Conditions: Homozygous Familial Hypercholesterolemia HoFH
Keywords: Evolocumab Hypercholesterolemia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 30
Healthy volunteers: no

Brief summary:
To describe the safety and tolerability of evolocumab in participants with homozygous familial hypercholesterolemia (HoFH) in India. All participants will receive evolocumab over an 8-week period.

Detailed description:
An open-label, multicentre, phase 4 study to describe the safety and tolerability of evolocumab in 30 Indian participants with HoFH. Subjects who meet the inclusion/exclusion criteria and laboratory assessments at screening will be enrolled and will be required to maintain their current lipid-lowering drug therapy throughout the duration of the trial. Participants will receive evolocumab 420 mg subcutaneous (SC) once monthly (QM) and study visits will occur approximately every 4 weeks. Apheresis participants will receive evolocumab 420 mg SC every 2 weeks to correspond with their apheresis schedule. Final administration of evolocumab (for all participants) will occur at week 8. The end of study (EOS) visit will occur at week 12 for all participants.

Arms:
arm 1: Evolocumab 420 mg subcutaneous (SC) once monthly (QM) or every 2 weeks (Q2W; for participants on apheresis).

Interventions: intervention 1: evolocumab
Intervention descriptions: intervention 1: Administered by SC injection via autoinjector (AI)/pen

Protocol document:
Prot_000.pdf: 
Product:  Evolocumab 
Protocol Number:  20170199 
Date:  16 August 2017 
Page 1 of 70 
CONFIDENTIAL 
Title Page 
Protocol Title: 
A Multicenter, Open-label, Single-arm, Study to 
Evaluate Safety and Tolerability of Repatha in 
Patients with Homozygous Familial 
Hypercholesterolemia (HoFH) in India 
Short Protocol Title: 
An Open-label Study to Characterize Safety and 
Tolerability of Repatha in Homozygous Familial 
Hypercholesterolemia in India 
Protocol Number: 
20170199 
Investigational Product: 
Evolocumab 
Trade Name: 
Repatha 
Sponsor 
Name of Sponsor: 
Amgen Inc. 
Address: 
One Amgen Center Drive, Thousand Oaks, CA, 
91320, USA 
Telephone Number: 
+1 805-447-1000
Key 
Sponsor 
Contact 
Name: 
 
Address: 
One Amgen Center Drive, Thousand Oaks, CA, 
91320, USA 
Telephone Number: 
Email Address: 
 
EudraCT Number: 
Not Applicable 
NCT Number: 
Not Available 
Protocol Date: 
Document Version 
Date 
Original 
04 August 2017 
Superseding 
Version 1 
16 August 2017 
Version/Date: 
Data Element 
Standards Version 
Date 
5.0 
20 March 2015 
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IRUSXUSRVHVRISRVWLQJRQ&OLQLFDOWULDOVJRY


Product:  Evolocumab 
Protocol Number:  20170199 
Date:  16 August 2017 
Page 2 of 70 
CONFIDENTIAL 
 
 
 
Confidentiality Notice 
Investigator's Agreement: 
I have read the attached protocol entitled A Multicenter, Open-label, Single-arm, Study 
to Evaluate Safety and Tolerability of Repatha in Patients with Homozygous Familial 
Hypercholesterolemia (HoFH) in India, dated 16 August 2017, 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), Declaration of Helsinki, and applicable 
national or regional regulations/guidelines. 
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) 
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:  Amgen’s general number in the US,  
1-805-447-1000. 


Product:  Evolocumab 
Protocol Number:  20170199 
Date:  16 August 2017 
Page 3 of 70 
CONFIDENTIAL 
 
 
 
Table of Contents 
Table of Contents ..................................................................................................... 3 
1. 
Protocol Synopsis..................................................................................................... 7 
2. 
Study Schema and Schedule of Activities ................................................................ 9 
2.1 
Study Schema .............................................................................................. 9 
2.2 
Schedule of Activities ................................................................................. 10 
3. 
Introduction ............................................................................................................ 12 
3.1 
Study Rationale .......................................................................................... 12 
3.2 
Background ................................................................................................ 12 
3.2.1 
Disease ....................................................................................... 12 
3.2.2 
Amgen Investigational Product Background:  Repatha .............. 13 
4. 
Objectives, Endpoints, and Hypotheses ................................................................. 14 
4.1 
Objectives and Endpoints ........................................................................... 14 
4.2 
Hypotheses ................................................................................................. 14 
5. 
Study Design .......................................................................................................... 14 
5.1 
Overall Design ............................................................................................ 14 
5.2 
Number of Subjects .................................................................................... 15 
5.2.1 
Replacement of Subjects ............................................................ 15 
5.2.2 
Number of Sites .......................................................................... 15 
5.3 
End of Study ............................................................................................... 15 
5.3.1 
End of Study Definition ............................................................... 15 
5.3.2 
Study Duration for Subjects ........................................................ 16 
5.4 
Justification for Investigational Product Dose ............................................. 16 
5.5 
Patient Input on Study Design .................................................................... 16 
6. 
Study Population .................................................................................................... 16 
6.1 
Inclusion Criteria ......................................................................................... 17 
6.2 
Exclusion Criteria ........................................................................................ 17 
6.3 
Subject Enrollment ..................................................................................... 18 
6.4 
Screen Failures .......................................................................................... 18 
7. 
Treatments ............................................................................................................. 19 
7.1 
Treatment Procedures ................................................................................ 19 
7.1.1 
Investigational Products ............................................................. 19 
7.1.2 
Non-investigational Products ...................................................... 19 
7.1.3 
Medical Devices ......................................................................... 20 
7.1.4 
Other Protocol-required Therapies ............................................. 20 
7.1.5 
Other Treatment Procedures ...................................................... 20 
7.1.6 
Product Complaints .................................................................... 20 
7.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ................................................ 21


Product:  Evolocumab 
Protocol Number:  20170199 
Date:  16 August 2017 
Page 4 of 70 
CONFIDENTIAL 
 
 
 
7.2 
Method of Treatment Assignment .............................................................. 21 
7.3 
Blinding ....................................................................................................... 21 
7.4 
Dose Modification ....................................................................................... 21 
7.4.1 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ...................................... 22
7.4.1.1 
Amgen Investigational Product:  Repatha ................ 22 
7.4.2 
Hepatotoxicity Stopping and Rechallenge Rules ........................ 22 
7.5 
Preparation/Handling/Storage/Accountability ............................................. 22 
7.6 
Treatment Compliance ............................................................................... 22 
7.7 
Treatment of Overdose ............................................................................... 22 
7.8 
Prior and Concomitant Treatment .............................................................. 22 
8. 
Discontinuation Criteria .......................................................................................... 23 
8.1 
Discontinuation of Study Treatment ........................................................... 23 
8.2 
Discontinuation From the Study ................................................................. 24 
8.2.1 
Reasons for Removal From Washout, Run-in or 
Invasive Procedures ................................................................... 24
8.2.2 
Reasons for Removal From Study ............................................. 24 
8.3 
Lost to Follow-up ........................................................................................ 25 
9. 
Study Assessments and Procedures ..................................................................... 25 
9.1 
General Study Periods ............................................................................... 25 
9.1.1 
Screening, Enrollment and/or Randomization ............................ 25 
9.1.2 
Treatment Period ........................................................................ 26 
9.1.3 
End of Study ............................................................................... 26 
9.2 
Description of General Study Assessments and Procedures ..................... 26 
9.2.1 
General Assessments ................................................................ 26 
9.2.1.1 
Informed Consent .................................................... 26 
9.2.1.2 
Demographics .......................................................... 26 
9.2.1.3 
Medical History ........................................................ 26 
9.2.1.4 
Physical Examination ............................................... 27 
9.2.1.5 
Physical Measurements ........................................... 27 
9.2.1.6 
Dietary Advice .......................................................... 27 
9.2.1.7 
Tanner Staging (Sexual Maturity Ratings) ............... 27 
9.2.2 
Efficacy Assessments ................................................................. 27 
9.2.3 
Safety Assessments ................................................................... 27 
9.2.3.1 
Adverse Events ........................................................ 27 
9.2.3.2 
Vital Signs ................................................................ 31 
9.2.3.3 
Vital Status ............................................................... 31 
9.2.4 
Clinical Laboratory Assessments ............................................... 31 
9.2.4.1 
Pregnancy Testing ................................................... 32 
9.2.5 
Pharmacogenetic Assessments ................................................. 32 
10. 
Statistical Considerations ....................................................................................... 32 


Product:  Evolocumab 
Protocol Number:  20170199 
Date:  16 August 2017 
Page 5 of 70 
CONFIDENTIAL 
 
 
 
10.1 
Sample Size Determination ........................................................................ 32 
10.2 
Analysis Sets, Subgroups, and Covariates ................................................ 32 
10.2.1 
Analysis Sets .............................................................................. 32 
10.2.2 
Covariates .................................................................................. 32 
10.2.3 
Subgroups .................................................................................. 33 
10.2.4 
Handling of Missing and Incomplete Data .................................. 33 
10.3 
Adaptive Design ......................................................................................... 33 
10.4 
Statistical Analyses ..................................................................................... 33 
10.4.1 
Planned Analyses ....................................................................... 33 
10.4.2 
Methods of Analyses .................................................................. 33 
10.4.2.1 
General Considerations ........................................... 33 
10.4.2.2 
Efficacy Analyses ..................................................... 33 
10.4.2.3
Safety Analyses .......................................................34
11. 
References ............................................................................................................. 35 
12. 
Appendices ............................................................................................................ 36 
Appendix 1.  List of Abbreviations and Definitions of Terms .................................. 37 
Appendix 2.  Clinical Laboratory Tests ................................................................... 39 
Appendix 3.  Study Governance Considerations .................................................... 41 
Regulatory and Ethical Considerations ...................................................... 41 
Informed Consent Process ......................................................................... 41 
Data Protection/Subject Confidentiality ...................................................... 43 
Publication Policy ....................................................................................... 44 
Investigator Signatory Obligations .............................................................. 45 
Data Quality Assurance .............................................................................. 45 
Source Documents ..................................................................................... 47 
Study and Site Closure ............................................................................... 48 
Compensation ............................................................................................ 48 
Appendix 4.  Safety Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting .......................................................... 49
Definition of Disease-related Event ............................................................ 49 
Definition of Adverse Event ........................................................................ 49 
Definition of Serious Adverse Event ........................................................... 50 
Definition of Adverse Device Effect ............................................................ 51 
Recording Adverse Events, Disease-related Events (if 
applicable), and Serious Adverse Events ................................... 52
Evaluating Adverse Events and Serious Adverse Events .......................... 53 
Reporting of Serious Adverse Event .......................................................... 54 
Adverse Device Effects:  Recording, Evaluating, and Reporting ................ 54 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy and 
Lactation Information .................................................................................. 58
Definition of Females of Childbearing Potential .......................................... 58 
Collection of Pregnancy Information ........................................................... 59 


Product:  Evolocumab 
Protocol Number:  20170199 
Date:  16 August 2017 
Page 6 of 70 
CONFIDENTIAL 
 
 
 
Collection of Lactation Information ............................................................. 61 
Appendix 6.  Sample Storage and Destruction ...................................................... 64 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and 
Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ................................................................................................... 66
Criteria for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other 
Protocol-required Therapies Due to Potential 
Hepatotoxicity ............................................................................. 66
Criteria for Rechallenge of Amgen Investigational Product and 
Other Protocol-required Therapies After Potential 
Hepatotoxicity ............................................................................. 67
Drug-induced Liver Injury Reporting and Additional 
Assessments .............................................................................. 68
Appendix 8.  Tanner Stages (Sexual Maturity Ratings) ......................................... 70 
List of Tables 
Table 2-1.  Schedule of Activities .................................................................................... 10 
Table 7-1.  Study Treatments .......................................................................................... 19 
Table 12-1.  Analyte Listing ............................................................................................. 40 
Table 12-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................... 67
List of Figures 
Figure 2-1.  Study Schema ............................................................................................... 9 
Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Form .................. 55 
Figure 12-2.  Pregnancy and Lactation Notification Worksheet ...................................... 62 


Product:  Evolocumab 
Protocol Number:  20170199 
Date:  16 August 2017 
Page 7 of 70 
CONFIDENTIAL 
 
 
 
1. 
Protocol Synopsis 
Protocol Title:  A Multicenter, Open-label, Single-arm, Study to Evaluate Safety and 
Tolerability of Repatha in Patients with Homozygous Familial Hypercholesterolemia 
(HoFH) in India 
Short Protocol Title:  An Open-label Study to Characterize Safety and Tolerability of 
Repatha in Homozygous Familial Hypercholesterolemia in India 
Study Phase:  4 
Indication:  Homozygous Familial Hypercholesterolemia (HoFH) 
Rationale 
In March 2017, Repatha® (evolocumab) was approved in India as prescription 
medication in combination with other lipid-lowering therapies for adults and adolescents 
aged 12 years and over with HoFH.  This non-comparative, interventional phase 4 study 
is designed to fulfil the postmarketing requirement to assess safety and tolerability of 
Repatha in Indian HoFH subjects when administered under the locally approved label. 
Objective(s)/Endpoint(s) 
Objectives 
Endpoints 
Primary 
x 
To characterize the safety and 
tolerability in homozygous familial 
hypercholesterolemia HoFH patients 
in India exposed to 12 weeks of 
Repatha 
x 
The subject incidence of 
treatment-emergent adverse events 
Secondary 
x 
To characterize the efficacy of 
12 weeks of Repatha on low-density 
lipoprotein cholesterol (LDL-C), 
apolipoprotein B (ApoB) and 
lipoprotein(a) [Lp(a)] in HoFH patients 
in India 
x 
Percent change from baseline in 
LDL-C at week 12 
x 
Percent change from baseline in 
ApoB at week 12 
x 
Percent change from baseline in Lp(a) 
at week 12 
Hypotheses
This phase 4 study is descriptive in nature, describing safety and tolerability of Repatha 
in subjects with HoFH in India. 
Overall Design 
This open-label, multicenter, non-comparative phase 4 study of Repatha is part of 
Amgen’s postmarketing requirement to the Indian Regulatory Authority.  The study 
population consists of approximately 30 Indian subjects with HoFH and for whom 
Repatha is indicated in accordance with the approved prescribing information in India.   
The assignment of subjects to protocol treatment will be decided by the investigator 
according to inclusion/exclusion criteria and laboratory assessments at screening 
(including fasting lipids).  Subjects who are enrolled will be instructed to continue to 


