery 
is also independent of education level, estimated intelligence quotient (IQ) and language 
or culture of origin (Yamashita et al, 2011; Yoshida et al, 2011; Boivin et al, 2010; 
Bangirana et al, 2009; Dingwall et al, 2009; Lim et al, 2009), allowing accurate 
classifications of cognitive dysfunction or cognitive change with reference only to a 
child’s age and gender. 
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 school children 
(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 
ADHD ([Mollica et all, 2004]: eight to 12 year olds; [Snyder et al, 2008]: six to 16 year 
olds), as well as the effects of computerized cognitive rehabilitation in pediatric cerebral 
malaria survivors as young as five years old (Bangirana et al, 2009). 
Additionally, regulatory authorities have approved the use of Cogstate tests for 
monitoring and evaluating the safety of CNS penetrant drugs in a range of pediatric 
indications, including epilepsy (NCT01389596), neurogenic detrusor over-activity 
(NCT01565694), bipolar depression (NCT02046369), schizophrenia (NCT01911429) 
and hyponatremia (NCT02012959) and in children as young as four years old.  In sports, 
Cogstate tests are being used to make return-to-play decisions in suspected concussion. 
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In Study 20120124, 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.  
• 
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.  
For rollover (HeFH) subjects, the Cogstate battery will be administered at the week 24 
visit and at EOS.  For HoFH subjects, the Cogstate battery will be administered at 
screening (practice assessment), day 1, week 24, week 48, and EOS. 
7.7.8 
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 
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one for genitals in males), because these characteristics may differ in their degree of 
maturity. 
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 2) and 
collection of data, including endpoints and adverse events.  The investigator must 
document the change to the Schedule of Assessments (Table 2) 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 Treatment or Study 
8.3.1 
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) 
• 
withdrawal of consent from study 
• 
death 
• 
lost to follow-up 
• 
decision by Sponsor (other than subject request, safety concern, lost to follow-up) 
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
• 
withdrawal of consent from study 
• 
death 
• 
lost to follow-up 
• 
decision by sponsor  
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease 
(eg, diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected, and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study or involves 
an intervention such as elective cosmetic surgery or a medical procedure while on study, 
is not considered an adverse event. 
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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 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria: 
• 
fatal 
• 
life threatening (places the subject at immediate risk of death) 
• 
requires in-patient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
congenital anomaly/birth defect 
• 
other medically important serious event 
An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).   
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, DILI (see Appendix A for 
drug-induced liver injury reporting criteria), or events that necessitate an emergency 
room visit, outpatient surgery, or urgent intervention. 
9.2 
Safety Event Reporting Procedures  
9.2.1 
Adverse Events 
9.2.1.1 
Reporting Procedures for All Adverse Events (Serious or 
Non-serious Adverse Events) 
Refer to Sections 9.2.1.2 and 9.2.1.3 for additional information regarding the reporting of 
serious adverse events. 
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For subjects enrolling in Study 20120124 after completion of Study 20120123 (HeFH 
subjects) the investigator is responsible for ensuring that all adverse events and all 
adverse device effects observed by the investigator or reported by the subject that occur 
after the first dose of investigational product/study treatment/protocol-required therapies 
through the end of Study 20120124 are reported using the Event CRF.   
For subjects not rolling over from Study 20120123 (HoFH subjects), the investigator is 
responsible for ensuring that all adverse events possibly related to study procedures, 
adverse device effects, and serious adverse events are reported from signing of the ICF.  
All other adverse events are reported that occur after enrollment.  The investigator is 
responsible for ensuring that all adverse events observed by the investigator or reported 
by the subject that occur from signing of the ICF or that occur after enrollment through 
the end of Study 20120124 are reported using the Event CRF.   
The investigator must assign the following adverse event attributes: 
• 
adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
• 
dates of onset and resolution (if resolved), 
• 
severity, 
• 
assessment of relatedness to investigational product (evolocumab and/or the 
device[s]:  the prefilled AI/Pen or AMD), or other protocol-required therapies, 
protocol-required procedure or activity, and 
• 
action taken. 
The adverse event grading scale used will be the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE).  The grading scale used in 
this study is referenced in Appendix A.   
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 Summary CRF. 
The investigator must assess whether the adverse event is possibly related to IMP 
(evolocumab).  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 evolocumab 
(investigational medicinal product)?  The investigator must assess whether the adverse 
event is possibly related to the prefilled AI/Pen or the AMD (investigational device(s) 
used to administer evolocumab).  The relationship is indicated by a “yes” or “no” 