Product:  Evolocumab 
Protocol Number:  20170199 
Date:  16 August 2017 
Page 8 of 70 
CONFIDENTIAL 
 
 
 
follow a diet limiting saturated fat to less than 7% of total daily calories and will be 
required to maintain their current lipid-lowering drug therapy throughout the duration of 
the trial. 
Number of Subjects 
Approximately 30 subjects with HoFH will be enrolled in the study. 
Summary of Subject Eligibility Criteria 
Key inclusion criteria include subjects 12 to 80 years of age with a clinical diagnosis of 
HoFH who are on a stable, low-fat diet, and taking pre-existing lipid-lowering therapies.  
Key exclusion criteria include use of mipomersen or lomitapide within 6 months of 
screening and has previously received evolocumab or any other proprotein convertase 
subtilisin/kexin type 9 (PCSK9)-inhibiting therapy. 
For a full list of eligibility criteria, please refer to Section 6.1 to Section 6.2. 
Treatments 
Subjects will receive Repatha 420 mg once monthly (QM) subcutaneous (SC) and study 
visits will occur approximately every 4 weeks (the week 4 study visit is optional:  subjects 
can either self-administer at home or visit study site and study staff will administer 
Repatha).  For subjects on apheresis, they may receive Repatha 420 mg SC every 
2 weeks to correspond with their apheresis schedule (the week 2 and week 6 study visits 
are optional:  subjects can either self-administer at home or visit study site and study 
staff will administer Repatha).  Final administration of Repatha will occur at week 8.  The 
end of study (EOS) visit and the last estimation of lipids will occur at week 12 for all 
subjects.  Subjects will be encouraged to complete all planned visits, study procedures, 
and measurements until the end of the study regardless of their adherence to Repatha 
administration.   
Procedures 
Informed consent must be obtained before starting any screening procedure.  The 
following procedures will occur per the Schedule of Activities:  physical examination, 
physical measurements, demographics, medical history, vital signs, dietary advice, 
adverse event assessment, concomitant therapies review, laboratory assessments, 
Tanner staging (for subjects < 18 years old only), and Repatha administration. 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 9.2 and the Schedule of Activities in Table 2-1 . 
Statistical Considerations 
Approximately 30 subjects with HoFH will be enrolled in this study.  The primary analysis 
set is the full analysis set (FAS), which includes all enrolled subjects who have received 
at least 1 dose of Repatha.  Unless specified otherwise, the FAS will be the default 
analysis set in this study. 
The final analysis will be performed at the end of the study (defined as when the last 
subject enrolled has completed the safety follow-up/EOS visit). 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor Name:  Amgen Inc. 


Product:  Evolocumab 
Protocol Number:  20170199 
Date:  16 August 2017 
Page 9 of 70 
CONFIDENTIAL 
 
 
 
2. 
Study Schema and Schedule of Activities 
2.1 
Study Schema 
Figure 2-1.  Study Schema 
Repatha
420 mg SC QM
Screening (up to 4 weeks)
Enrollment N = 30
Safety follow-up/EOS
Week 1 
(Day 1)
Treatment Period
IP = investigational product; QM = once monthly; SC = subcutaneous
a For subjects on apheresis only.
Follow-up Period
Week 12
(4 weeks post 
last dose of IP)
Week 8
Week 4
End of Study Visit
Week 2a
Week 6a
 


Product:  Evolocumab 
Protocol Number:  20170199 
Date:  16 August 2017 
Page 10 of 70 
CONFIDENTIAL 
 
 
 
2.2 
Schedule of Activities 
Table 2-1.  Schedule of Activities 
Procedure 
Screening  
(up to 4 weeks 
before day 1) 
Treatment Period 
Follow-up 
Notes 
W1 
(day 1) W2a 
W4b 
W6a 
W8 
W12c 
General and Safety Assessments 
Informed consent 
X 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
Includes specific eCRFs for lactation status and 
HoFH clinical criteria 
Demographics 
X 
 
 
 
 
 
 
Physical examination  
X 
X 
 
 
 
 
X 
 
Physical measurements:  weight 
X 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
Vital signs (BP, HR) 
X 
X 
 
 
 
X 
X 
 
Dietary advice 
X 
 
 
 
 
 
 
AE/SAE/ADE/DRE 
X 
X 
Xd 
Xd 
Xd 
X 
X 
 
Concomitant therapies review 
X 
X 
Xd 
Xd 
Xd 
X 
X 
 
Tanner staginge 
X 
 
 
 
 
X 
 
Laboratory Assessmentsf 
Urine and/or serum pregnancy 
test (females of childbearing 
potential only) 
X 
 
 
 
 
X 
Additional on-treatment pregnancy testing may be 
performed at the investigator’s discretion if there 
is suspicion that a female subject is pregnant or 
per local laws and regulations. 
Page 1 of 2 
Abbreviations and footnotes defined on last page of table. 


Product:  Evolocumab 
Protocol Number:  20170199 
Date:  16 August 2017 
Page 11 of 70 
CONFIDENTIAL 
 
 
 
Table 2-1.  Schedule of Activities 
Procedure 
Screening  
(up to 4 weeks 
before day 1) 
Treatment Period 
Follow-up 
Notes 
W1 
(day 1) W2a 
W4b 
W6a 
W8 
W12c 
Laboratory Assessmentsf (continued) 
Hematology 
X 
 
 
 
 
 
 
 
Chemistry 
X 
 
 
 
 
 
 
 
Fasting lipids, ApoA1, ApoB 
X 
X 
 
 
 
X 
X 
 
Lp(a) 
X 
X 
 
 
 
X 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
Pharmacogenetics samples 
(optional) 
 
X 
 
 
 
 
 
 
Study Treatment 
Amgen investigational product 
 
X 
Xa 
X 
Xa 
X 
 
Administration at weeks 2 and 6 are for subjects 
on apheresis only. 
Page 2 of 2 
ADE = adverse device effect; AE = adverse event; Apo = apolipoprotein; BP = blood pressure; DRE = disease-related events; eCRF = electronic case report form; 
EOS = end of study; FCBP = female of childbearing potential; HoFH = homozygous familial hypercholesterolemia; HR = heart rate; Lp(a) = lipoprotein (a); 
SAE = serious adverse event; W = Week 
a Subjects on apheresis only:  may initiate treatment with 420 mg every 2 weeks to correspond with their apheresis schedule.  On weeks 2 and 6, subjects can 
self-administer Repatha at home, no site visit required.  However, if the subject prefers, they can visit study site and study staff will administer Repatha. 
b For all subjects:  on week 4, subjects can self-administer Repatha at home, no site visit required.  However, if the subject prefers, they can visit study site and study 
staff will administer Repatha. 
c The EOS visit will occur at week 12 (4 weeks after last dose of Repatha). 
d Will call if subject chooses to administer Repatha at home. 
e In pediatric subjects 12 to 17 years of age (includes the year after the subject completes the 17th year after birth but not the day of completing the 18th year after 
birth). 
f Subjects will fast for 9 hours and abstain from strenuous exercise for 72 hours before each blood collection for clinical laboratory tests. 


Product:  Evolocumab 
Protocol Number:  20170199 
Date:  16 August 2017 
Page 12 of 70 
CONFIDENTIAL 
 
 
 
3. 
Introduction 
3.1 
Study Rationale 
In March 2017, Repatha£ (evolocumab) was approved in India as prescription 
medication in combination with other lipid-lowering therapies for adults and adolescents 
aged 12 years and over with homozygous familial hypercholesterolemia (HoFH).  This 
non-comparative, interventional phase 4 study is designed to fulfil the postmarketing 
requirement to assess safety and tolerability of Repatha in Indian HoFH subjects when 
administered under the locally approved label. 
3.2 
Background 
3.2.1 
Disease 
Homozygous familial (most commonly referred to as HoFH) is a rare genetic disorder 
occurring in approximately 1:1 000 000 individuals.  Many of these represent compound 
heterozygotes possessing different mutations on each of the low-density lipoprotein 
receptor (LDLR) alleles (Goldstein et al, 2001).  The geographical prevalence and 
characterization of the specific LDLR mutations among homozygous patients though 
often well known in western population; is not so well characterized in India.  The 
incidence of major cardiovascular illness among homozygous individuals is higher than 
that of affected familial hypercholesterolemia heterozygotes, with events such as 
myocardial infarction happening by the second decade of life (Goldstein et al, 2001).  
Due to the rapid and aggressive nature of atherosclerosis in HoFH, it is commonly 
studied and treated as a disease beginning in childhood and manifesting with untoward 
morbidity and mortality in affected adults.  This also applies to other, even more rare 
genetic causes of dyslipidemia that fall under the umbrella diagnosis of familial 
hypercholesterolemia.  These conditions include mutations in proprotein convertase 
subtilisin/kexin type 9 (PCSK9; dominant-gain of function), apolipoprotein B (ApoB; 
dominant-loss of function) and autonomic recessive hypercholesterolemia (ARF; 
recessive-loss of function).  High-dose statin therapy has reduced both low-density 
lipoprotein cholesterol (LDL-C) (in the range of 10% to 25%) as well as cardiovascular 
event rates among patients with HoFH (Neil et al, 2008; Raal et al, 1997).  However, the 
response to therapy has been limited in part by the biology underlying this disease, and 
possibly by the concomitant elevation of PCSK9 levels that result from statin treatment 
(Lakoski et al, 2009).  In addition to maximal medical therapy, some patients have been 
placed on a biweekly to weekly schedule of lipid apheresis, a process similar to 
hemodialysis where LDL-C is physically removed from their circulation.  Though a 


Product:  Evolocumab 
Protocol Number:  20170199 
Date:  16 August 2017 
Page 13 of 70 
CONFIDENTIAL 
 
 
 
helpful tool in the treatment of HoFH, this invasive procedure is cumbersome, expensive, 
and not readily available in India. 
HoFH LDL receptor mutation results in impaired LDL receptor function and impaired 
LDL-C clearance.  The response variability is based on LDL receptor functionality 
according to the genetic defect associated with the LDL receptor activities even between 
subjects confirmed as HoFH.  Therapies supporting LDL-C clearance through LDL-C 
receptor function, like Repatha, can be expected to further reduce LDL-C with existing 
pharmacologic therapies.  Repatha in addition to lipid-lowering therapies in HoFH 
subjects, shown to have a safety profile response and being effective and well-tolerated 
(Raal et al, 2014). 
3.2.2 
Amgen Investigational Product Background:  Repatha 
Repatha (evolocumab) is a full human monoclonal IgG2 directed against human PCSK9.  
Repatha binds to PCSK9 and inhibits circulating PCSK9 from binding to the LDLR, 
preventing PCSK9-mediated LDLR degradation and permitting LDLR to recycle back to 
the liver cell surface.  By inhibiting the binding of PCSK9 to LDLR, Repatha increases 
the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C 
levels.  Following single subcutaneous (SC) administration of 140 mg or 420 mg of 
Repatha, maximum suppression of circulating unbound PCSK9 occurred by 4 hours.  
Unbound PCSK9 concentrations returned toward baseline when Repatha concentrations 
decreased below the limit of quantitation.  Repatha has been found to be effective in 
reducing LDL-C levels in patients with HoFH in the TESLA study.  This study was a 
multicenter, double-blind, randomized, placebo-controlled, 12-week trial in 49 patients 
with HoFH.  In this trial, 33 patients received SC injections of 420 mg of Repatha once 
monthly (QM) and 16 patients received placebo as an adjunct to other lipid-lowering 
therapies (eg, statins, ezetimibe).  The mean age at baseline was 31 years, 49% were 
women, 90% White, 4% were Asian, and 6% other.  The trial included 10 adolescents 
(ages 13 to 17 years), 7 of whom received Repatha.  The mean LDL-C at baseline was 
349 mg/dL with all patients on statins (atorvastatin or rosuvastatin) and 92% on 
ezetimibe.  In these patients with HoFH, the difference between Repatha and placebo in 
mean percent change in LDL-C from baseline to week 12 was -31% (95% CI:  -44%,  
-18%; p < 0.0001) (Raal et al, 2014). 
A detailed description of the chemistry, pharmacology, efficacy, and safety of Repatha is 
provided in the Investigator’s Brochure. 