response to the question: Is there a reasonable possibility that the event may have been 
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caused by the investigational device?  Relatedness means that there are facts or 
reasons to support a relationship between IP and the event. 
The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity (eg, administration of investigational product, protocol-required 
therapies, device(s) and/or procedure (including any screening procedure(s)).  This 
relationship is indicated by a “yes” or “no” response to the question:  “Is there a 
reasonable possibility that the event may have been caused by a study activity 
(eg, administration of investigational product, protocol-required therapies, device(s)), 
and/or procedure”? 
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the investigator's judgment) are not to be 
recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. 
The Investigator is expected to follow reported adverse events until stabilization or 
reversibility.  
9.2.1.2 
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 Event CRF.   
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event (eSAE) Contingency Report Form within 24 hours of the 
investigator’s knowledge of the event.  See Appendix B for a sample of the eSAE 
Contingency Report Form.  For EDC studies where 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. 
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The investigator must assess whether the serious adverse event is possibly related to 
IMP(evolocumab).  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 
evolocumab (investigational medicinal product)?  The investigator must assess whether 
the serious adverse event is possibly related to the prefilled AI/Pen or the AMD 
(investigational device[s] used to administer evolocumab).  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 investigational device(s)?  Relatedness means that 
there are facts or reasons to support a relationship between IP and the event. 
The investigator must assess whether the serious adverse event is possibly related to 
any study-mandated activity or procedure.  This relationship is indicated by a “yes” or 
“no” response to the question:  “Is there a reasonable possibility that the event may have 
been caused by a study activity or procedure”? 
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility.  
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  The investigator 
may be asked to provide additional follow-up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the Event CRF. 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
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.  
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. 
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9.2.1.3 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after end of study.  However, these serious 
adverse events can be reported to Amgen.  In some countries (eg, European Union [EU] 
member states), investigators are required to report serious adverse events that they 
become aware of after end of study.  If serious adverse events are reported, the 
investigator is to report them to Amgen within 24 hours following the investigator’s 
knowledge of the event.  See Appendix B for a sample of the eSAE Contingency Report 
Form. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases for the purposes of expedited 
reporting.  
9.3 
Pregnancy and Lactation Reporting 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking evolocumab report the pregnancy to Amgen as specified below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur through 15 weeks after the last dose of evolocumab. 
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C).  Amgen Global Patient Safety will 
follow-up with the investigator regarding additional information that may be requested. 
If a female subject becomes pregnant during the study, the investigator should attempt 
to obtain information regarding the birth outcome and health of the infant.  If a male 
subject's female partner becomes pregnant, the investigator should discuss obtaining 
information regarding the birth outcome and health of the infant from the pregnant 
partner. 
Any termination of the pregnancy will be reported to Amgen Global Patient Safety 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, stillbirth, 
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or neonatal death or there is a fetal or neonatal congenital anomaly) the investigator will 
report the event as a serious adverse event. 
If a female subject breastfeeds while taking evolocumab, report the lactation case to 
Amgen as specified below.  
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur through 15 weeks after the last dose of evolocumab.  
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up with 
the investigator regarding additional information that may be requested. 
10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoint 
• 
Treatment emergent adverse events at week 80 
10.1.1.2 
Secondary Endpoints 
10.1.1.2.1 
Secondary Efficacy Endpoints 
• 
Percent change from baseline at week 80 in: 
− 
LDL-C 
− 
Non-HDL-C 
− 
ApoB 
− 
Total cholesterol/HDL-C ratio 
− 
ApoB/ApoA1 ratio 
• 
Change from baseline in LDL-C at week 80 
10.1.1.2.2 
Secondary Safety Endpoints 
• 
Change from baseline in steroid hormones (FSH, LH, ACTH, DHEA-S, cortisol, 
estradiol/testosterone [females/males, respectively]) at week 80 
• 
Abnormal muscle and liver enzyme levels (CK, AST, ALT) at week 80 
• 
Change from baseline in cIMT at week 80 
• 
Change from baseline in growth (height and weight) and pubertal development 
(Tanner staging) at weeks 24, 48 and 80 
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10.1.1.3 
Exploratory Endpoints 
• 
Change from baseline and percent change from baseline at each scheduled 
assessment in the following: 
− 
LDL-C 
− 
Total cholesterol 
− 
Non-HDL-C 
− 
ApoB 
− 
Total cholesterol/HDL-C ratio 
− 
ApoB/ApoA1 ratio 
− 
Triglycerides 
− 
VLDL-C 
− 
HDL-C 
− 
ApoA1 
− 
Lp(a) 
• 
Change from baseline at each scheduled assessment in the following: 
− 
Proprotein convertase subtilisin/kexin type 9 (PCSK9) 
− 
High sensitivity C-reactive protein (hsCRP) 
10.1.1.4 
Other Safety Endpoints  
• 
Select safety laboratory values and vital signs at each scheduled assessment 
• 
Incidence of anti-evolocumab antibody (binding and neutralizing) formation 
• 
Abnormal neurological examination findings  
• 
ECG parameters (such as RR, PR, QRS, QT, and QTc intervals) at each scheduled 
assessment 
• 
Change from baseline score in the components of the Cogstate battery at each 
scheduled administration 
10.1.1.5 
Pharmacokinetics Endpoints 
• 
Serum concentration of evolocumab at each scheduled assessment 
10.1.2 
Analysis Sets 
The full analysis set (FAS) includes all subjects with HeFH from parent study 20120123 
who are enrolled and dosed all subjects with HoFH who are enrolled and dosed in this 
study.  
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10.2 
Sample Size Considerations 
Approximately 124 subjects are anticipated to enroll in this trial.  This corresponds to at 
least 70% rollover for subjects with HeFH from the parent study 20120123 and at least 
10 subjects with HoFH enrolling in this study. 
10.3 
Planned Analyses 
10.3.1 
Data Monitoring Committee (DMC) 
An external independent DMC has been established to formally review the accumulating 
data from this study 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.  Details are provided in the DMC charter. 
10.3.2 
Interim Analysis and Early Stopping Guidelines 
The interim analysis will be conducted when all the enrolled subjects in the study 
have opportunity to experience 28 weeks of investigation product exposure or 
have early terminated from the study.  At that time, the database related to the 
interim analyses of the study will be cleaned, processed and a snapshot will be 
taken.  Unless specified otherwise, the FAS will be the default analysis set in this 
study. Similar to the primary analysis, the interim data will be summarized by 
cohort (HeFH and HoFH).  Statistical analysis in this interim analysis is descriptive 
in nature for all safety and efficacy endpoints if applicable.  No statistical 
hypotheses testing or missing value imputation is planned.  There is no study 
stopping rule for either futility or efficacy and the current design or execution of 
the study will continue without any changes regardless of the result of the interim 
analysis. 
10.3.3 
Primary Analysis 
To evaluate the safety, tolerability and effect of 80 weeks of SC evolocumab when 
added to standard of care in pediatric subjects 10 to 17 years of age with HeFH or 
HoFH, the primary analysis will be conducted when all the enrolled subjects in the study 
have either completed all the scheduled visits up to and including week 80 or have early 
terminated from the study.  Unless specified otherwise, the FAS will be the default 
analysis set in this study and data will be summarized by cohort (HeFH and HoFH). 
The primary analysis will include estimation for all the endpoints.  No formal hypotheses 
will be tested in this study.  
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10.4 
Planned Methods of Analysis  
10.4.1 
General Considerations 
Statistical analyses in this open label study are descriptive in nature.  No statistical 
inference or missing value imputation is planned. 
Subject disposition, demographics and baseline characteristics will be summarized. 
Summary statistics for continuous variables will include the number of subjects, mean, 
median, standard deviation or standard error, minimum, and maximum.  For categorical 
variables, the frequency and percentage will be given. 
For efficacy analyses, the baseline value is defined as: 
• 
Subjects that participated in parent Study 20120123 and with baseline data from the 
parent study:  the baseline is defined as the baseline of the qualifying parent study. 
• 
Subjects not enrolling from a parent study or without baseline data from the parent 
study:  the baseline is defined as the baseline in this study. 
Subjects will be summarized according to whether subject rolled over from a parent 
study and their treatment allocation from a parent study when applicable. 
10.4.2 
Primary Endpoint 
The current Medical Dictionary for Regulatory Activities (MedDRA) version at the time of 
the data lock will be used to code all adverse events (AE) to a system organ class and a 
preferred term.  The following analyses will be performed on FAS.  
Treatment emergent adverse events will be tabulated by system organ class and 
preferred term at week 80.  Tables of fatal adverse events, serious adverse events, 
device related adverse events, adverse events leading to withdrawal from investigational 
product, and significant treatment-emergent adverse events will also be provided.  
10.4.3 
Secondary Endpoints 
10.4.3.1 
Secondary Efficacy Endpoints 
Summary statistics on FAS will be provided for the secondary efficacy endpoints.  
Efficacy laboratory parameters (LDL-C, non-HDL-C, ApoB, total cholesterol/HDL-C ratio 
and ApoB/ApoA1 ratio) will be summarized using descriptive statistics at week 80.  
10.4.3.2 
Secondary Safety Endpoints 
Summary statistics on FAS will be provided for the secondary safety endpoints.  
Change from baseline in steroid hormone levels (FSH, LH, ACTH, DHEA-S, cortisol, 
estradiol in females, testosterone in males), and cIMT at week 80 will be summarized 
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using descriptive statistics at week 80.  Summary of abnormal muscle and liver enzymes 
will also be provided.  
Change from baseline in growth parameters (height and weight) will be summarized 
using descriptive statistics at weeks 24, 48 and 80.  Shift from baseline in Tanner 