Product:  Evolocumab 
Protocol Number:  20170199 
Date:  16 August 2017 
Page 14 of 70 
CONFIDENTIAL 
 
 
 
4. 
Objectives, Endpoints, and Hypotheses 
4.1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
x 
To characterize the safety and 
tolerability in homozygous familial 
hypercholesterolemia HoFH patients 
in India exposed to 12 weeks of 
Repatha. 
x 
The subject incidence of treatment-
emergent adverse events 
Secondary 
x 
To characterize the efficacy of 
12 weeks of Repatha on low-density 
lipoprotein cholesterol (LDL-C), 
apolipoprotein B (ApoB) and 
lipoprotein(a) [Lp(a)] in HoFH patients 
in India 
x 
Percent change from baseline in 
LDL-C at week 12 
x 
Percent change from baseline in 
ApoB at week 12 
x 
Percent change from baseline in Lp(a) 
at week 12 
4.2 
Hypotheses 
This phase 4 study is descriptive in nature, describing safety and tolerability of Repatha 
in subjects with HoFH in India. 
5. 
Study Design 
5.1 
Overall Design 
This open-label, multicenter, non-comparative phase 4 study of Repatha is part of 
Amgen’s post-marketing requirement to the Indian Regulatory Authority.  The study 
population consists of approximately 30 Indian subjects with HoFH and for whom 
Repatha is indicated in accordance with the approved prescribing information in India.   
The assignment of subjects to protocol treatment will be decided by the investigator 
according to inclusion/exclusion criteria and laboratory assessments at screening 
(including fasting lipids).  Subjects who are enrolled will be instructed to continue to 
follow a diet limiting saturated fat to less than 7% of total daily calories (Iyengar et al, 
2016) and will be required to maintain their current lipid-lowering drug therapy 
throughout the duration of the trial.  Subjects will receive Repatha 420 mg QM SC and 
study visits will occur approximately every 4 weeks (the week 4 study visit is optional:  
subjects can either self-administer at home or visit study site and study staff will 
administer Repatha).  For subjects on apheresis, they may receive Repatha 420 mg SC 
every 2 weeks to correspond with their apheresis schedule (the week 2 and week 6 


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study visits are optional:  subjects can either self-administer at home or visit study site 
and study staff will administer Repatha).  If the subject chooses to self-administer 
Repatha at home during the optional site visits, the staff will call the subject to collect 
any adverse events or changes in concomitant medication.  Final administration of 
Repatha (for all subjects) will occur at week 8.  The end of study (EOS) visit and the last 
estimation of lipids will occur at week 12 for all subjects.  The following procedures will 
occur per the Schedule of Activities:  physical examination, physical measurements, 
demographics, medical history, vital signs, dietary advice, adverse event assessment, 
concomitant therapies review, laboratory assessments, Tanner staging (for 
subjects < 18 years old only), and Repatha administration (see Table 2-1).  Subjects will 
be encouraged to complete all planned visits, study procedures, and measurements until 
the end of the study regardless of their adherence to Repatha administration.   
The overall study design is described by a study schema in Section 2.1.  The endpoints 
are defined in Section 4.1. 
5.2 
Number of Subjects 
Approximately 30 subjects with HoFH will be enrolled in the study. 
Subjects in this clinical investigation shall be referred to as “subjects”.  For the sample 
size justification, see Section 10.1. 
5.2.1 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
5.2.2 
Number of Sites 
Approximately 15 investigative sites in India will be included in the study.  Sites that do 
not enroll subjects within 3 months of site initiation may be closed.  
5.3 
End of Study 
5.3.1 
End of Study Definition 
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), for the purposes of conducting the primary analysis, whether the 
study concluded as planned in the protocol or was terminated early. 
The primary completion date is the date when the last subject has completed the 
assessments for week 12. 
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 


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when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study:  The EOS date is defined as the date when the last subject across all 
sites is assessed or receives an intervention for evaluation in the study (ie, last subject 
last visit), following any additional parts in the study (eg, safety follow-up), as applicable. 
5.3.2 
Study Duration for Subjects 
After signing the informed consent, the subject should be enrolled within 4 weeks.  
Including the screening period, the investigational product administration dates 
(weeks 1, 4, and 8 [and weeks 2 and 6 for subjects on apheresis]), and an EOS visit that 
occurs at week 12 (4 weeks after last dose of investigational product), the total duration 
of study participation for a subject will be up to approximately 16 weeks. 
5.4 
Justification for Investigational Product Dose 
The Repatha dose being used in this study is in accordance with the terms of its 
marketing authorization in India.  The dose for this study is 420 mg given QM SC for 
8 weeks.  For subjects on apheresis, they may initiate treatment with 420 mg SC every 
2 weeks to correspond with their apheresis schedule. 
Repatha will be administered at 140 mg in 1.0 mL (3 administrations by prefilled 
autoinjector/pen [AI/pen]) for a total of 3.0 mL (420 mg evolocumab) administered.  The 
SC injections should be administered in a consecutive fashion with all injections 
completed within 30 minutes. 
5.5 
Patient Input on Study Design 
Not applicable. 
6. 
Study Population 
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/Web 
Response System (IxRS). 
Eligibility criteria will be evaluated during screening. 
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Appendix 3). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be provided. 


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6.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
101 
If the subject is t 18 years of age, the subject has provided informed consent 
prior to initiation of any study specific activities/procedures.  If the subject is 
< 18 years of age, the subject’s legally acceptable representative has provided 
informed consent 
102 
Male or female t 12 to d 80 years of age at the time of signing the informed 
consent 
103 
Clinical diagnosis of HoFH based on a history of an untreated LDL-C 
concentration greater than 500 mg/dL (13 mmol/L) together with either xanthoma 
before 10 years of age or evidence of familial hypercholesterolemia in both 
parents 
104 
On a stable, low-fat diet and taking pre-existing lipid-lowering therapies (such as 
statins, cholesterol-absorption inhibitors, bile-acid sequestrants or nicotinic acid, 
or combinations thereof) with no plan to change medication or dosage within 
4 weeks of screening and during the time frame of the trial, with fasting central 
laboratory LDL-C concentration > 130 mg/dL (3.4 mmol/L) at screening 
105 
Fasting triglycerides d 400 mg/dL (4.5 mmol/L) by central laboratory at screening 
6.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply. 
201 
Use of mipomersen or lomitapide within 6 months of screening. 
202 
Known active infection or major hematologic, renal, metabolic, gastrointestinal, 
hepatic, or endocrine dysfunction. 
203 
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(ies).  Other investigational procedures while participating in this study 
are excluded. 
204 
Female subject is pregnant or breastfeeding or planning to become pregnant or 
breastfeed during treatment and for an additional 15 weeks after the last dose of 
Repatha.  (Females of childbearing potential should only be included in the study 
after a confirmed menstrual period and a negative highly sensitive urine or serum 
pregnancy test). 
205 
Female subjects of childbearing potential unwilling to use an acceptable method 
of effective contraception during treatment and for an additional 15 weeks after 
the last dose of Repatha.  Refer to Appendix 5 for additional contraceptive 
information. 
206 
Subject has known sensitivity to any of the products to be administered during 
dosing. 
207 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures or completion. 


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208 
Subject has previously received evolocumab or any other PCSK9-inhibiting 
therapy. 
6.3 
Subject Enrollment 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form, and all other 
subject information and/or recruitment material, if applicable (see Appendix 3). 
The subject or the subject’s legally acceptable representative must personally sign and 
date the IRB/IEC and Amgen approved informed consent before commencement of 
study-specific procedures. 
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 electronic case report form (eCRF). 
Each subject who enters into the screening period for the study (up to 4 weeks before 
enrollment) receives a unique subject identification number before any study-related 
activities/procedures are performed.  The subject identification number will be assigned 
IxRS.  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. 
6.4 
Screen Failures 
Subjects t 18 years of age who are considered for entry into the study and have the 
risks and benefits of participating in the study explained will enter screening by signing 
and dating the informed consent form for this study.  If the subject is < 18 years of age, 
the subject’s legally acceptable representative has to provide informed consent.  
Screening should be completed and the subject randomized or screen failed within 
4 weeks of signing the informed consent. 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
criteria, medical history, prior therapies, and any serious adverse events. 


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Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened. 
7. 
Treatments 
Study treatment is defined as any investigational product(s) or medical device(s) 
intended to be administered to a study subject according to the study protocol. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of each treatment shown in Table 7-1 below. 
7.1 
Treatment Procedures 
7.1.1 
Investigational Products 
Table 7-1.  Study Treatments 
Study Treatment Name 
Amgen Investigational Product:a 
Repatha 
Dosage Formulation 
Repatha will be presented as a sterile, preservative-free 
solution in a single-use, disposable, handheld mechanical 
(spring-based) prefilled AI/pen for fixed dose, SC 
injection.  The prefilled AI/pen contains a 1-mL deliverable 
volume of 140 mg/mL evolocumab. 
Unit Dose Strength(s)/ 
Dosage Level(s) and Dosage 
Frequency 
140 mg/mL 
420 mg QM 
(subjects on apheresis:  420 mg Q2W) 
Route of Administration 
SC 
Accountability 
The amount dispensed, amount returned, date dispensed, 
date returned, package lot number of Repatha is to be 
recorded on each subject's eCRF(s). 
Dosing Instructions 
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).  If IP is administered on site, it must 
be performed after all scheduled assessments.  After IP 
administration at the first dosing visit, subjects will remain 
at site for observation for at least 30 minutes before being 
discharged. 
Device 
AI/pen
AI/Pen = autoinjector/pen; eCRF = electronic case report form; IP = investigational product; 
QM = once monthly; Q2W = every 2 weeks; SC = subcutaneous 
a Repatha will be manufactured and packaged by Amgen and distributed using Amgen clinical 
study drug distribution procedures. 
7.1.2 
Non-investigational Products 
There are no non-Amgen non-investigational products used in this study. 


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7.1.3 
Medical Devices 
The investigational medical device(s) provided by Amgen for use in this study are 
prefilled AI/pens (Table 7-1). 
The Repatha AI/pen is a single-use, disposable, handheld mechanical “spring-based” 
device for fixed dose SC injection of 140 mg/mL of Repatha with a 1-mL deliverable 
volume. 
Additional details are in the IPIM. 
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard care. 
Non-investigational medical devices (eg, syringes, sterile needles), 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. 
7.1.4 
Other Protocol-required Therapies 
All lipid-lowering drugs (statins, fibrates and ezetimibe, bile-acid sequestering resin, 
omega 3 fatty acids or niacin) 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).  All such therapy needs to be unchanged during 
the entire time of screening and study participation unless a change is clinically 
necessary.  
7.1.5 
Other Treatment Procedures 
There are no other treatment procedures required by this study. 
7.1.6 
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), device(s), or combination product(s) provisioned and/or 
repackaged/modified by Amgen.  Drug(s) or device(s) includes investigational product.   
x 
Repatha 
x 
AI/pen 


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Any product complaint(s) associated with an investigational product(s), 
non-investigational product(s), device(s), or combination product(s) supplied by Amgen 
are to be reported according to the instructions provided in the IPIM. 
7.1.7 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
The following treatments are not permitted during the study, including screening: 
x 
treatments for inhibition of PCSK9 or any investigational therapies other than study 
provided investigational product 
x 
mipomersen or lomitapide 
x 
other drugs (besides those mentioned above) that significantly affect lipid 
metabolism (eg, systemic cyclosporine, systemic steroids [intravenous, 
intramuscular, or oral; Note:  hormone replacement therapy is permitted], vitamin A 
x 
all lipid therapies not taken at the time of screening and enrollment. 
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 
cytochrome P450 3A (CYP3A) (eg, itraconazole, ketoconazole, and other antifungal 
azoles), macrolide antibiotics (erythromycin, clarithromycin) and the ketolide antibiotic 
(telithromycin), human immunodeficiency virus (HIV) or hepatitis C virus (HCV) protease 
inhibitors, antidepressant nefazodone and grapefruit juice in large quantities (> 1 quart 
daily [approximately 1 L]) should not be used during the study.  
7.2 
Method of Treatment Assignment 
Subjects who meet eligibility criteria will be assigned to treatment with investigational 
product. 
The treatment assignment date is to be documented in the subject’s medical record and 
on the enrollment eCRF. 
7.3 
Blinding 
This is an open-label study; blinding procedures are not applicable. 
7.4 
Dose Modification 
There will be no dose adjustments in this study.  If, in the opinion of the investigator, a 
subject is unable to tolerate the dose, that subject will discontinue Repatha but will 
continue to return for all other study procedures and measurements until the end of the 
study. 


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7.4.1 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
7.4.1.1 
Amgen Investigational Product:  Repatha 
The decision to rechallenge the subject after therapy changes should be discussed and 
agreed unanimously by the subject, investigator, and Amgen.  If signs or symptoms 
recur with rechallenge of Repatha, then Repatha should be permanently discontinued. 
The reason for dose stopping and rechallenge of Repatha is to be recorded on each 
subject’s eCRF. 
7.4.2 
Hepatotoxicity Stopping and Rechallenge Rules 
Refer to Appendix 7 for details regarding drug-induced liver injury (DILI) guidelines, as 
specified in the Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation, July 2009. 
7.5 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product and/or device during the study are provided in the 
IPIM. 
7.6 
Treatment Compliance 
Administration of Repatha will occur at the study site at week 1 (day 1), week 4 (option 
to self-administer at home or at site), and week 8.  For subjects on apheresis, they may 
also receive Repatha on week 2 and week 6 to correspond with their apheresis schedule 
(option to administer at home or at site).  Non-compliance is to be documented in the 
medical file and will be reflected in the eCRF.  Non-compliant subjects are to be 
re-educated on the importance of adhering to the study drug administration schedule 
and reminded that repeated cycles of non-compliance could be a reason for 
discontinuation of study treatment. 
7.7 
Treatment of Overdose 
The effects of overdose of this product are not known. 
7.8 
Prior and Concomitant Treatment 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 7.1.7. 
Concomitant therapies are to be collected from informed consent through the EOS study 
visit. 


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For concomitant therapies, collect therapy name, indication, dose, unit, frequency, route, 
start date, and stop date.  
All details for lipid regulating treatment will be collected on the appropriate eCRF. 
8. 
Discontinuation Criteria 
Subjects have the right to withdraw from investigational product and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
and for any reason without prejudice to their future medical care by the physician or at 
the institution. 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, device, and/or other protocol-required therapies, protocol procedures, or the 
study as a whole at any time prior to study completion for the reasons listed in 
Sections 8.1, 8.2.1, and 8.2.2. 
8.1 
Discontinuation of Study Treatment 
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 possibilities for continuation of the Schedule of Activities (see Table 2-1) 
including different options of follow-up (eg, in person, by phone/mail, through 
family/friends, in correspondence/communication with other treating physicians, from the 
review of medical records) and collection of data, including endpoints, adverse events, 
and must document this decision in the subject’s medical records.  Subjects who have 
discontinued investigational product and/or other protocol-required therapies or 
procedures should not be automatically removed from the study.  Whenever safe and 
feasible, it is imperative that subjects remain on-study to ensure safety surveillance 
and/or collection of outcome data. 
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 Appendix 3. 