staging at weeks 24, 48 and 80 will be summarized.  
10.4.4 
Other Safety Endpoints 
All analysis of the other safety endpoints will use the FAS.  
Laboratory Parameters 
Selected safety laboratory parameters will be summarized using descriptive statistics.  
Vital Signs 
Vital signs will be summarized using descriptive statistics. 
Neurologic examination 
The incidence of abnormal neurologic findings overall and in each exam area will be 
summarized by treatment group. 
Cogstate battery 
Change from baseline score in the components of the Cogstate battery at each 
scheduled administration will be summarized using descriptive statistics. 
Anti-evolocumab antibodies 
The incidence and percentages of subjects who develop anti-evolocumab antibodies 
(binding and neutralizing) at any time will be tabulated. 
ECG 
Summaries over time and/or changes from baseline over time will be provided for all 
ECG parameters.   
Subjects’ maximum change from baseline in QTcF will be categorized and the number 
and percentage of subjects in each group will be summarized. 
Subjects’ maximum post baseline values will also be categorized and the number and 
percentage of subjects in each group will be summarized. 
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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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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.   
• 
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 Council for Harmonization Good Clinical Practice (ICH 
GCP) Guidelines, it is required that the investigator and institution permit authorized 
representatives of the company, of the regulatory agency(s), and the IRB/IEC direct 
access to review the subject’s original medical records for verification of study-related 
procedures and data.  Direct access includes examining, analyzing, verifying, and 
reproducing any records and reports that are important to the evaluation of the study.  
The investigator is obligated to inform and obtain the consent of the subject to permit 
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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.  
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. 
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CRF entries may be considered source data if the CRF is the site of the original 
recording (ie, there is no other written or electronic record of data). 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.  Elements should include:   
• 
Subject files containing completed CRF, informed consent forms, and subject 
identification list 
• 
Study files containing the protocol with all amendments, 
Evolocumab 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 CRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Amgen Clinical Monitor is responsible for verifying the CRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical 
research.  The Clinical Monitor is to have access to subject medical records and other 
study-related records needed to verify the entries on the CRFs. 
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function (or 
designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy storage 
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areas, laboratories) and review of study-related records will occur to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 
Data capture for this study is planned to be electronic: 
• 
All source documentation supporting entries into the CRFs must be maintained and 
readily available. 
• 
Updates to CRFs will be automatically documented through the software’s “audit 
trail”. 
• 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During this 
review, subject data are checked for consistency, omissions, and any apparent 
discrepancies.  In addition, the data are reviewed for adherence to the protocol and 
GCP.  To resolve any questions arising from the clinical data management review 
process, data queries are created in the EDC system database for site resolution 
and subsequently closed by the EDC system or by an Amgen reviewer. 
• 
The investigator signs only the Investigator Verification Form for this electronic data 
capture study or the investigator applies an electronic signature in the EDC system if 
the study is set up to accept an electronic signature.  This signature indicates that 
investigator inspected or reviewed the data on the CRF, the data queries, and 
agrees with the content. 
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 2), 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 may facilitate 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 
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not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
International Committee of Medical Journal Editors Recommendations for the Conduct of 
Reporting, Editing, and Publications of Scholarly Work in Medical Journals, which states: 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published; and (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 need to meet conditions 
1, 2, 3, and 4. 
• 
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals 
must 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 must qualify for authorship, and all those who 
qualify are to be listed. 
• 
Each author must have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
12.7 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 
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13. 
REFERENCES 
Abifadel M, 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. 
Abramson, M. J., Benke, G. P., Dimitriadis, C., Inyang, I. O., Sim, M. R., Wolfe, R. S., & 
Croft, R. J. (2009). Mobile telephone use is associated with changes in cognitive function 
in young adolescents. Bioelectromagnetics, 30(8), 678-86. doi:10.1002/bem.20534 
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;18:355-375. 
Bangirana P, Giordani B, John CC, Page C, et al. Immediate neuropsychological and 
behavioral benefits of computerized cognitive rehabilitation in Ugandan pediatric 
cerebral malaria survivors. J Dev Behav Pediatr. 2009; 30(4): 310-8.  
Boivin, M. J., Busman, R. A., Parikh, S. M., Bangirana, P., Page, C. F., Opoka, R. O., & 
Giordani, B. (2010). A pilot study of the neuropsychological benefits of computerized 
cognitive rehabilitation in Ugandan children with HIV. Neuropsychology, 24(5), 667-73. 
doi:10.1037/a0019312. 
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. 
Dingwall, K., Lewis, M., Maruff, P. & Cairney, S. Reliability of repeated cognitive testing 
in healthy Indigenous Australian adolescents. Australian Psychologist 44, 224–234 
(2009). 
Evolocumab Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc. 
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. 
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.  
International Committee of Medical Journal Editors, Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals:  Writing and Editing for Biomedical 
Publication.  2013.  http://www.icmje.org/ 
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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. 
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, T. V., Heo, M., Whiteford, L. M., & Faith, M. S. (2012). Effects on cognitive 
performance of eating compared with omitting breakfast in elementary schoolchildren. 
J Dev Behav Pediatr, 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. 
Lim, Y. Y. et al. A method for cross-cultural adaptation of a verbal memory assessment. 
Behavior research methods 41, 1190–200 (2009). 
Mayes, L., Snyder, P. J., Langlois, E., & Hunter, N. (2007). Visuospatial working memory 
in school-aged children exposed in utero to cocaine. Child Neuropsychology, 13(3), 
205-18. doi:10.1080/09297040600888753 
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. 
Mollica, C., Maruff, P., & Vance, A. (2004). Development of a statistical approach to 
classifying treatment response in individual children with ADHD. Human 
Psychopharmacology, 19, 445-456. 
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, J. K., Hickling, S., Li, J., Ambrosini, G. L., Jacques, A., & Oddy, W. 
H. (2014). Prospective associations between dietary patterns and cognitive performance 
during adolescence. Journal of Child Psychology and Psychiatry, and Allied Disciplines. 
doi:10.1111/jcpp.12209 
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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]. 
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. 
Snyder AM, Maruff P, Pietrzak RH, Cromer JR, et al. 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): 211-26.  
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. 
Yamashita, Y., Mukasa, A., Anai, C., Honda, Y., Kunisaki, C., Koutaki, J., et al. (2011). 
Summer treatment program for children with attention deficit hyperactivity disorder: 
Japanese experience in 5 years. Brain Dev, 33(3), 260-7. 
doi:10.1016/j.braindev.2010.09.005 
Yoshida, T. et al. Criterion and construct validity of the CogState Schizophrenia Battery 
in Japanese patients with schizophrenia. PloS one 6, e20469 (2011). 
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 AEs (CTCAE) Version 4.0 for 
AE grading and information.  The CTCAE is available at the following link: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications\ctc.htm. 
Pediatric Drug-induced Liver Injury Reporting & Additional Assessments 
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation according to the criteria specified in Section 6.5.1 require 
the following: 
• 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded). 
• 
The appropriate CRF (eg, Event CRF) that captures information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities is to be completed 
and sent to the Amgen. 
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.1.3. 
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 
Table 1 or who experience AST or ALT elevations > 3x ULN or 2-fold increases above 
baseline values for subjects with elevated values before drug are to undergo a period of 
“close observation” until abnormalities return to normal or to the subject’s baseline 
levels. 
Assessments that are to be performed during this period include: 
1. Repeat liver tests AST, ALT, ALP, bilirubin (total and direct), and INR within 
24 hours. 
2. In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve. 
3. Obtain pediatric gastroenterologist or pediatric hepatologist consult. 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
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• 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL.  The following are to be considered depending on the clinical situation: 
− 
Complete blood count with differential to assess for eosinophilia 
− 
Serum total immunoglobulin IgG, Anti-nuclear antibody, Anti Smooth Muscle 
Antibody, and Liver Kidney Microsomal antibody 1 to assess for autoimmune 
hepatitis 
− 
Serum acetaminophen (paracetamol) levels 
− 
A more detailed history of: 
• 
Prior and/or concurrent diseases or illness 
• 
Exposure to environmental and/or industrial chemical agents  
• 
Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting, and fever 
• 
Prior and/or concurrent use of alcohol, recreational drugs and special diets 
• 
Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
− 
Viral serologies 
− 
Creatinine phosphokinase, haptoglobin, LDH, and peripheral blood smear 
− 
Appropriate liver imaging if clinically indicated 
• 
Appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected  
• 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  
The “close observation period” is to continue for a minimum of 4 weeks after 
discontinuation of all investigational product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in the corresponding CRFs. 
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Appendix B.  Sample Electronic Serious Adverse Event Contingency Report Form 
 