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Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
x 
decision by sponsor 
x 
lost to follow-up 
x 
death 
x 
ineligibility determined 
x 
protocol deviation 
x 
non-compliance  
x 
adverse event 
x 
subject request 
x 
pregnancy 
8.2 
Discontinuation From the Study 
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, and must document the 
subject’s decision to withdraw in the subject’s medical records.   
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly (see 
Appendix 6 for further details).  Refer to the Schedule of Activities (Table 2-1) for data to 
be collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
8.2.1 
Reasons for Removal From Washout, Run-in or Invasive Procedures 
Not applicable. 
8.2.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
x 
decision by sponsor 
x 
withdrawal of consent from study 
x 
death 
x 
lost to follow-up 


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8.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
x 
The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or is able to 
continue in the study. 
x 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where possible, 
3 telephone calls and, if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods).  These contact attempts are to be 
documented in the subject’s medical record. 
x 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
x 
For subjects who are lost to follow-up, 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. 
9. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Table 2-1).  
As protocol waivers or exemptions are not allowed if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the subject is to continue or 
discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
9.1 
General Study Periods 
9.1.1 
Screening, Enrollment and/or Randomization 
Informed consent must be obtained before starting any screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  After the subject or legal 
representative has signed the informed consent form, the site will register the subject in 
the IxRS and screen the subject in order to assess eligibility for participation.  The 
screening window is up to 4 weeks. 


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All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
If a subject has not met all eligibility criteria at the end of the screening period, the 
subject will be registered as a screen fail.  Screen fail subjects may be eligible for 
re-screening. 
9.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (Table 2-1).  On-study visits may be 
completed within ± 7 days.  The date of the first dose of investigational product is 
defined as day 1 (week 1).  All subsequent doses and study visits will be scheduled 
based on the day 1 date.  Administration of protocol-required therapies is to be 
administered last during each visit that it is required. 
9.1.3 
End of Study 
Upon permanent discontinuation from the study for any reason, the EOS visit will be 
performed 4 weeks (± 2 days) after the last dose of investigational product. 
9.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
time points. 
9.2.1 
General Assessments  
9.2.1.1 
Informed Consent 
All subjects or their legally authorized representative must sign and personally date the 
IRB/IEC approved informed consent before any study-specific procedures are 
performed. 
9.2.1.2 
Demographics 
Demographic data collection including sex and age will be collected in order to study 
their possible association with subject safety and treatment effectiveness.   
9.2.1.3 
Medical History 
The investigator or designee will collect a complete medical and surgical history that 
started prior to enrollment through signing of the informed consent form.  Medical history 
will include information on the subject's concurrent medical conditions, including cardiac 
risk factors and congestive heart failure details.  The current severity will be collected for 


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each condition that has not resolved.  Record all findings on the appropriate medical 
history eCRF. 
In addition to the medical history above, HoFH by clinical diagnosis must date back to 
the original diagnosis. 
9.2.1.4 
Physical Examination  
Physical examination will be performed as per standard of care.  Physical examination 
findings should be recorded on the appropriate eCRF (eg, medical history, event). 
9.2.1.5 
Physical Measurements 
Weight (in kilograms) should be measured without shoes. 
9.2.1.6 
Dietary Advice 
Subjects who are enrolled will be instructed to continue to follow a diet limiting saturated 
fat to less than 7% of total daily calories (Iyengar et al, 2016). 
9.2.1.7 
Tanner Staging (Sexual Maturity Ratings) 
Tanner staging is widely used to assess adolescents’ physical development during 
puberty in 5 stages (up to 18 years of age).  Also known as Sexual Maturity Ratings, 
Tanner stages are a way of assessing the degree of maturation of secondary sexual 
characteristics (see Appendix 8 for guidance).  The developmental stages of the 
adolescent’s sexual characteristics will be rated and recorded separately on appropriate 
eCRF (ie, one stage for pubic hair and one for breasts in females, one stage for pubic 
hair and one for genitals in males), because these characteristics may differ in their 
degree of maturity. 
9.2.2 
Efficacy Assessments 
Efficacy will be determined as percent change from baseline in LDL-C, ApoB, and Lp(a) 
at week 12 (collected as indicated in Table 12-1). 
9.2.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities. 
9.2.3.1 
Adverse Events 
9.2.3.1.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
9.2.3.1.1.1 
Disease-related Events 
Disease-related events are defined in Appendix 4. 


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The investigator is responsible for ensuring that all disease-related events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through the EOS visit are reported using the Event eCRF.   
Disease-related events assessed by the investigator to be more severe than expected 
and/or related to the investigational product and determined to be serious, must be 
reported on the Event eCRF as serious adverse events. 
Disease-related events pre-defined for this study include:  manifestations and 
complications of atherosclerotic vascular disease such as coronary artery disease, 
angina, myocardial infarction, ischemic stroke, transient ischemic attack, carotid artery 
disease, peripheral vascular disease (including complications such as claudication), and 
testing suggesting progression of atherosclerotic vascular disease. 
9.2.3.1.1.2 
Adverse Events 
The adverse event grading scale to be used for this study will be the Common 
Terminology Criteria for Adverse Events (CTCAE) and is described in Appendix 4. 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after signing of the informed consent 
through the EOS visit are reported using the Event eCRF. 
9.2.3.1.1.3 
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 EOS visit are reported using the Event eCRF. 
All serious adverse events will be collected, recorded, and reported to the sponsor or 
designee within 24 hours, as indicated in Appendix 4.  The investigator will submit any 
updated serious adverse event data to the sponsor within 24 hours of it being available. 
The criteria for grade 4 in the CTCAE grading scale differs from the regulatory criteria for 
serious adverse events.  It is left to the investigator’s judgment to report these grade 4 
abnormalities as serious adverse events. 
9.2.3.1.1.4 
Serious Adverse Events After the Protocol-required Reporting 
Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after EOS.  However, these serious adverse 
events can be reported to Amgen.  Per local requirements in some countries, 
investigators are required to report serious adverse events that they become aware of 


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after EOS.  If serious adverse events are reported, the investigator is to report them to 
Amgen within 24 hours following the investigator’s knowledge of the event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases and handled accordingly based 
on relationship to investigational product.  
The method of recording, evaluating, and assessing causality of adverse events, 
adverse device effects, disease-related events, and serious adverse events and the 
procedures for completing and transmitting serious adverse event reports are provided 
in Appendix 4. 
9.2.3.1.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the subject is the 
preferred method to inquire about adverse event occurrence. 
9.2.3.1.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is required to 
proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 8.3).  
Further information on follow-up procedures is given in Appendix 4. 
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Event eCRF.
9.2.3.1.4 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met.  


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The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy and forwarded 
to investigators as necessary. 
An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB/IEC, if appropriate according to local requirements. 
9.2.3.1.5 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects and, if indicated, female 
partners of male subjects will be collected after the start of study treatment and until 
4 weeks after the last dose of investigational product. 
If a pregnancy is reported, the investigator is to inform Amgen within 24 hours of learning 
of the pregnancy and/or lactation and is to follow the procedures outlined in Appendix 5.  
Amgen Global Patient Safety will follow-up with the investigator regarding additional 
information that may be requested. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events. 
Further details regarding pregnancy and lactation are provided in Appendix 5. 
9.2.3.1.6 
Adverse Device Effects 
In order to fulfill regulatory reporting obligations worldwide, the investigator is 
responsible for the detection and documentation of any adverse device effects that occur 
during the study with such devices.  
An adverse device effect is any adverse event related to the use of a combination 
product or medical device.  Adverse device effects include adverse events resulting from 
insufficient or inadequate instructions for use, adverse events resulting from any 
malfunction of the device, or adverse events resulting from use error or from intentional 
misuse of the device. 


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All adverse device effects are to be reported as adverse events following the same 
reporting periods and procedures. 
Product complaints are described in Section 7.1.6. 
Further details regarding adverse device effects can be found in Appendix 4. 
9.2.3.2 
Vital Signs 
The following measurements must be performed:  systolic/diastolic blood pressure, and 
heart rate.  Subject must be in a supine position in a rested and calm state for at least 
5 minutes before blood pressure assessments are conducted.  If the subject is unable to 
be in the supine position, the subject should be in most recumbent position as possible.  
The position selected for a subject should be the same that is used throughout the study 
and documented on the vital sign eCRF.  Record all measurements on the vital signs 
eCRF. 
9.2.3.3 
Vital Status 
Vital status must be obtained for all subjects within the limits of local law.  This includes 
subjects who may have discontinued study visits with or without withdrawing consent 
and should include interrogation of public databases, if necessary.  If deceased, the date 
and reported cause of death should be obtained. 
9.2.4 
Clinical Laboratory Assessments 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities for the timing and frequency.  
The investigator is responsible for reviewing laboratory test results and recording any 
clinically relevant changes occurring during the study in the Event eCRF.  The 
investigator must determine 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. 
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities.  


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9.2.4.1 
Pregnancy Testing 
A high sensitive (urine or serum) pregnancy test should be completed at screening for 
females of childbearing potential.   
Note:  Females who have undergone a bilateral tubal ligation/occlusion should have 
pregnancy testing per protocol requirements.  (If a female subject, or the partner of a 
male subject, becomes pregnant it must be reported on the Pregnancy Notification 
Worksheet, see Figure 12-2).  Refer to Appendix 5 for contraceptive requirements.  
A pregnancy test should be performed at week 12/EOS after discontinuing protocol-
required therapies. 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 
9.2.5 
Pharmacogenetic Assessments 
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed.  These optional pharmacogenetic analyses focus on 
inherited genetic variations (such as those of the PCSK9 gene or the LDLR gene) to 
evaluate their possible correlation to the disease and/or responsiveness to the therapies 
used in this study.  The goals of the optional studies include the use of genetic markers 
to help in the investigation of cardiovascular disease and/or to identify subjects who may 
have positive or negative response to Repatha.  No additional samples are collected for 
this part of the study.  For subjects who consent to this/these analysis/analyses, DNA 
may be extracted. 
The final disposition of samples will be described in Appendix 6. 
10. 
Statistical Considerations 
10.1 
Sample Size Determination 
Approximately 30 subjects with HoFH will be enrolled in this study. 
10.2 
Analysis Sets, Subgroups, and Covariates 
10.2.1 
Analysis Sets 
The primary analysis set is the full analysis set (FAS), which includes all enrolled 
subjects who have received at least 1 dose of Repatha.  Unless specified otherwise, the 
FAS will be the default analysis set in this study. 
10.2.2 
Covariates 
No covariates will be used in this study. 


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10.2.3 
Subgroups 
No subgroups will be used in this study. 
10.2.4 
Handling of Missing and Incomplete Data 
Incomplete adverse event start dates and concomitant medications start or stop dates 
will be imputed and the detailed rules will be specified in statistical analysis plan. 
No imputation will be done for the secondary endpoints. 
10.3 
Adaptive Design 
Not applicable. 
10.4 
Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock.  Below 
is a summary of the timing and methods for the planned statistical analyses.  To 
preserve study integrity, the final analysis will be conducted and reported following the 
EOS, as defined in Section 5.3.1. 
10.4.1 
Planned Analyses 
The final analysis will be performed at the end of the study (defined as when the last 
subject enrolled has completed the safety follow-up/EOS visit). 
10.4.2 
Methods of Analyses 
10.4.2.1 
General Considerations 
Statistical analyses are descriptive in nature.  No statistical inference 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. 
10.4.2.2 
Efficacy Analyses 
Endpoint 
Statistical Analysis Methods 
Primary 
Not applicable. 
Secondary 
Descriptive statistics will be summarized for each secondary endpoint. 
Exploratory 
Not applicable.


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10.4.2.3 
Safety Analyses 
10.4.2.3.1 
Analyses of Primary Safety Endpoint(s) 
Endpoint 
Statistical Analysis Methods 
Primary 
Subject incidence of treatment-emergent adverse events will be summarized. 
10.4.2.3.2 
Adverse Events and Disease-related Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  Tables of fatal adverse events, serious adverse events, 
drug related adverse events, adverse events leading to withdrawal from investigational 
product, and treatment-emergent adverse events will also be provided.  Subject 
incidence of disease-related events, fatal disease-related events, and device-related 
events, if applicable, will be tabulated by system organ class and preferred term. 
10.4.2.3.3 
Exposure to Investigational Product 
The number of days on investigational product and the total dose of investigational 
product will be summarized using descriptive statistics. 
10.4.2.3.4 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving concomitant medications will be 
summarized by preferred term or category for each treatment group as coded by the 
World Health Organization Drug (WHODRUG) dictionary. 


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11. 
References 
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. 
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/. 
Iyengar SS, Puri R, Narasingan SN, et al.  Lipid Association of India Expert Consensus 
Statement on Management of Dyslipidemia in Indians 2016:  Part 1.  Supp.  The Journal 
of the Association of Physicians of India.  March 2016. 
Lakoski SG, Lagace TA, Cohen JC, Horton JD, Hobbs HH.  Genetic and Metabolic 
Determinants of Plasma PCSK9 Levels.  J Clin Endocrinol Metab.  
2009;94(7):2537-2543. 
Lifshitz F, editor.  Pediatric Endocrinology, Volume 2:  Growth, Adrenal, Sexual, Thyroid, 
Calcium, and Fluid Balance Disorders.  5th ed.  New York, NY:  Informa Healthcare; 
2007. 
Neil A, Cooper J, Betteridge J, et al.  Reductions in all-cause, cancer, and coronary 
mortality in statin-treated patients with heterozygous familial hypercholesterolaemia:  a 
prospective registry study.  European Heart Journal.  2008;29:2625-2633. 
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)61345-61348 [Epub ahead of print]. 
Raal FJ, Pilcher GJ, Illingworth DR, et al.  Expanded-dose simvastatin is effective in 
homozygous familial hypercholesterolaemia.  Atherosclerosis.  1997;135:249-256.  
 