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Approved 
 
 

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Approved 
 
 

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Appendix C.  Sample Pregnancy and Lactation Notification Worksheets 
 
Approved 
 
 

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Approved 
 
 

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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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Date:  27 May 2020 
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FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 4 
Protocol Title:  Open-label, Single-arm, Multicenter Study to Evaluate the 
Safety, Tolerability and Efficacy of Evolocumab for LDL-C Reduction, as 
Add-on to Diet and Lipid-lowering Therapy, in Pediatric Subjects From 
10 to 17 Years of Age With Heterozygous Familial Hypercholesterolemia 
(HeFH) or Homozygous Familial Hypercholesterolemia (HoFH) 
HAUSER-OLE 
 
Amgen Protocol Number (Evolocumab) 20120124 
EudraCT number 2015-002276-25 
 
Amendment Date: 
27 May 2020 
 
Rationale: 
The following changes were made to the protocol, dated 27 May 2020. 
• 
Added interim analysis for all enrolled subjects 
• 
Updated number of subjects expected to roll over from Study 20120123 into 
study 20120124 to approximately 111 subjects and 10 subjects with 
Homozygous Familial Hypercholesterolemia (HoFH) with an expected total 
enrollment of approximately 124 subjects. 
− 
Updated Study Schema figure with new enrollment number 
• 
Align with current protocol template: 
− 
Removed language regarding the collection of Disease Related Events 
(DRE). 
− 
Added statement “This protocol was developed, reviewed, and approved 
in accordance with Amgen’s standard operating procedures.” 
− 
Deleted “subject incidence of” wording in the endpoints as endpoints are 
intended to present summary statistics of individual subject data. 
− 
Removed details from study monitoring and data collection to restrict 
Amgen (or designee) correcting obvious data errors in the clinical trial 
database 
• 
Change in key Sponsor contact details 
 
Approved 
 
 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  26 April 2017 
Page 1 of 20 
Amendment 3 
Protocol Title:  Open-label, Single-arm, Multicenter Study to Evaluate the Safety, 
Tolerability and Efficacy of Evolocumab for LDL-C Reduction, as Add-on to Diet 
and Lipid-lowering Therapy, in Pediatric Subjects From 10 to 17 Years of Age With 
Heterozygous Familial Hypercholesterolemia (HeFH) or Homozygous Familial 
Hypercholesterolemia (HoFH) 
 