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12. 
Appendices 


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Appendix 1.  List of Abbreviations and Definitions of Terms 
Abbreviation or Term 
Definition/Explanation 
AI 
autoinjector 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ApoB 
apolipoprotein B 
ARF 
autonomic recessive hypercholesterolemia 
BIL 
bilirubin 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CPK 
creatine phosphokinase 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP3A 
cytochrome P450 3A 
DILI 
drug-induced liver injury  
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EOS 
end of study 
End of Study for Individual 
Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject 
End of Study (primary 
completion) 
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), for the purposes of conducting the primary 
analysis, whether the study concluded as planned in the protocol 
or was terminated early  
End of Study (end of trial) 
defined as the date when the last subject is assessed or 
receives an intervention for evaluation in the study (ie, last 
subject last visit), following any additional parts in the study 
(eg, long-term follow-up), as applicable 
End of Treatment 
defined as the last assessment for the protocol-specified 
treatment phase of the study for an individual subject 
FAS 
full analysis set 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HoFH 
homozygous familial hypercholesterolemia 
HRT 
hormonal replacement therapy 
ICF 
informed consent form 


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Abbreviation or Term 
Definition/Explanation 
ICH 
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IPIM 
Investigational Product Instruction Manual 
IRB 
institutional review board 
IUD 
intrauterine device 
IUS 
intrauterine hormonal-releasing system 
Interactive Voice Response 
System (IVRS) 
telecommunication technology that is linked to a central 
computer in real time as an interface to collect and process 
information   
Interactive Web Response 
System (IWRS) 
web based technology that is linked to a central computer in real 
time as an interface to collect and process information  
IxRS 
interactive voice/web response system 
LDH 
lactate dehydrogenase 
LDL-C 
low-density lipoprotein cholesterol 
LDLR 
low-density lipoprotein receptor 
Lp(a) 
lipoprotein(a) 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
POR 
Proof of Receipts 
QM 
once monthly 
SC 
subcutaneous 
Source Data 
Information from an original record or certified copy of the 
original record containing patient information for use in clinical 
research.  The information may include, but is not limited to, 
clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents (original records 
or certified copies).  (ICH Guideline [E6]).  Examples of source 
data include Subject identification, Randomization identification, 
and Stratification Value. 
Study Day 1 
defined as the first day that protocol-specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject 
TBL 
total bilirubin 
ULN 
upper limit of normal 
WHODRUG 
World Health Organization Drug 


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Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 12-1 will be performed by the central laboratory.  Subjects will 
fast for 9 hours and abstain from strenuous exercise for 72 hours before each blood 
collection for clinical laboratory tests. 
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Sections 6.1 to 6.2. 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 


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Table 12-1.  Analyte Listing 
Central Laboratory:  
Chemistry 
Central Laboratory:  
Urinalysis 
Central Laboratory:  
Hematology 
Central Laboratory:  
Other Labs 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
Calcium 
Adjusted calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Uric acid 
Total bilirubin 
ALP 
LDH 
AST (SGOT) 
ALT (SGPT) 
Specific gravity 
pH 
Blood 
Protein Glucose 
Bilirubin 
WBC 
RBC 
Epithelial cells 
Bacteria 
Casts 
Crystals 
RBC 
Hemoglobin 
Hematocrit 
Platelets 
WBC 
Differential: 
x 
Neutrophils 
x 
Eosinophils 
x 
Basophils 
x 
Lymphocytes 
x 
Monocytes 
Serum pregnancy 
Fasting lipid panel: 
x Total cholesterol 
x LDL-C 
x HDL-C 
x VLDL-C 
x non-HDL-C 
ApoA1 
ApoB 
Lp(a) 
 
 
 
Local labs 
Urine pregnancy 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; Apo = apolipoprotein; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; HDL-C = high-density lipoprotein cholesterol; LDH = lactate 
dehydrogenase; LDL-C = low-density lipoprotein cholesterol; Lp(a) = lipoprotein (a); non-HDL-C = non-high-
density lipoprotein cholesterol; RBC = red blood cell count; SGOT = serum glutamic-oxaloacetic 
transaminase; SGPT = serum glutamic-pyruvic transaminase; VLDL-C = very low-density lipoprotein 
cholesterol; WBC = white blood cell count. 


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Appendix 3.  Study Governance Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
x 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
x 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
x
Applicable laws and regulations
The protocol, protocol amendments, informed consent form, Investigator’s Brochure, and 
other relevant documents (eg, subject recruitment advertisements) must be submitted to 
an institutional review board/independent ethics committee (IRB/IEC) by the investigator 
and reviewed and approved by the IRB/IEC.  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. 
Amgen may amend the protocol at any time.  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 must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
The investigator will be responsible for the following: 
x 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
x 
Obtaining annual IRB/IEC approval/renewal throughout the duration of the study.  
Copies of the investigator’s reports and the IRB/IEC continuance of approval must be 
sent to Amgen 
x 
Notifying the IRB/IEC of serious adverse events occurring at the site, deviations from 
the protocol or other adverse event reports received from Amgen, in accordance with 
local procedures 
x 
Overall conduct of the study at the site and adherence to requirements of Title 21 of 
the US Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and all 
other applicable local regulations 
Informed Consent Process 
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 sample 


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informed consent form are to be communicated formally in writing from the Amgen Trial 
Manager to the investigator.  The written informed consent form is to be prepared in the 
language(s) of the potential patient population. 
The investigator or his/her delegated representative will explain to the subject, or his/her 
legally authorized representative, the aims, methods, anticipated benefits, and potential 
hazards of the study before any protocol-specific screening procedures or any 
investigational product(s) is/are administered, and answer all questions regarding the 
study.   
Subjects must be informed that their participation is voluntary.  Subjects or their legally 
authorized representative defined as 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 will then be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study site.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
informed consent form. 
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 unless it is a local requirement.  The 
investigator shall then inform the primary care physician.  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.  Subject withdrawal of consent or discontinuation from 


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study treatment and/or procedures must also be documented in the subject’s medical 
records; refer to Section 8. 
Subjects must be re-consented to the most current version of the informed consent 
form(s) during their participation in the study.  
The original signed informed consent form is to be retained in accordance with 
institutional policy, and a copy of the informed consent form(s) must be provided to the 
subject or the subject’s legally authorized 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.  (Refer to ICH GCP guideline, Section 4.8.9). 
The informed consent form (ICF) will contain a separate section that addresses the use 
of remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each subject the objectives of the exploratory 
research.  Subjects will be told that they are free to refuse to participate and may 
withdraw their specimens at any time and for any reason during the storage period.  A 
separate signature will be required to document a subject’s agreement to allow any 
remaining specimens to be used for exploratory research.  Subjects who decline to 
participate will not provide this separate signature. 
Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
Subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
On the electronic case report form (eCRF) 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 age (in accordance with local laws and regulations). 


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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 ICH GCP Guidelines, it is required that the investigator and institution 
permit authorized representatives of the company, of the regulatory agency(s), and the 
IRB/IEC direct access to review the subject’s original medical records for verification of 
study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of 
the study.   
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
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 
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 (ICMJE) Recommendations for the 
Conduct of Reporting, Editing, and Publications of Scholarly Work in Medical Journals, 
which states: 
Authorship credit is to 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. 


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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. 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
x 
A recognized expert in the therapeutic area 
x 
An investigator who provided significant contributions to either the design or 
interpretation of the study 
x 
An investigator contributing a high number of eligible subjects 
Data Quality Assurance 
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, centrally or 
adjudicated data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the eCRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.   


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The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
Clinical monitors will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of subjects are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements per the sponsor’s monitoring plan.  
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 eCRFs, are resolved. 
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, eCRFs and other 
pertinent data) provided that subject confidentiality is respected. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research & Development Compliance 
and Audit function (or designees).  Inspection of site facilities (eg, pharmacy, 
protocol-required therapy storage areas, laboratories) and review of study-related 
records will occur to evaluate the study conduct and compliance with the protocol, ICH 
GCP, and applicable regulatory requirements. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Amgen (or designee) will perform Self-Evident Corrections to obvious data errors in the 
clinical trial database.  Self-Evident Corrections will be documented in the eCRF 
Standard Instructions and the eCRF Specific Instructions, both of these will be available 
through the electronic data capture (EDC) system.  Examples of obvious data errors that 
may be corrected by Amgen (or designee) include deletion of obvious duplicate data (ie, 
the same results sent twice with the same date with different visit, [eg, week 12 and end 
of study]) and updating a specific response if the confirming datum is provided in the 
“other, specify” field (eg, for race, reason for ending study). 
eCRFs must be completed in English.  TRADENAMES® (if used) for concomitant 
medications may be entered in the local language.  Consult the country-specific 
language requirements. 


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All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
Source Documents 
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 eCRFs will be included on the Amgen Delegation of Authority Form. 
Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
Source documents are original documents, data, and records from which the subject’s 
eCRF 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.  Source documents may also include data captured in the 
Interactive Voice Response System/Interactive Web Response System (IxRS) (if used, 
such as subject ID and randomization number) and eCRF entries if the eCRF is the site 
of the original recording (ie, there is no other written or electronic record of data, such as 
paper questionnaires for a clinical outcome assessment). 
Data reported on the eCRF or entered in the electronic eCRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available. 
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 
Elements to include: 
x 
Subject files containing completed eCRFs, informed consent forms, and subject 
identification list 
x 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 


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x 
Investigational product-related correspondence including Proof of Receipts (POR), 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Study and Site Closure 
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP.  
Both Amgen and the investigator reserve the right to terminate the investigator’s 
participation in the study according to the Clinical Trial Agreement.  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. 
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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Appendix 4.  Safety Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting 
Definition of Disease-related Event 
Disease-related Event Definition 
x 
Disease-related events are events (serious or non-serious) anticipated to occur in 
the study population due to the underlying disease.  See Section 9.2.3.1.1.1 for the 
list of disease-related events.   
x 
Disease-related events that would qualify as an adverse event or serious adverse 
event: 
 
An event based on the underlying disease that is worse than expected as 
assessed by the investigator for the subject’s condition or if the investigator 
believes there is a causal relationship between the investigational 
product(s)/study treatment/protocol-required therapies and disease worsening, 
this must be reported as an adverse event or serious adverse event. 
x 
Disease-related events that do not qualify as adverse events or serious adverse 
events:  
 
An event which is part of the normal course of disease under study 
(eg, disease progression in oncology or hospitalization due to disease 
progression) is to be reported as a disease-related event.   
Definition of Adverse Event 
Adverse Event Definition 
x 
An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment.   
x 
Note:  An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a treatment, combination 
product, medical device, or procedure. 
Events Meeting the Adverse Event Definition 
x 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, electrocardiogram [ECG], radiological scans, vital 
signs measurements), including those that worsen from baseline, that are 
considered clinically significant in the medical and scientific judgment of the 
investigator (ie, not related to progression of underlying disease). 
x
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
x 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
x 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
x 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication.  Overdose per se will not be reported as an 


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adverse event/serious adverse event unless it is an intentional overdose taken with 
possible suicidal/self-harming intent.  Such overdoses are to be reported 
regardless of sequelae.
x 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an adverse event or serious adverse event.  Such instances will be 
captured in the efficacy assessments.  However, the signs, symptoms, and/or 
clinical sequelae resulting from lack of efficacy will be reported as adverse event or 
serious adverse event if they fulfill the definition of an adverse event or serious 
adverse event. 
Events NOT Meeting the Adverse Event Definition 
x 
Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that 
leads to the procedure is the adverse event. 
x 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
x 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
Definition of Serious Adverse Event 
A Serious Adverse Event is defined as any untoward medical occurrence 
that, meets at least 1 of the following serious criteria: 
Results in death (fatal) 
Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting.  Complications that occur during 
hospitalization are an adverse event.  If a complication prolongs hospitalization or 
fulfills any other serious criteria, the event is serious.  When in doubt as to whether 
“hospitalization” occurred or was necessary, the adverse event is to be considered 
serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an adverse event. 


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Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious 
adverse event reporting is appropriate in other situations such as important 
medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition.  
These events are typically to be considered serious. 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
Definition of Adverse Device Effect 
The detection and documentation procedures for adverse device effects described in 
this protocol apply to all Amgen medical devices provided for use in the study (see 
Section 7.1.3 for the list of Amgen medical devices). 
Adverse Device Effect Definition 
An adverse device effect is any adverse event related to the use of a combination 
product or medical device.  Adverse device effects include adverse events resulting 
from insufficient or inadequate instructions for use, adverse events resulting from any 
malfunction of the device, or adverse events resulting from use error or from 
intentional misuse of the device. 


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Recording Adverse Events, Disease-related Events (if applicable), and Serious 
Adverse Events 
Adverse Event, Disease-related Event (if applicable) and Serious Adverse Event 
Recording 
x 
When an adverse event, disease-related event or serious adverse event occurs, it 
is the responsibility of the investigator to review all documentation (eg, hospital 
progress notes, laboratory, and diagnostics reports) related to the event. 
x 
The investigator will then record all relevant adverse event/disease-related 
event/serious adverse event information in the Event electronic case report form 
(eCRF). 
 
Additionally, the investigator is required to report a fatal disease-related event 
on the Event eCRF. 
x 
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 (or toxicity defined below); 
 
Assessment of relatedness to investigational product, other protocol-required 
therapies, or devices; and 
 
Action taken. 
x 
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record as a single event with the worst severity on the Event eCRF. 
x 
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to Amgen in lieu of completion of the Event eCRF page. 
x 
If specifically requested, the investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the 
medical records.  In this case, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records before 
submission to Amgen. 
x 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious 
adverse event. 


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Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The investigator will make an assessment of severity for each adverse event and 
serious adverse event reported during the study.  The assessment of severity will be 
based on:  
The Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 which is 
available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Assessment of Causality 
x 
The investigator is obligated to assess the relationship between investigational 
product and device and each occurrence of each adverse event/serious adverse 
event. 
x 
Relatedness means that there are facts or reasons to support a relationship 
between investigational product and the event. 
x 
The investigator will use clinical judgment to determine the relationship. 
x 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
x 
The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 
x 
For each adverse event/serious adverse event, the investigator must document in 
the medical notes that he/she has reviewed the adverse event/serious adverse 
event and has provided an assessment of causality. 
x 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report.  However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the serious adverse event data. 
x 
The investigator may change his/her opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated 
causality assessment. 
x 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 


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Follow-up of Adverse Event and Serious Adverse Event 
x 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 
Amgen to elucidate the nature and/or causality of the adverse event or serious 
adverse event as fully as possible.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 
care professionals. 
x 
If a subject is permanently withdrawn from protocol-required therapies because of 
a serious adverse event, this information must be submitted to Amgen. 
x 
If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Amgen with a copy of any post-mortem 
findings including histopathology. 
x 
New or updated information will be recorded in the originally completed Event 
eCRF. 
x
The investigator will submit any updated serious adverse event data to Amgen
within 24 hours of receipt of the information. 
Reporting of Serious Adverse Event 
Serious Adverse Event Reporting via Electronic Data Collection Tool
x 
The primary mechanism for reporting serious adverse event will be the electronic 
data capture (EDC) system via the Safety Report Form.  
x 
If the EDC system is unavailable for more than 24 hours, then the site will report 
the information to Amgen using an Electronic Serious Adverse Event (eSAE) 
Contingency Form (paper form; see Figure 12-1) within 24 hours of the 
investigator’s knowledge of the event. 
x 
The site will enter the serious adverse event data into the electronic system as 
soon as it becomes available. 
x 
After the study is completed at a given site, the EDC system will be taken off-line to 
prevent the entry of new data or changes to existing data. 
x 
If a site receives a report of a new serious adverse event from a study subject or 
receives updated data on a previously reported serious adverse event after the 
EDC has been taken off-line, then the site can report this information on an eSAE 
Contingency Form (paper form; see Figure 12-1). 
Adverse Device Effects:  Recording, Evaluating, and Reporting 
x 
Any adverse event resulting from an adverse device effect that occur during the 
study will be documented in the subject’s medical records, in accordance with the 
investigator’s normal clinical practice, and on the Event eCRF page. 
x 
It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by Amgen) at the time of the initial 
report and describes any corrective or remedial actions taken to prevent recurrence 
of the incident. 


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Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Form 


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Appendix 5.  Contraceptive Guidance and Collection of Pregnancy and Lactation 
Information 
Study-specific contraception requirements for adult female subjects of childbearing 
potential or for pediatric subjects who have reached puberty are outlined in Section 6.2. 
Adult female subjects of childbearing potential or for pediatric studies who have reached 
puberty must receive pregnancy prevention counseling and be advised of the risk to the 
fetus if they become pregnant during treatment and for 15 weeks after the last dose of 
protocol-required therapies. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered female of childbearing potential: 
x 
premenopausal female with 1 of the following: 
 
documented hysterectomy; 
 
documented bilateral salpingectomy; or 
 
documented bilateral oophorectomy. 
Note:  Site personnel documentation from the following sources is acceptable:  
1) review of subject’s medical records; 2) subject’s medical examination; or 
3) subject’s medical history interview. 
x 
premenarchal female 
x 
postmenopausal female 
 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
 
Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
Contraception Methods for Female Subjects 
Acceptable Methods of Effective Contraception 
x 
combined (estrogen and progestogen containing) or progestogen-only hormonal 
methods given via oral, intravaginal, transdermal, injectable, or implantable route) 


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x 
intrauterine device (IUD) 
x 
intrauterine hormonal-releasing system (IUS) 
x 
bilateral tubal ligation/occlusion 
x 
vasectomized partner (provided that partner is the sole sexual partner of the female 
subject of childbearing potential and that the vasectomized partner has received 
medical assessment of the surgical success) 
x 
sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments; the reliability of sexual 
abstinence must be evaluated in relation to the duration of the trial and the preferred 
and usual lifestyle of the subject) 
x 
male or female condom with or without spermicide 
x 
cap, diaphragm or sponge with spermicide 
x 
double-barrier method:  the male uses a condom and the female may choose either 
a cap, diaphragm, or sponge with spermicide (a female condom is not an option due 
to the risk of tearing when both partners use a condom) 
Contraception Methods for Male Subjects  
Male participants are not required to use birth control during treatment with evolocumab.  
However, they should let their female partner know that they are in this study. 
Unacceptable Methods of Birth Control for Female Subjects 
Birth control methods that are considered unacceptable in clinical trials include: 
x 
periodic abstinence (calendar, symptothermal, postovulation methods) 
x 
withdrawal (coitus interruptus) 
x 
spermicides only 
x 
lactational amenorrhea method 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
x 
Investigator will collect pregnancy information on any female subject who becomes 
pregnant while taking protocol-required therapies through 15 weeks. 
x 
Information will be recorded on the Pregnancy Notification Worksheet (see 
Figure 12-2).  The worksheet must be submitted to Amgen Global Patient Safety 
within 24 hours of learning of a subject’s pregnancy.  (Note:  Sites are not required 
to provide any information on the Pregnancy Notification Worksheet that violates the 
country or regions local privacy laws). 
x 
After obtaining the female subject’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy and infant 
health information and complete the pregnancy questionnaire for any female subject 
who becomes pregnant while taking protocol-required therapies through 15 weeks 
of the study drug.  This information will be forwarded to Amgen Global Patient 


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Safety.  Generally, infant follow-up will be conducted up to 12 months after the birth 
of the child (if applicable). 
x 
Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.  
x 
While pregnancy itself is not considered to be an adverse event or serious adverse 
event, any pregnancy complication or report of a congenital anomaly or 
developmental delay, fetal death, or suspected adverse reactions in the neonate will 
be reported as an adverse event or serious adverse event.  Note that an elective 
termination with no information on a fetal congenital malformation or maternal 
complication is generally not considered an adverse event, but still must be reported 
to Amgen as a pregnancy exposure case. 
x 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a serious adverse event. 
x 
Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Appendix 4.  While the 
investigator is not obligated to actively seek this information in former study 
subjects, he or she may learn of a serious adverse event through spontaneous 
reporting.  
x 
Any female subject who becomes pregnant while participating will discontinue study 
treatment (see Section 8.1 for details). 
Male Subjects With Partners Who Become Pregnant or Were Pregnant at the Time of 
Enrollment 
x 
In the event a male subject fathers a child during treatment, and for an additional 
15 weeks after discontinuing protocol-required therapies, the information will be 
recorded on the Pregnancy Notification Worksheet.  The worksheet (see 
Figure 12-2) must be submitted to Amgen Global Patient Safety within 24 hours of 
the site’s awareness of the pregnancy.  (Note:  Sites are not required to provide any 
information on the Pregnancy Notification Worksheet that violates the country or 
regions local privacy laws). 
x 
The investigator will attempt to obtain a signed authorization for release of 
pregnancy and infant health information directly from the pregnant female partner to 
obtain additional pregnancy information. 
x 
After obtaining the female partner’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy outcome and 
infant health information on the pregnant partner and her baby and complete the 
pregnancy questionnaires.  This information will be forwarded to Amgen Global 
Patient Safety. 
x 
Generally, infant follow-up will be conducted up to 12 months after the birth of the 
child (if applicable).  
x 
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. 


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Collection of Lactation Information 
x 
Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 15 weeks. 
x 
Information will be recorded on the Lactation Notification Worksheet (see below) 
and submitted to Amgen Global Patient Safety within 24 hours of the investigator’s 
knowledge of event. 
x 
Study treatment will be discontinued if female subject breastfeeds during the study 
as described in exclusion criterion 204. 
x 
With the female subjects signed authorization for release of mother and infant 
health information, the investigator will collect mother and infant health information 
and complete the lactation questionnaire on any female subject who breastfeeds 
while taking protocol-required therapies through 15 weeks after discontinuing 
protocol-required therapies. 


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Figure 12-2.  Pregnancy and Lactation Notification Worksheet 


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Appendix 6.  Sample Storage and Destruction 
Any blood samples collected according to the Schedule of Activities (Table 2-1) can be 
analyzed for any of the tests outlined in the protocol and for any tests necessary to 
minimize risks to study subjects.  This includes testing to ensure analytical methods 
produce reliable and valid data throughout the course of the study.  This can also 
include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.  
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
cardiovascular disease, the dose response and/or prediction of response to Repatha, 
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, or other exploratory studies are not 
placed in the subject’s medical record and are not to be made available to the subject, 
members of the family, the personal physician, or other third parties, except as specified 
in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
[sample types (eg, blood, tumor)] samples and any other components from the cells can 
be located and destroyed.  Samples will be destroyed once all protocol-defined 
procedures are completed.  However, information collected from samples prior to the 
request for destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 


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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 
Appendix 3 for subject confidentiality. 


Product:  Evolocumab 
Protocol Number:  20170199 
Date:  16 August 2017 
Page 66 of 70 
CONFIDENTIAL 
 
 
 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and Follow-up 
Assessments and Study Treatment Rechallenge Guidelines 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis (as 
described below) may meet the criteria for withholding or permanent discontinuation of 
Amgen investigational product or other protocol-required therapies, as specified in the 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, 
July 2009. 
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.  
Important alternative causes for elevated AST/ALT and/or TBL values include, but are 
not limited to: 
x 
hepatobiliary tract disease 
x 
viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes 
simplex virus, varicella, toxoplasmosis, and parvovirus) 
x 
right-sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia 
x 
exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants and mushrooms 
x 
heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit BIL glucuronidation (eg, indinavir, 
atazanavir) 
x 
alpha-1 antitrypsin deficiency 
x 
alcoholic hepatitis 
x 
autoimmune hepatitis 
x 
Wilson’s disease and hemochromatosis 
x 
nonalcoholic fatty liver disease including steatohepatitis 
x 
non-hepatic causes (eg, rhabdomylosis, hemolysis) 
If investigational product(s) is/are withheld, the subject is to be followed for possible 
drug-induced liver injury (DILI) according to recommendations in the last section of this 
appendix.  


Product:  Evolocumab 
Protocol Number:  20170199 
Date:  16 August 2017 
Page 67 of 70 
CONFIDENTIAL 
 
 
 
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 (see next section in this appendix). 
Table 12-2.  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 
-- 
> 1.5x ULN (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 8x ULN at any time 
> 5x ULN but < 8x ULN for t 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, and 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 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject is to be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then Amgen investigational product and 
other protocol-required therapies, as appropriate is to be permanently discontinued.  
Subjects who clearly meet the criteria for permanent discontinuation (as described in 
Table 12-2) are never to be rechallenged.


Product:  Evolocumab 
Protocol Number:  20170199 
Date:  16 August 2017 
Page 68 of 70 
CONFIDENTIAL 
 
 
 
Drug-induced Liver Injury Reporting and 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 the above, require 
the following: 
x 
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) 
x 
The appropriate electronic case report form (eCRF) (eg, Event eCRF) that captures 
information necessary to facilitate the evaluation of treatment-emergent liver 
abnormalities is to be completed and sent to 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. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Table 12-2 or who experience AST or ALT elevations > 3 x upper limit of normal (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:  
x 
repeat AST, ALT, ALP, BIL (total and direct), and INR within 24 hours  
x 
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 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL.  
The following are to be considered depending on the clinical situation: 
x 
complete blood count (CBC) with differential to assess for eosinophilia 
x 
serum total immunoglobulin IgG, anti-nuclear antibody, anti-smooth muscle antibody, 
and liver kidney microsomal antibody -1 to assess for autoimmune hepatitis 
x 
serum acetaminophen (paracetamol) levels 


Product:  Evolocumab 
Protocol Number:  20170199 
Date:  16 August 2017 
Page 69 of 70 
CONFIDENTIAL 
 
 
 
x 
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 
x 
viral serologies 
x 
creatine phosphokinase (CPK), haptoglobin, lactate dehydrogenase (LDH), and 
peripheral blood smear 
x 
appropriate liver imaging if clinically indicated 
x 
appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected 
x 
hepatology consult (liver biopsy may be considered in consultation with a 
hepatologist) 
Follow the subject and the laboratory tests (ALT, AST, TBL, and 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 eCRFs.  


Product:  Evolocumab 
Protocol Number:  20170199 
Date:  16 August 2017 
Page 70 of 70 
CONFIDENTIAL 
 
 
 
 
 
 
 
Appendix 8.  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 


Product:  Evolocumab 
Protocol Number:  20170199 
Date:  16 August 2017 
Page 1 of 4 
CONFIDENTIAL 
 
 
Superseding Version 1 
Protocol Title:  A Multicenter, Open-label, Single-arm, Study to Evaluate Safety 
and Tolerability of Repatha in Patients With Homozygous Familial 
Hypercholesterolemia (HoFH) in India 
 
Amgen Protocol Number (evolocumab) 20170199 
 
Superseding Version Date: 
16 August 2017 
 
Rationale: 
A superseding version of this protocol has been drafted to address the following errors 
identified after publication of the original protocol (dated 04 August 2017): 
• 
In the Schedule of Activities (Table 2-1) additional visits were added to the table to 
account for subjects on apheresis (weeks 2 and 6).  During the update of the table, 
the scheduled visits for vital signs and 2 laboratory assessments were not moved 
accordingly to week 8 (they were mistakenly left at the renamed column for week 4). 
• 
Contraception guidance provided in exclusion criteria 205 required alignment with 
the information provided in Appendix 5. 
• 
In addition, administrative updates were made to account for this superseding 
version. 