Amgen Protocol Number Evolocumab 20120124 
2015-002276-25 
 
Amendment Date: 
26 April 2017 
 
Rationale: 
This is Amendment 3 for Evolocumab Study 20120124.  The primary change to the 
protocol is to clarify that investigational product (IP) will be administered using either an 
autoinjector/pen (AI/Pen) or automated mini-doser (AMD).   
In addition, the following were clarified to ensure alignment with study procedures: 
• 
Update the number of sites expected for the study 
• 
Add AMD product information and option for device use, upon availability 
• 
Clarify IP administration performed during a study visit must occur after all other 
procedures 
• 
Clarify Cogstate testing and carotid intima-media thickness (cIMT) imaging will be 
performed prior to IP administration during a study visit 
• 
Clarify apheresis is only permitted for subjects with homozygous familial 
hypercholesterolemia (HoFH) 
• 
Add QM administration by AMD will consist of 1 injection of 420 mg / 3.5 mL 
deliverable volume of evolocumab 
• 
Clarify enrollment should be on day 1 or as close as possible to day 1 and no earlier 
than 5 days prior to day 1 
• 
Align safety definitions and reporting procedures with current protocol template 
• 
Administrative, typographical, and formatting changes were made throughout the 
protocol 
CONFIDENTIAL 
 
Approved 
 
 

Approved 
 
 
Product:  Evolocumab 
Protocol Number:  20120124 
Date:  22 June 2016 
Page 1 of 34 
CONFIDENTIAL 
 
Amendment 2 
Protocol Title:  Open-label, Single-arm, Multicenter Study to Evaluate the Safety, 
Tolerability and Efficacy of Evolocumab for LDL-C Reduction, as Add-on to Diet 
and Lipid-lowering Therapy, in Pediatric Subjects From 10 to 17 Years of Age With 
Heterozygous Familial Hypercholesterolemia (HeFH) or Homozygous Familial 
Hypercholesterolemia (HoFH) 
HAUSER-OLE 
Amgen Protocol Number (Evolocumab) 20120124 
EudraCT number 2015-002276-25 
 
Amendment Date: 
22 June 2016 
Rationale: 
This protocol is being amended to: 
• 
Clarify primary endpoint language. 
• 
Add language that defines baseline lab values for rollover and de novo subjects. 
• 
Clarify/update eligibility criteria: 
o Rollover subjects should not have experienced treatment-related serious 
adverse events in Study 20120123. 
o Fix typo regarding liver function tests. 
o Clarified exclusion criteria regarding lab values; removed language regarding 
retesting as this is addressed in Section 7.2.1.3. 
• 
Clarify that biomarker samples will only be collected where permitted by local law. 
• 
Update number of sites in study and which countries are participating; as well as 
clarifying that sites from parent Study 20120123 will retain their same site number in 
the current study. 
• 
Clarify that all 3 investigational product (IP) injections must be completed within 
30 minutes and that all subjects will be held for observation for at least 30 minutes 
after first IP administration. 
• 
Update Schedule of Assessments and Study Procedures: 
o Allow for a 4-week screening window for rollover subjects and for those 
subjects who exceed the 4-week window, which procedures must be redone. 
o Update collection points for creatinine kinase. 
o Clarify language in several footnotes. 
o Add additional analytes for urinalysis. 
o Remove thyroid stimulating hormone (TSH) as an analyte. 

Approved 
 
 
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Date:  22 June 2016 
Page 2 of 34 
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o Clarify when lipid panel results will be unblinded. 
o Clarify that blood draw procedures must be performed before apheresis (if 
applicable). 
• 
Update protocol to align with current protocol template language: 
o Safety:  hepatotoxicity, medical devices, product complaints, safety event 
definitions and reporting. 
o Publication policy. 
• 
Update safety reporting forms. 
• 
Make administrative and editorial changes throughout the protocol. 

Product:  Evolocumab 
Protocol Number:  20120124 
Date:  10 September 2015 
Page 1 of 19 
CONFIDENTIAL 
 
 
Amendment 1 
Protocol Title:  Open-label, Single-arm, Multicenter Study to Evaluate the Safety, 
Tolerability and Efficacy of Evolocumab for LDL-C Reduction, as Add-on to Diet 
and Lipid-lowering Therapy, in Pediatric Subjects From 10 to 17 Years of Age With 
Heterozygous Familial Hypercholesterolemia (HeFH) or Homozygous Familial 
Hypercholesterolemia (HoFH) 
 
Amgen Protocol Number Evolocumab (AMG 145) 20120124 
EudraCT number 2015-002276-25 
 
Original, Date: 
27 May 2015 
Amendment 1, Date: 
10 September 2015 
 
Rationale: 
• 
To address regulatory feedback. 
• 
To add safety assessments.