Product:  Evolocumab 
Protocol Number:  20170199 
Date:  16 August 2017 
Page 2 of 4 
CONFIDENTIAL 
 
 
Description of Changes 
Section:  Global 
Change:  Updated version date from 04 August 2017 to 16 August 2017. 
Section:  Title Page 
Add: 
Protocol Date: 
Document Version 
Date 
Original 
04 August 2017 
Superseding Version 
1 
16 August 2017 
 


Product:  Evolocumab 
Protocol Number:  20170199 
Date:  16 August 2017 
Page 3 of 4 
CONFIDENTIAL 
 
 
Section:  2.2 Schedule of Activities, Table 2-1 
Replace: 
Procedure 
Screening  
(up to 4 weeks 
before day 1) 
Treatment Period 
Follow-up 
Notes 
W1 
(day 1) W2a 
W4b 
W6a 
W8 
W12c 
General and Safety Assessments 
Vital signs (BP, HR) 
X 
X 
 
X 
 
 
X 
 
Laboratory Assessmentsf 
Fasting lipids, ApoA1, ApoB 
X 
X 
 
X 
 
 
X 
 
Lp(a) 
X 
X 
 
X 
 
 
X 
 
With: 
Procedure 
Screening  
(up to 4 weeks 
before day 1) 
Treatment Period 
Follow-up 
Notes 
W1 
(day 1) W2a 
W4b 
W6a 
W8 
W12c 
General and Safety Assessments 
Vital signs (BP, HR) 
X 
X 
 
 
 
X 
X 
 
Laboratory Assessmentsf 
Fasting lipids, ApoA1, ApoB 
X 
X 
 
 
 
X 
X 
 
Lp(a) 
X 
X 
 
 
 
X 
X 
 
 


Product:  Evolocumab 
Protocol Number:  20170199 
Date:  16 August 2017 
Page 4 of 4 
CONFIDENTIAL 
 
 
Section:  6.2 Exclusion Criteria 
Replace: 
205 
Female subjects of childbearing potential unwilling to use 1 highly effective 
method of contraception or acceptable method of effective contraception during 
treatment and for an additional 15 weeks after the last dose of Repatha.  Refer to 
Appendix 5 for additional contraceptive information. 
With: 
205 
Female subjects of childbearing potential unwilling to use an acceptable method 
of effective contraception during treatment and for an additional 15 weeks after 
the last dose of Repatha.  Refer to Appendix 5 for additional contraceptive 
information. 

SAP_001.pdf: 
Product:  AMG 145
Protocol Number:  20170199
Date:  09 March 2019
Page 1 of 19
CONFIDENTIAL 
Statistical Analysis Plan
Protocol Title:
A Multicenter, Open-label, Single-arm, Study to 
Evaluate Safety and Tolerability of Repatha in 
Patients with Homozygous Familial 
Hypercholesterolemia (HoFH) in India
Short Protocol Title:
An Open-label Study to Characterize Safety and 
Tolerability of Repatha in Homozygous Familial 
Hypercholesterolemia in India
Protocol Number:
20170199
NCT Number:
Not Available
Authors:
Sponsor:
Amgen Inc.
One Amgen Center Drive, Thousand Oaks, CA
SAP Date:
Document Version
Date
Original (v[1.0])
09 March 2019
Version Number
Date
(DDMMMYYYY)
Summary of Changes, 
including rationale for changes
Original (v1.0)
09MAR2019
NCT Number: NCT03403374
This NCT number has been applied to the document for 
purposes of posting on Clinicaltrials.gov


Product:  $0* 
Protocol Number:  20170199 
Date:  09 March 2019 
Page 2 of 19 
CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents .............................................................................................................. 2 
1. 
Introduction .............................................................................................................. 6 
2. 
Objectives, Endpoints and Hypotheses .................................................................... 6 
2.1 
Objectives and Endpoints ............................................................................. 6 
2.2 
Hypotheses  .................................................................................................. 6 
3. 
Study Overview ........................................................................................................ 6 
3.1 
Study Design ................................................................................................ 6 
3.2 
Sample Size ................................................................................................. 7 
3.3 
Adaptive Design ........................................................................................... 7 
4. 
Covariates and Subgroups ....................................................................................... 7 
4.1 
Planned Covariates ...................................................................................... 7 
4.2 
Subgroups .................................................................................................... 7 
5. 
Definitions ................................................................................................................ 7 
5.1 
Study Time Points ........................................................................................ 7 
5.2 
Demographics and Baseline Related Definitions ......................................... 8 
5.3 
Other Related Definitions ............................................................................. 9 
6. 
Analysis Sets .......................................................................................................... 10 
6.1 
Full Analysis Set ......................................................................................... 10 
6.1.1 
Primary Analysis Set .................................................................. 10 
6.2 
Safety Analysis Set ..................................................................................... 10 
6.3 
Per Protocol Set(s) ..................................................................................... 10 
6.4 
Health-related Quality-of-Life or Health Economics Analyses 
Set(s) .......................................................................................................... 10 
6.5 
Pharmacokinetic/Pharmacodynamic Analyses Set(s) ................................ 10 
6.6 
Interim Analyses Set(s) .............................................................................. 10 
6.7 
Study-specific Analysis Sets ....................................................................... 11 
7. 
Planned Analyses .................................................................................................. 11 
7.1 
Interim Analysis and Early Stopping Guidelines ......................................... 11 
7.2 
Primary Analysis ......................................................................................... 11 
7.3 
Final Analysis ............................................................................................. 11 
8. 
Data Screening and Acceptance ............................................................................ 11 
8.1 
General Principles ...................................................................................... 11 
8.2 
Data Handling and Electronic Transfer of Data .......................................... 11 
8.3 
Handling of Missing and Incomplete Data .................................................. 11 
8.3.1 
Patterns of Missing Data ............................................................ 11 
8.3.2 
Handling of Incomplete Dates .................................................... 12 
8.4 
Detection of Bias ........................................................................................ 12 


Product:  $0* 
Protocol Number:  20170199 
Date:  09 March 2019 
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CONFIDENTIAL  
 
 
8.5 
Outliers ....................................................................................................... 12 
8.6 
Distributional Characteristics ...................................................................... 13 
8.7 
Validation of Statistical Analyses ................................................................ 13 
9. 
Statistical Methods of Analysis ............................................................................... 13 
9.1 
General Considerations .............................................................................. 13 
9.2 
Subject Accountability ................................................................................ 13 
9.3 
Important Protocol Deviations .................................................................... 13 
9.4 
Demographic and Baseline Characteristics ................................................ 14 
9.5 
Efficacy Analyses ....................................................................................... 14 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) ................................... 14 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) .............................. 14 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 14 
9.6 
Safety Analyses .......................................................................................... 14 
9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 14 
9.6.2 
Adverse Events  ......................................................................... 14 
9.6.3 
Laboratory Test Results ............................................................. 15 
9.6.4 
Vital Signs ................................................................................... 15 
9.6.5 
Physical Measurements ............................................................. 15 
9.6.6 
Electrocardiogram ...................................................................... 15 
9.6.7 
Antibody Formation .................................................................... 15 
9.6.8 
Exposure to Investigational Product ........................................... 15 
9.6.9 
Exposure to Non-investigational Product ................................... 15 
9.6.10 
Exposure to Other Protocol-required Therapy ............................ 15 
9.6.11 
Exposure to Concomitant Medication ......................................... 15 
9.7 
Other Analyses ........................................................................................... 16 
9.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ......................... 16 
9.7.2 
Analyses of Clinical Outcome Assessments .............................. 16 
9.7.3 
Analyses of Health Economic Endpoints .................................... 16 
9.7.4 
Analyses of Biomarker Endpoints ............................................... 16 
10. 
Changes From Protocol-specified Analyses .......................................................... 16 
11. 
Literature Citations / References ............................................................................ 16 
12. 
Prioritization of Analyses ........................................................................................ 16 
13. 
Data Not Covered by This Plan .............................................................................. 16 
14. 
Appendices ............................................................................................................ 17 
Appendix A.  Analytical Study Week Assignments ................................................. 18 
Appendix B.  Common Terminology Criteria for Adverse Events ........................... 19 


Product:  $0* 
Protocol Number:  20170199 
Date:  09 March 2019 
Page 4 of 19 
CONFIDENTIAL  
 
 
List of Tables 
Table 8-1.  Imputation Rules for Incomplete Dates ......................................................... 12 


Product:  AMG 145
Protocol Number:  20170199
Date:  09 March 2019
Page 5 of 19
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List of Abbreviations and Definition of Terms
Abbreviation or Term
Definition/Explanation
AE
adverse event
ApoA1
apolipoprotein A1
ApoB
apolipoprotein B
BP
blood pressure
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DIIR
data issue identification and resolution
DRE
disease-related event
eCRF
electronic case report form
EOS
end of study
FAS
full analysis set
GSO-DM
global study operation-data management
HDL-C
high-density lipoprotein cholesterol
HoFH
homozygous familial hypercholesterolemia
HR
heart rate
IP
investigational product
IPD
important protocol deviation
LDL-C
low-density lipoprotein cholesterol
Lp(a)
lipoprotein(a)
MedDRA
Medical Dictionary for Regulatory Activities
PCSK9
proprotein convertase subtilisin/kexin type 9
QM
once monthly
SC
subcutaneous
VLDL-C
very low-density lipoprotein cholesterol
WHODRUG
World Health Organization Drug


Product:  AMG 145
Protocol Number:  20170199
Date:  09 March 2019
Page 6 of 19
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1.
Introduction
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol for study 20170199, AMG 145
dated 16 August 2017. The scope of this plan includes the analyses that are planned 
and will be executed by the Amgen Global Biostatistical Science department unless 
otherwise specified.
2.
Objectives, Endpoints and Hypotheses
2.1
Objectives and Endpoints
Objectives
Endpoints
Primary

To characterize the safety and tolerability 
in homozygous familial 
hypercholesterolemia HoFH patients in 
India exposed to 12 weeks of Repatha

Subject incidence of treatment-emergent 
adverse events
Secondary

To characterize the efficacy of 12 weeks 
of Repatha on low-density lipoprotein 
cholesterol (LDL-C), apolipoprotein B 
(ApoB) and lipoprotein(a) [Lp(a)] in HoFH 
patients in India

Percent change from baseline in LDL-C at 
week 12

Percent change from baseline in ApoB at 
week 12

Percent change from baseline in Lp(a) at 
week 12
2.2
Hypotheses 
This phase 4 study is descriptive in nature, describing safety and tolerability of Repatha 
in subjects with HoFH in India.
3.
Study Overview
3.1
Study Design
This open-label, multicenter, non-comparative phase 4 study of Repatha is part of 
Amgen’s post marketing requirement to the Indian Regulatory Authority.  The study 
population consists of approximately 30 Indian subjects with HoFH and for whom 
Repatha is indicated in accordance with the approved prescribing information in India.
The assignment of subjects to protocol treatment will be decided by the investigator according to 
inclusion/exclusion criteria and laboratory assessments at screening (including fasting lipids).  
Subjects who are enrolled will be instructed to continue to follow a diet limiting saturated fat to 
less than 7% of total daily calories and will be required to maintain their current lipid-lowering drug 
therapy throughout the duration of the trial. Subjects will receive Repatha 420 mg once monthly 
(QM) subcutaneous (SC) and study visits will occur approximately every 4 weeks. For subjects on 


Product:  AMG 145
Protocol Number:  20170199
Date:  09 March 2019
Page 7 of 19
CONFIDENTIAL 
apheresis, they may receive Repatha 420 mg SC every 2 weeks to correspond with their 
apheresis schedule. Final administration of Repatha will occur at week 8. The end of study (EOS) 
visit and the last estimation of lipids will occur at week 12 for all subjects.
3.2
Sample Size
Approximately 30 subjects with HoFH will be enrolled in the study.
3.3
Adaptive Design
Not Applicable.
4.
Covariates and Subgroups
4.1
Planned Covariates
No covariates will be used in this study.
4.2
Subgroups
No subgroups will be used in this study.
5.
Definitions
5.1
Study Time Points
Enrollment Date 
The enrollment date is defined as the date collected on the electronic case report form 
(eCRF).
Study Day 1 
For each subject, Study Day 1 is defined as the first day of IP administration in this 
study. If a subject never received IP, then Study Day 1 is defined as the date of 
enrollment.
Study Day 
For each subject, and for a given study visit date, Study Day is defined as the number of 
days since Study Day 1: 
Study Day = (study visit date – Study Day 1 date) + 1 
If the date of interest is prior to the Study Day 1: 
Study Day = (study visit date – Study Day 1 date), so that the day prior to Study Day 1 is 
study day -1.


Product:  AMG 145
Protocol Number:  20170199
Date:  09 March 2019
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End of Investigational Product (EOIP) Date 
For each subject, the end of investigational product date is defined as the date of 
decision was made to end investigational product recorded on the End of Investigational 
Product Administration form in eCRF. 
End of Study (EOS) Date 
For each subject, the end of study date is the date recorded on the End of Study eCRF.
Last IP Dose Date
For each subject, the Last IP Dose Date is defined as the last day of IP administration in 
this study:

If the last dose was administered non-clinic, then Last IP Dose Date is defined 
as the final dose date reported by the subject on the Non-Clinic Final 
Investigational Product Dose Date Form in eCRF.

If the last dose was administered in-clinic, then Last IP Dose Date is the last 
start date captured on the Investigational Product Administration (In-clinic) form 
in eCRF.
Study End Date 
The study end date is the last EOS date of all enrolled subjects.
5.2
Demographics and Baseline Related Definitions
Age 
Age at enrollment is the subject’s age in years that derived in the clinical database.
Baseline Lipid and Lipid-related Values
The baseline for fasting lipids (total cholesterol, HDL-C, LDL-C, VLDL-C and non-hdl-c), 
ApoA1, ApoB, Lp(a) and their derived parameters (eg, ratio between them) is defined as
the mean of the two most recent non-missing fasting concentrations measured through 
central lab prior to or on Study Day 1. If for any reason only 1 value is available, then 
that value will be used as baseline.
Other Baseline Values
For PCSK9 and all other variables, the baseline value is defined as the last non-missing
value collected prior to or on Study Day 1.


Product:  AMG 145
Protocol Number:  20170199
Date:  09 March 2019
Page 9 of 19
CONFIDENTIAL 
Change from Study Day 1  
The arithmetic difference between a post Study Day 1 value and Study Day 1 value for a
given time point: 
Change from Study Day 1 = (post Study Day value – Study Day 1 value) 
Percent Change from Study Day 1 
100 x [(post Study Day value – Study Day 1 value) / Study Day 1 value] 
Change from Baseline 
The arithmetic difference between a post-baseline value and baseline for a given time 
point: Change from baseline = (Post-baseline value – Baseline value) 
Percent Change from Baseline 
100 x [(Post-baseline value – Baseline value) / Baseline value] 
Baseline CHD Risk Factors 2 or more (yes/no) 
A subject will be categorized as having 2 or more CHD Risk Factors (Y/N) from the list of 
the modified NCEP ATP III risk factors: current cigarette smoking, hypertension, type II 
diabetes mellitus and family history of premature CHD as recoded in the eCRF form, and 
low HDL-C defined as baseline HDL-C < 40 mg/dL in men and < 50 mg/dL in women.
5.3
Other Related Definitions
Analytical Study Week Assignments 
Analytical windows will be used to assign parameters to study weeks. The algorithm is 
provided in Appendix A.  . 
Investigational Product (IP)
IP is Repatha 420 mg QM SC. 
IP Exposure Period in Months 
IP Exposure Period = [min (Last IP Dose Date + 28 days, EOS Date) – First IP Dose 
Date + 1] / 365.25 * 12 
Treatment Emergent Adverse Events 
Events are categorized as Adverse Events (AEs) starting on or after first dose of 
investigational product as determined by the flag indicating if the value of the Events 
eCRF question “Did event start before first dose of investigational product?” is No or 


Product:  AMG 145
Protocol Number:  20170199
Date:  09 March 2019
Page 10 of 19
CONFIDENTIAL 
missing and up to including 30 days after the end of investigational product or the End of 
Study date, whichever is earlier. 
Treatment Emergent Disease-Related Events 
Treatment emergent disease-related events are events categorized as Disease-related 
Events (DREs) starting on or after first dose of investigational product as determined by 
the flag indicating if the value of the Events eCRF question “Did event start before first 
dose of investigational product?” is No or missing and up to including 30 days after the 
end of investigational product or the End of Study date, whichever is earlier.
Reflexive Approach for LDL-C and VLDL-C
For all analyses related to LDL-C and VLDL-C, unless specified otherwise, a reflexive 
approach will be used. When calculated LDL-C is less than 40 mg/dL or triglycerides 
are > 400 mg/dL, the ultracentrifugation LDL-C and VLDL-C value from the same blood 
sample will be used instead of calculated LDL-C and VLDL-C, if available.
6.
Analysis Sets
6.1
Full Analysis Set
The full analysis set includes all enrolled subjects who have received at least 1 dose of 
Repatha. Unless specified otherwise, the FAS will be the default analysis set in this 
study.
6.1.1
Primary Analysis Set
The primary analysis set is the full analysis set (FAS).
6.2
Safety Analysis Set
The safety analysis set is the full analysis set (FAS).
6.3
Per Protocol Set(s)
Not applicable.
6.4
Health-related Quality-of-Life or Health Economics Analyses Set(s)
Not applicable.
6.5
Pharmacokinetic/Pharmacodynamic Analyses Set(s)
Not applicable.
6.6
Interim Analyses Set(s)
There is no planned interim analysis for this study.


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6.7
Study-specific Analysis Sets
Not applicable.
7.
Planned Analyses
7.1
Interim Analysis and Early Stopping Guidelines
There is no planned interim analysis for this study.
7.2
Primary Analysis
Not applicable.
7.3
Final Analysis
The final analysis will be performed at the end of the study (defined as when the last 
subject enrolled has completed the safety follow-up/EOS visit).
8.
Data Screening and Acceptance
8.1
General Principles
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses.
8.2
Data Handling and Electronic Transfer of Data
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses.  This study will use the RAVE
database.
All data collected in the eCRF will be extracted from RAVE. Protocol deviations will be
transferred from eClinical. Details on data transfer will be provided in the Data Transfer 
Plan.
8.3
Handling of Missing and Incomplete Data
8.3.1
Patterns of Missing Data
Subjects may be missing specific data points for various reasons. In general, data may 
be missing due to a subject’s early withdrawal from study, a missed visit, or 
non-evaluability of a data point or an endpoint at a particular point in time. In the Data 
Issue Identification and Resolution (DIIR) processes, queries will be made to the sites to 
distinguish true missing values from other unknown values (eg, due to measurement or 
sample processing error).
All attempts will be made to capture missing or partial data for this trial prior to the 
database lock. 
There will be no imputation for missing data.


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8.3.2
Handling of Incomplete Dates
Adverse event and concomitant medications with completely or partially missing dates 
will be queried. After the query is resolved, if the date is still incomplete with year only or 
year and month only, the start date will be imputed as described in Table below: 
Table 8-1.  Imputation Rules for Incomplete Dates
Missing
Imputation
Exception
Start date (AE and 
concomitant 
medication)
Day
1
Default to Study 
Day 1 if an event 
starts the same year 
and month as Study 
Day 1
Day/Month
1-Jan
Default to Study 
Day 1 if an event 
started the same year 
as Study Day 1
8.4
Detection of Bias
Major protocol deviations likely to impact the analysis and interpretation of the endpoints 
have the potential to bias the results of the study. Important protocol deviations likely to 
impact the analysis and interpretation of the efficacy endpoints will be tabulated in the 
Clinical Study Report (CSR).
Because of its prospective, observational nature, this study is more greatly affected by
bias than interventional clinical trials. Missing or incomplete data is a potential risk for 
bias. Before the study begins, initiation visits will be carried out to complete site trainings
for the protocol and other study specific procedures. The investigator will be given clear 
guidelines for CRF completion for this study to ensure that he/she makes every effort to 
collect complete data. In the Data Issue Identification and Resolution (DIIR) process, 
queries will be made to the sites minimize the missing data as described in
Section 8.3.1.
8.5
Outliers
Various methods, including univariate summaries, histograms, scatterplots, box plots, 
and line graphs, may be used to identify outliers in key safety and efficacy variables. 
Extreme data points will be identified during the blinded review of the data prior to 
database lock. Such data points will be reviewed with clinical data management to 
ensure accuracy. The primary analyses will include outliers in the data. Sensitivity
analyses may be undertaken if extreme outliers for a variable are observed.


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8.6
Distributional Characteristics
Statistical analyses in this study are descriptive in nature. There are no distributional 
requirements for the planned analyses.
8.7
Validation of Statistical Analyses
Programs will be developed and maintained and output will be verified in accordance 
with current risk-based quality control procedures.  
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.  
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later.
9.
Statistical Methods of Analysis
9.1
General Considerations
Statistical analyses in this study will be descriptive in nature. No statistical inference is 
planned. There will be no imputation for missing data.
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.
Final analyses will be based on data collected from this study. The final analysis will be 
conducted when all subjects have either completed all the scheduled study visits or have 
early terminated from the study. At that time, the database will be cleaned, processed 
and locked. All endpoints will be analyzed based on this snapshot.
9.2
Subject Accountability
The number of subjects screened, enrolled, receiving IP, and completing the study will 
be summarized from all enrolled subjects. Study discontinuation and IP discontinuation 
will be tabulated separately by reasons for discontinuation from all enrolled subjects. 
The number of subjects included in and excluded from the full analysis set will be 
summarized.
9.3
Important Protocol Deviations
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 


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prior to database lock.  These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the course of the study.  Eligibility deviations are defined 
in the protocol.
9.4
Demographic and Baseline Characteristics
Baseline demographics, weight, cardiovascular medical history, laboratory parameters, 
vital signs and concomitant medication will be summarized for all enrolled subjects.
9.5
Efficacy Analyses
The percent change from baseline to week 12 for LDL-C, ApoB and Lp(a) will be 
summarized. In addition, descriptive statistics of actual values and change from baseline
will be provided.
9.5.1
Analyses of Primary Efficacy Endpoint(s)
Not applicable.
9.5.2
Analyses of Secondary Efficacy Endpoint(s)
Descriptive statistics will be summarized for each secondary endpoint.
9.5.3
Analyses of Exploratory Efficacy Endpoint(s)
Not applicable.
9.6
Safety Analyses
9.6.1
Analyses of Primary Safety Endpoint(s)
Subject incidence of treatment-emergent adverse events will be summarized. 
9.6.2
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version [21.0] or later will be 
used to code all events categorized as adverse events and disease-related events to a 
system organ class and a preferred term.
The subject incidence of adverse events will be summarized for all treatment-emergent 
adverse events, serious adverse events, adverse events leading to withdrawal of 
investigational product, fatal adverse events and adverse events of interest.  
Subject incidence of all treatment-emergent adverse events, serious adverse events, 
adverse events leading to withdrawal of investigational product, and fatal adverse events 
will be tabulated by system organ class and preferred term in alphabetical order.  
Subject incidence of events of interest (standardized MedDRA queries and/or Amgen 
customized queries) will also be summarized according to their categories and preferred 
term. Current event of interest to be analyzed is hypersensitivity for this study.


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Summaries of treatment-emergent and serious adverse events will be tabulated by 
system organ class and preferred term.
Subject incidence of disease-related events will be summarized for all 
treatment-emergent disease-related events and fatal disease-related events.
9.6.3
Laboratory Test Results
Descriptive statistics will be provided for actual values and changes from baseline in 
selected laboratory parameters at protocol-specified scheduled visits provided in the 
protocol Table 2-1. Laboratory analytes are provided in the protocol Table 12-1.
9.6.4
Vital Signs
Systolic and diastolic blood pressure and heart rate will be summarized using descriptive 
statistics at each scheduled visit. Summaries will also include the change from baseline 
at each scheduled visit.
9.6.5
Physical Measurements
Weight (in kilograms) will be summarized as baseline characteristics. Descriptive
statistics will be provided.
9.6.6
Electrocardiogram
Not applicable.
9.6.7
Antibody Formation
Not applicable.
9.6.8
Exposure to Investigational Product
Descriptive statistics will be produced to describe the patient-month exposure to 
investigational product and patient-month duration of study participation. 
9.6.9
Exposure to Non-investigational Product
Not applicable.
9.6.10
Exposure to Other Protocol-required Therapy
Not applicable.
9.6.11
Exposure to Concomitant Medication
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in protocol Section 7.1.7. The number and proportion of subjects receiving 
concomitant therapies will be summarized by preferred term as coded by the World 
Health Organization Drug (WHO DRUG) dictionary.


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9.7
Other Analyses
Not applicable.
9.7.1
Analyses of Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Endpoints
Not applicable.
9.7.2
Analyses of Clinical Outcome Assessments
Not applicable.
9.7.3
Analyses of Health Economic Endpoints
Not applicable.
9.7.4
Analyses of Biomarker Endpoints
Not applicable.
10.
Changes From Protocol-specified Analyses
There are no changes to the protocol-specified analyses.
11.
Literature Citations / References
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, 
and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third 
Report of the National Cholesterol Education Program (NCEP) Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult 
Treatment Panel III) final report. Circulation. 2002;106:3143-3421.
12.
Prioritization of Analyses
Not applicable.
13.
Data Not Covered by This Plan
Currently there are no pre-planned analyses for the biochemical cardiovascular 
biomarker objective.


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14.
Appendices


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Appendix A.  Analytical Study Week Assignments
Selected endpoints will be summarized by scheduled study visits in descriptive analyses. 
Since the actual visits may not exactly coincide with their scheduled visit day, the actual 
visit day is mapped to the study visit generally by non-overlapping consecutive intervals 
covering the entire time continuum, with scheduled visit time being the center of each 
interval. The mapping intervals for all distinct schedules are summarized in the following 
table. 
Scheduled Visit 
Week
Target Study 
Day
Vital Signs 
(BP, HR)
Physical
Examinations
Fasting lipids, 
ApoA1, ApoB
Lp(a)
Week 1 (Day1)
1
< =1
< =1
< =1
< =1
Week 8
57
(1,70]
N/A
(1,70]
(1,70]
Week 12
85
> 70
> 1
> 70
> 70
Handling multiple records assigned to an analytical study week: 
If there is more than one record in a study week interval, the analytical record for that 
specific study week will be defined as the record closest to the scheduled study day of 
that specific study week (7×study week). If two records are equidistant from the 
scheduled day, then the earlier record will be chosen. If there are multiple records on the 
same day, the last record will be used.


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Appendix B.  Common Terminology Criteria for Adverse Events
Refer to the NCI Common Terminology Criteria for AEs (CTCAE) Version 4.0, published: 
May 29, 2009 (v4.03: June 14, 2010) for AE and lab shift grading and information. The 
CTCAE is available at the following link: http://evs.nci.nih.gov/ftp1/CTCAE/About.html